US10385069B2 - Imidazo[2,1-B]thiazole and 5,6-dihydroimidazo[2,1-B]thiazole derivatives useful as S100-inhibitors - Google Patents

Imidazo[2,1-B]thiazole and 5,6-dihydroimidazo[2,1-B]thiazole derivatives useful as S100-inhibitors Download PDF

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US10385069B2
US10385069B2 US15/545,573 US201515545573A US10385069B2 US 10385069 B2 US10385069 B2 US 10385069B2 US 201515545573 A US201515545573 A US 201515545573A US 10385069 B2 US10385069 B2 US 10385069B2
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thia
diazatricyclo
dodeca
pentaene
carboxylic acid
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US20180282348A1 (en
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Ulf Wellmar
Stephen EAST
Marie BAINBRIDGE
Colin MACKINNON
James Carr
Jonathan HARGRAVE
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Active Biotech AB
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
    • C07D513/14—Ortho-condensed systems

Definitions

  • the present invention relates to imidazo[2,1-b]thiazole and 5,6-dihydroimidazo[2,1-b]thiazole derivatives, pharmaceutical compositions of these derivatives and their use as medicaments. More particularly the invention relates to imidazo[2,1-b]thiazole and 5,6-dihydroimidazo[2,1-b]thiazole derivatives for use in the treatment of cancer, autoimmune disorders, inflammatory disorders and neurodegenerative disorders.
  • S100A9 belongs to the S100-family of calcium-binding proteins and has been recognized as an attractive novel therapeutic target for the treatment of e.g. autoimmunity, inflammatory disease, neurodegenerative disease and cancer.
  • Other S100 proteins have distinct roles in many different biological processes and are connected to a number of diseases including cancer, cardiomyopathies, atherosclerosis, Alzheimer's disease and inflammatory diseases.
  • Twenty-one of the human genes, including S100A9, are located at chromosomal region 1q21, which is frequently altered in tumors (Marenholz et al., 2004). Interestingly, although the primary sequence diverges between family members, the 3D-structures of the different proteins are very similar.
  • S100A9 is often co-expressed with S100A8, another member of the S100 protein family, and they are highly expressed in myeloid cells, such as neutrophils and monocytes, but can also be induced in other cells or tissues (Srikrishna 2012). They form non-covalent homo- and heterocomplexes that can be specifically released in response to cellular activation (Foell et al., 2007, Ryckman et al., 2003). S100A9 can functionally be described as a damage-associated molecular pattern (DAMP) molecule which is released in tissues and induces signaling by interacting with receptors such as RAGE and TLR4 (Foell et al., 2007).
  • DAMP damage-associated molecular pattern
  • S100A9 also has intracellular roles in addition to its extracellular functions, e.g. by binding to the cytoskeleton and influencing cytoskeletal rearrangements and thereby cellular migration (Srikrishna 2012).
  • a pro-inflammatory role for S100A9 is supported by elevated S100A9 serum levels in inflammatory diseases and by high concentrations of S100A9 at local sites of inflammation, for example in the synovial fluid of rheumatoid arthritis patients (Foell et al., 2004) or osteoarthritis patients (van Lent 2012) where high levels correlate with joint destruction.
  • S100A9 in the coupling between the immune system and cancer is also supported by studies showing that S100A8 and S100A9 are highly expressed in and important for the function of myeloid-derived suppressor cells (MDSCs) (Cheng et al., 2008, Sinha et al., 2008, Wang et al., 2013), a mixture of immature myeloid cells that suppress T- and NK-cell activation and promote angiogenesis and tumor growth.
  • MDSCs myeloid-derived suppressor cells
  • S100A9 Although a number of possible biological functions of S100A9 have been proposed, the exact role of S100A9 in inflammation, in cancer and in other diseases is still unknown.
  • Members of the S100 protein family have been reported to interact with the pro-inflammatory molecule RAGE and studies showed that S100A9 is the strongest RAGE binder within the S100 family in the presence of physiological levels of Ca 2+ and Zn 2+ (Bjirk et al. 2009).
  • TLR4 toll-like receptor 4
  • the S100A9-TLR4 interaction appears to be strictly dependent on the presence of physiological levels of both Ca 2+ and Zn 2+ .
  • EMMPRIN Another receptor for S100A9 that may be important in cancer is EMMPRIN (CD 147), this protein is expressed on different cell types and the S100A9-EMMPRIN interaction has been shown to be involved in melanoma metastasis (Hibino et al., 2013).
  • S100A8 and S100A9 proteins have predominantly been described as cytoplasmic proteins that are secreted from myeloid cells upon activation. It is generally believed that the major biological functions relevant to inflammation require the release of the S100 proteins to the extracellular space. In this model, extracellular S100A9 would bind to e.g. the pro-inflammatory receptors RAGE and TLR4 and result in an inflammatory response. This is supported by studies showing that S100A9 induces TNF production in human monocytes via TLR4 (Riva et al. 2012, Cesaro et al. 2012). Also, S100A9 in complex with S100A8 has shown growth promoting activity directly on tumors cells via RAGE signaling (Ghavami et al., 2008). S100A9 also exists in a membrane-associated form on monocytes (Bhardwaj et al., 1992). Membrane associated S100A9 opens up for the possibility of cell-cell or cell-ECM signaling involving S100A9.
  • S100A9 has strong connections to neurodegenerative disease.
  • S100A9 is upregulated in the brain in Alzheimer's disease (AD) patients and in mouse disease models (Shepherd et al., 2006, Ha et al., 2010).
  • AD Alzheimer's disease
  • mouse disease models Shepherd et al., 2006, Ha et al., 2010.
  • knock-down or deletion of S100A9 in mice models of AD inhibits cognition decline and plaque burden in the brain (Ha et al., 2010, Chang et al., 2012).
  • a role for RAGE is also evident in AD where inhibition of RAGE reduces disease in a mouse AD model (Deane et al., 2013). Inhibition of S100A9 and its interactions represents a new promising approach for therapeutic intervention in AD and other neurodegenerative diseases.
  • WO 02/069965 discloses certain benzimidazole derivatives, as modulators of the interaction between RAGE and its ligands for the management, treatment, control, or as an adjunct treatment for diseases in humans caused by RAGE, e.g. acute and chronic inflammation, the development of diabetic late complications such as increased vascular permeability, nephropathy, atherosclerosis, and retinopathy, the development of Alzheimer's disease, erectile dysfunction, and tumor invasion and metastasis.
  • Antiallergic effect was reported by Ager 1988, anxiolytic effect by Clements-Jewery 1988 (inactive in flunitrazepam receptor binding) and SIRT1 activation by Vu et al 2009 (inactive).
  • blood sugar reducing effect was reported in U.S. Pat. No. 4,137,320 and activity against hepatitis C was reported in WO2006008556.
  • imidazo[2,1-b]thiazole derivatives are commercially available, or have been disclosed in the literature, but have not hitherto been disclosed for use in therapy.
  • a first aspect is a compound of formula (I)
  • b is an integer of from 0 to 4; ring A is a 5- to 7-membered, aromatic or non-aromatic carbocycle or heterocycle; Q is a direct bond, CH 2 , CH(OH) or NH; R 1 is R 4 C(O), cyano, or tetrazolyl; R 4 is H, R 5 O, or NHR 6 ; R 5 is H or C1-C6 alkyl; R 6 is H, cyano, C1-C6 alkyl, or R 7 S(O) 2 ; R 7 is C1-C6 alkyl, C3-C6 cycloalkyl, R 5 (CH 2 ) y , or 5- or 6-membered aryl or heteroaryl, said aryl or heteroaryl optionally being substituted by one or more moieties independently selected from C1-C6 alkyl, R 8 is R 9 O, R 10 R 11 N or R 12 OC(O); R 9 is H
  • R 13 is H, C1-C6 alkyl, R 20 C(O), R 21 S(O) 2 , R 22 O(CH 2 ) j , R 23 R 24 N(CH 2 ) k , or benzyl
  • R 14 is H or C1-C6 alkyl; or R 13 and R 14 , together with the nitrogen atom to which they are both attached, form a 4- to 6-membered ring, said ring optionally being substituted by one or more substituents independently selected fromoxo, halogen, C1-C6 alkyl, R 25 C(O), R 26 OC(O), and R 27 O(CH 2 ) m
  • R 15 is H, C1-C6 alkyl or R 28 C(O);
  • R 16 and R 17 are selected from H and C1-C6 alkyl;
  • R 18 is H, C1-C6 alkyl, R 29 OC(O)(CH
  • the compounds of formula (I) as defined herein above are useful as inhibitors of interactions between S100A9 and interaction partners such as RAGE, TLR4 and EMMPRIN.
  • a further aspect is a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein above for use as an inhibitor of interactions of S100A9 and its interaction partners and for use in the treatment of disorders associated with functions of S100A9, e.g. inflammatory diseases, neurodegenerative diseases, autoimmune diseases and cancer.
  • a further aspect is a compound of formula (I)
  • ring A, b, R 1 , R 2 , R′ 1 , R′ 2 , each R 3 , and Q are as defined herein above, for use in therapy, e.g. for the treatment of a disorder selected from inflammatory diseases, neurodegenerative diseases, autoimmune diseases and cancer, provided that the compound is not
  • composition comprising a compound of formula (I)
  • the pharmaceutical composition of the invention is useful for the treatment of diseases selected from inflammatory diseases, autoimmune diseases, neurodegenerative diseases and cancer.
  • a further aspect is a compound of formula (I)
  • ring A, b, R 1 , R 2 , R′ 1 , R′ 2 , each R 3 , and Q are as defined herein above, for use in the treatment of a disorder selected from inflammatory diseases, neurodegenerative diseases, autoimmune diseases and cancer, provided that the compound is not
  • a further aspect is a compound of formula (I)
  • ring A, b, R 1 , R 2 , R′ 1 , R′ 2 , each R 3 , and Q are as defined herein above, for use in the treatment of a disorder selected from inflammatory diseases, neurodegenerative diseases, and cancer, e.g. for the treatment of inflammatory diseases, provided that the compound is not
  • a further aspect is a compound of formula (I)
  • ring A, b, R 1 , R 2 , R′ 1 , R′ 2 , each R 3 , and Q are as defined herein above, for use in the treatment of a disorder selected from neurodegenerative diseases, autoimmune diseases and cancer, e.g. autoimmune diseases, provided that the compound is not
  • Still a further aspect is a compound of formula (I)
  • ring A, b, R 1 , R 2 , R′ 1 , R′ 2 , each R 3 , and Q are as defined herein above, for use in the treatment of a disorder selected from neurodegenerative diseases and cancer.
  • Still a further aspect is a compound of formula (I)
  • ring A, b, R 1 , R 2 , R′ 1 , R′ 2 , each R 3 , and Q are as defined herein above, for use in the treatment of a neurodegenerative disorder.
  • Still a further aspect is a compound of formula (I)
  • ring A, b, R 1 , R 2 , R′ 1 , R′ 2 , each R 3 , and Q are as defined herein above, for use in the treatment of cancer.
  • Another aspect is the use of a compound of formula (I) as defined hereinfor use in the treatment of a disorder selected from inflammatory diseases, neurodegenerative diseases, autoimmune diseases and cancer, or a pharmaceutically acceptable salt of such compound, in the manufacturing of a medicament for use in the treatment of any of said disorders, e.g. in the manufacturing of a medicament for use in the treatment of a disorder selected from neurodegenerative diseases, autoimmune diseases and cancer.
  • Still another aspect is a method of treatment of a disorder selected from inflammatory diseases, neurodegenerative diseases, autoimmune diseases and cancer, by administration of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, to a mammal in need of such treatment.
  • FIG. 1 is a schematic representation of an assay of the inhibition of the interaction between biotinylated human S100A9 and human RAGE-Fc using a small molecule S100A9 binder.
  • alkyl either alone or as part of a radical, includes straight or branched chain alkyl of the general formula C n H 2n+1 .
  • C1-C6 alkyl includes any alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • C1-C4 alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl.
  • C1-C3 alkyl includes methyl, ethyl, n-propyl and isopropyl.
  • cycloalkyl refers to a cyclic alkyl radical of the general formula C n H 2n ⁇ 1 .
  • C3-C6 cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • phenyl refers to a C 6 H 5 radical of the formula
  • benzyl refers to a radical of the formula
  • heterocyclic ring refers to a saturated or unsaturated and aromatic or non-aromatic cyclic moiety containing at least one heteroatom in the ring.
  • carbocycle refers to a saturated or unsaturated and aromatic or non-aromatic cyclic moiety having only carbon atoms in the ring.
  • a cycloalkyl is a saturated carbocycle
  • a cycloalkenyl is an unsaturated carbocycle
  • benzene is an aromatic carbocycle.
  • heteroaryl refers to a heterocyclyl that is aromatic.
  • halogen refers to F, Cl, Br and I, preferably F, Cl and Br.
  • hydroxy refers to a radical of the formula
  • alkoxy refers to a radical of the formula RO, wherein R is alkyl.
  • RO refers to a radical of formula
  • cyano refers to a radical of the formula
  • tetrazolyl refers to a radical of the formula
  • a term of the type RS refers to a radical of formula
  • a term of the type RS(O) 2 refers to a radical of formula
  • ROC(O) refers to a radical of formula
  • RR′N refers to a radical of formula
  • a is an integer of from i to ii, and when i is 0, the radical is
  • “Pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use.
  • pharmaceutically acceptable salt of a compound refers to a salt that is pharmaceutically acceptable, as defined herein, and that possesses the desired pharmacological activity of the parent compound.
  • Pharmaceutically acceptable salts include acid addition salts formed with inorganic acids, e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; or formed with organic acids, e.g.
  • a metal ion
  • Acceptable organic bases include e.g. diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, morpholine, and tromethamine.
  • Acceptable inorganic bases include e.g. ammonia, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.
  • any asymmetric carbon atom may be present in the (R)- or (S)-configuration, and the compound may be present as a mixture of its stereoisomers, e.g. a racemic mixture, or one stereoisomer only.
  • any hydrogen atom may be replaced by a deuterium ( 2 H), and any such deuterated compound of formula (I), comprising one or more deuteriums in place of the corresponding number of hydrogen atoms, is considered to be within the scope of the invention.
  • “Therapeutically effective amount” means an amount of a compound that, when administered to a subject for treating a disease state, is sufficient to effect such treatment for the disease state.
  • the “therapeutically effective amount” will vary depending on the compound, the disease state being treated, the severity of the disease treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending medical or veterinary practitioner, etc.
  • treatment is an approach for obtaining beneficial or desired results including clinical results.
  • beneficial or desired clinical results can include, but are not limited to, allevation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total) whether detectable or undetectable.
  • the term can also mean prolonging survival as compared to expected survival without the treatment.
  • mammal refers to a human or any mammalian animal, e.g. a primate, a farm animal, a pet animal, or a laboratory animal. Examples of such animals are monkeys, cows, sheep, horses, pigs, dogs, cats, rabbits, mice, rats etc. Preferably, the mammal is a human.
  • cancer refers to any malignant growth or tumor caused by abnormal and uncontrolled cell division; it may spread to other parts of the body through the lymphatic system or the blood stream and includes both solid tumors and blood-borne tumors.
  • Exemplary cancers include adrenocortical carcinoma, AIDS-related cancers, AIDS-related lymphoma, anal cancer, anorectal cancer, appendix cancer, childhood cerebellar astrocytoma, childhood cerebral astrocytoma, basal cell carcinoma, biliary cancer, extrahepatic bile duct cancer, intrahepatic bile duct cancer, urinary bladder cancer, bone and joint cancer, osteosarcoma and malignant fibrous histiocytoma, brain tumor, brain stem glioma, cerebellar astrocytoma, cerebral astrocytoma/malignant glioma, ependymoma, medulloblastoma, visual pathway and hypothalamic glioma, breast cancer, bronchi
  • autoimmune disorder refers to any disorder arising from an inappropriate immune response of the body against substances and tissues normally present in the body (autoimmunity). Such response may be restricted to certain organs or involve a particular tissue in different places.
  • exemplary autoimmune disorders are acute disseminated encephalomyelitis (ADEM), Addison's disease, agammaglobulinemia, alopecia areata, amyotrophic lateral sclerosis, ankylosing spondylitis, antiphospholipid syndrome, antisynthetase syndrome, atopic allergy, atopic dermatitis, autoimmune aplastic anemia, autoimmune cardiomyopathy, autoimmune enteropathy, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, autoimmune lymphoproliferative syndrome, autoimmune peripheral neuropathy, autoimmune pancreatitis, autoimmune polyendocrine syndrome, autoimmune progesterone dermatitis, autoimmune thrombocytopenic purpura,
  • ADAM acute dis
  • inflammatory disorder refers to a pathological state associated with inflammation, typically caused by leukocyte infiltration.
  • the inflammatory disorder may be acute or chronic.
  • exemplary inflammatory disorders include inflammatory skin diseases, including, without limitation, psoriasis and atopic dermatitis, systemic scleroderma and sclerosis, responses associated with inflammatory bowel disease (IBD) (such as Crohn's disease and ulcerative colitis), ischemic reperfusion disorders including surgical tissue reperfusion injury, myocardial ischemic conditions such as myocardial infarction, cardiac arrest, reperfusion after cardiac surgery and constriction after percutaneous transluminal coronary angioplasty, stroke, and abdominal aortic aneurysms, cerebral edema secondary to stroke, cranial trauma, hypovolemic shock, asphyxia, adult respiratory distress syndrome, acute-lung injury, Behcet's Disease, dermatomyositis; polymyositis; multiple sclerosis (MS); dermatitis
  • neurogenerative disorder refers to disorders associated with a progressive loss of structure or function of neurons affecting the structure or function of the brain, spinal cord or peripheral nervous system.
  • exemplary neurodegenerative disorders include mitochondrial encephalomyopathies and gut dysmotility syndromes, ataxia syndromes including Friedreich's ataxia and spinocerebellar ataxia (SCA), spinal cord injury, familial and sporadic amyotrophic lateral sclerosis (FALS and ALS, respectively), familial and sporadic Parkinson's disease, familial and sporadic Alzheimer's disease, Huntington's disease, olivopontocerebellar atrophy, multiple system atrophy, progressive supranuclear palsy, diffuse lewy body disease and synucleinopathies, Down Syndrome, corticodentatonigral degeneration, progressive familial myoclonic epilepsy, strionigral degeneration, torsion dystonia, familial tremor, Gilles de la Tourette syndrome, and Haller
  • excipient refers to pharmaceutically acceptable chemicals, such as known to those of ordinary skill in the art of pharmacy to aid the administration of the medicinal agent. It a compound that is useful in preparing a pharmaceutical composition, generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipients that are acceptable for veterinary use as well as human pharmaceutical use. Exemplary excipients include binders, surfactants, diluents, disintegrants, antiadherents, and lubricants.
  • ring A is a 5- to 7-membered, aromatic or non-aromatic carbocycle or heterocycle.
  • ring A is 5- or 6-membered. In some other embodiments, ring A is 6- or 7-membered. In some embodiments, ring A is 6-membered. In some other embodiments, ring A is 5-membered. In still other embodiments, ring A is 7-membered.
  • Ring A may be either aromatic or non-aromatic. In some embodiments, when ring A is aromatic, ring A is 6-membered. In some embodiments, when ring A is aromatic, said ring is benzene.
  • Ring A may be either carbocyclic or heterocyclic. In some embodiments, ring A is carbocyclic. In some other embodiments, ring A is heterocyclic.
  • ring A when ring A is non-aromatic, said ring is mono-unsaturated e.g. a ring of formula
  • ring A when ring A is non-aromatic, said ring is di-unsaturated.
  • ring A is a 5- to 7-membered, aromatic or non-aromatic carbocycle, or a 5- to 7-membered, non-aromatic heterocycle.
  • ring A is a 5- to 7-membered, aromatic or non-aromatic carbocycle, or a 6-membered, non-aromatic heterocycle, e.g. a 6-membered, non-aromatic heterocycle containing one heteroatom in the ring.
  • said heterocycle may contain one or more heteroatoms in the ring.
  • said heterocycle when ring A is a heterocycle, e.g. a 6-membered, non-aromatic heterocycle, said heterocycle contains an oxygen atom in the ring.
  • ring A when ring A is a 6-membered, non-aromatic heterocycle, ring A contains one heteroatom in the ring.
  • the heteroatom is oxygen.
  • ring A is selected from
  • R 3 and b are as defined herein.
  • the compound of formula (I) more particularly is as represented by formula (Ia)
  • R 1 , R 2 , R′ 1 , R′ 2 , each R 3 and Q are as defined herein.
  • the compound of formula (I) more particularly is as represented by formula (Ib)
  • w is an integer of from 1 to 3, e.g. an integer of from 1 to 2, in particular w is 2.
  • the moiety Q is a direct bond, CH 2 , CH(OH) or NH.
  • Q is CH 2 , NH or CHOH, e.g. Q is CH 2 or CHOH.
  • Q is a direct bond, CH 2 , or CH(OH).
  • Q is a direct bond or CH 2 , i.e. the compound may be represented by formula (Ic)
  • ring A, b, R 1 , R 2 , R′ 1 , R′ 2 , and each R 3 are as defined herein, and x is 0 or 1.
  • Q is a direct bond, i.e. x in formula (Ic) is 0. In some other embodiments, Q is CH 2 , i.e. x in formula (Ic) is 1.
  • R 1 is R 4 C(O), cyano, or tetrazolyl. In some embodiments, R 1 is R 4 C(O) or tetrazolyl. In some other embodiments, R 1 is R 4 C(O) or cyano. In some particular embodiments, R 1 is R 4 C(O), i.e. the compound may be represented by formula (Id)
  • R 4 is H, R 5 O, or NHR 6 . In some embodiments, R 4 is R 5 O or NHR 6 . In some particular embodiments, R 4 is R 5 O, i.e. the compound of formula (I) is as represented by formula (Ie)
  • R 5 is H or C1-C6 alkyl.
  • said alkyl more particularly may be selected from C1-C5 alkyl, or C1-C4 alkyl, or C1-C3 alkyl.
  • said alkyl more particularly is methyl, ethyl or tert-butyl, e.g. R 5 is selected from methyl and ethyl, or R 5 is ethyl.
  • R 5 is H or C1-C4 alkyl, e.g. H or C1-C3 alkyl, e.g. H, methyl or ethyl; or H or ethyl.
  • R 5 is C1-C6 alkyl. In some other embodiments, R 5 is H, i.e. the compound of formula (I) more particularly is as represented by formula (If)
  • R 4 is NHR 6 , i.e. the compound may be represented by formula (Ig)
  • R 6 is H, cyano, C1-C6 alkyl, or R 7 S(O) 2 .
  • R 6 is H, cyano, or R 7 S(O) 2 .
  • R 6 is cyano or R 7 S(O) 2 .
  • R 6 is H or R 7 S(O) 2 .
  • R 6 is R 7 S(O) 2 , i.e. the compound may be represented by formula (Ih)
  • R 7 is C1-C6 alkyl, C3-C6 cycloalkyl, R 8 (CH 2 ) y , or 5- or 6-membered aryl or heteroaryl, said aryl or heteroaryl optionally being substituted by one or more moieties independently selected from C1-C6 alkyl.
  • R 7 is C1-C6 alkyl or C3-C6 cycloalkyl, e.g. R 7 is C1-C6 alkyl.
  • R 7 is optionally substituted 5- or 6-membered aryl or heteroaryl.
  • R 7 is C1-C6 alkyl, C3-C6 cycloalkyl, or R 8 (CH 2 ) y , e.g. R 7 is R 8 (CH 2 ) y .
  • R 7 is C1-C6 alkyl, it more particularly may be selected from C1-C4 alkyl, or from C1-C3 alkyl, e.g. from methyl or ethyl.
  • R 7 is C3-C6 cycloalkyl, it more particularly may be selected from C3-C5 cycloalkyl, or C3-C4 cycloalkyl, e.g. cyclopropyl.
  • R 7 is optionally substituted 5- or 6-membered aryl or heteroaryl
  • said aryl or heteroaryl e.g. may be phenyl or 5- or 6-membered heteroaryl containing 1, 2, 3 or 4 heteroatoms in the ring, e.g. 1, 2 or 3 heteroatoms in the ring, and any substituent e.g. may be selected from C1-C4 alkyl, or from C1-C3 alkyl, e.g. any substituent is methyl.
  • R 7 may be optionally substituted phenyl or isoxazolyl, e.g.
  • R 7 is optionally substituted phenyl or isoxazol-4-yl.
  • R 7 is phenyl or 3,5-dimethyloxazol-4-yl, e.g. R 7 is phenyl.
  • R 8 (CH 2 ) y y is an integer of from 1 to 4.
  • y is an integer of from 1 to 3, e.g. y is 2 or 3.
  • y is an integer of from 2 to 4, e.g. y is 3.
  • R 8 is R 9 O, R 10 R 11 N or R 12 OC(O). In some embodiments, R 8 is R 9 O or R 10 R 11 N. In some particular embodiments, R 8 is R 9 O. In some other particular embodiments, R 8 is R 10 R 11 N.
  • R 7 is R 9 O(CH 2 ) y , wherein y is as defined herein above, e.g. y is 2 or 3. In some other embodiments, R 7 is R 10 R 11 N(CH 2 ) y , wherein y is as defined herein above, e.g. y is 2 or 3, in particular 3. In still other embodiments, R 7 is R 12 OC(O)(CH 2 ) y , wherein y is as defined herein above, e.g. y is 2 or 3, in particular 2.
  • R 9 is H or C1-C6 alkyl, e.g. H or C1-C4 alkyl, or H or C1-C3 alkyl, in particular H or methyl. In some embodiments, R 9 is H. In some other embodiments, R 9 is as defined herein above, but is not H.
  • R 10 and R 11 are independently selected from H and C1-C6 alkyl, or R 10 and R 11 , together with the nitrogen atom to which they are both attached, form a 4- to 6-membered ring.
  • R 10 and R 11 when R 10 and R 11 are selected from H or C1-C6 alkyl, they more particularly are selected from C1-C6 alkyl, e.g. from C1-C4 alkyl, or from C1-C3 alkyl, e.g. R 10 and R 11 may both be ethyl. In some embodiments, when R 10 and R 11 are selected from H or C1-C6 alkyl, they more particularly are selected from H and C1-C4 alkyl, or from H and C1-C3 alkyl.
  • R 8 is R 10 R 11 N
  • R 10 and R 11 together with the nitrogen atom to which they are both attached, form a 4- to 6-membered ring.
  • the ring when R 10 and R 11 , together with the nitrogen atom to which they are both attached, form a 4- to 6-membered ring, the ring more particularly is a 5- to 6-membered ring, or a 6-membered ring.
  • Said ring optionally contains one or more further heteroatoms, e.g. one or more further heteroatoms selected from N, O and S, or from N and O.
  • the ring may be saturated or unsaturated and heteroaromatic or non-aromatic.
  • the ring is non-aromatic, e.g. non-aromatic and saturated, e.g. the ring is morpholino.
  • R 12 is H or C1-C6 alkyl.
  • R 12 is H or C1-C4 alkyl, e.g. H or C1-C3 alkyl, in particular H or methyl.
  • R 12 is as defined herein above, but is not H.
  • R 8 is a moiety selected from hydroxy, methoxy, diethylamino, morpholino and methoxycarbonyl.
  • R 2 is H, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, halogen, cyano, R 13 R 14 N(CH 2 ) d , R 15 O(CH 2 ) e , R 16 S(CH 2 ) f , R 17 C(O)(CH 2 ) g ,
  • R 2 is C1-C6 alkyl
  • said alkyl e.g. may be selected from C1-C4 alkyl, or C1-C3 alkyl, e.g. methyl.
  • any alkyl group in a compound of formula (I) may be substituted by one or more F.
  • R 2 when R 2 is C1-C6 alkyl, R 2 more particularly is selected from methyl or trifluoromethyl.
  • R 2 is C2-C6 alkenyl
  • said alkenyl e.g. may be selected from C2-C4 alkenyl, or from C2-C3 alkenyl, e.g. R 2 may be prop-1-en-2-yl.
  • R 2 is C3-C6 cycloalkyl
  • said cycloalkyl e.g. may be C3-C5 cycloalkyl, or C3-C4 cycloalkyl, e.g. cyclopropyl.
  • R 2 is halogen
  • said halogen e.g. may be Cl, Br or I.
  • R 2 is H, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, or halogen, e.g. R 2 is H, C1-C6 alkyl, C2-C6 alkenyl, or C3-C6 cycloalkyl, or R 2 is H, C1-C6 alkyl, or C3-C6 cycloalkyl, or R 2 is H or C1-C6 alkyl.
  • R 2 is H, R 13 R 14 N(CH 2 ) d , or
  • R 2 is H or R 13 R 14 N(CH 2 ) d . In some other embodiments, R 2 is R 13 R 14 N(CH 2 ) d or
  • R 2 is H or
  • R 2 is H, i.e. the compound may be represented by formula (Ij)
  • R 2 is R 13 R 14 N(CH 2 ) d ; i.e. the compound may be represented by formula (Ik)
  • d is an integer of from 0 to 4, e.g. from 0 to 3, or from 0 to 2; e.g. d is 0 or 1. In some embodiments, d is 0. In some other embodiments, d is 1.
  • R 13 is H, C1-C6 alkyl, R 20 C(O), R 21 S(O) 2 , R 22 O(CH 2 ) j , R 23 R 24 N(CH 2 ) k , or benzyl, and R 14 is H or C1-C6 alkyl; or R 13 and R 14 , together with the nitrogen atom to which they are both attached, form a 4- to 6-membered ring, said ring optionally being substituted by one or more substituents independently selected fromoxo, halogen, C1-C6 alkyl, R 25 C(O), R 26 OC(O), and R 27 O(CH 2 ) m .
  • R 13 is H, C1-C6 alkyl, R 20 C(O), R 21 S(O) 2 , R 22 O(CH 2 ) j , R 23 R 24 N(CH 2 ) k , or benzyl, and R 14 is H or C1-C6 alkyl.
  • R 13 when R 13 is H, C1-C6 alkyl, R 20 C(O), R 21 S(O) 2 , R 22 O(CH 2 ) j , R 23 R 24 N(CH 2 ) k , or benzyl; R 13 more particularly is C1-C6 alkyl, R 20 C(O), R 21 S(O) 2 , R 22 O(CH 2 ) j , R 23 R 24 N(CH 2 ) k , or benzyl; e.g.
  • R 13 is C1-C6 alkyl, R 20 C(O), R 21 S(O) 2 , R 22 O(CH 2 ) j , or R 23 R 24 N(CH 2 ) k , or R 13 is C1-C6 alkyl.
  • R 13 is C1-C6 alkyl, it e.g. may be C1-C4 alkyl, or C1-C3 alkyl, e.g. methyl.
  • R 20 is H or C1-C6 alkyl, e.g. R 20 is H or C1-C4 alkyl, or H or C1-C3 alkyl, such as H or methyl.
  • R 20 is C1-C6 alkyl, e.g. C1-C4 alkyl, or C1-C3 alkyl, in particular methyl.
  • R 21 is H or C1-C6 alkyl, e.g. R 21 is H or C1-C4 alkyl, or H or C1-C3 alkyl, such as H or methyl. In some embodiments, R 21 is C1-C6 alkyl, e.g. C1-C4 alkyl, or C1-C3 alkyl, in particular methyl.
  • R 13 is R 22 O(CH 2 ) j
  • j is an integer of from 0 to 4, e.g. from 0 to 3, or from 0 to 2; and R 22 is H or C1-C6 alkyl, e.g. R 22 is H or C1-C4 alkyl, or H or C1-C3 alkyl, such as H or methyl.
  • R 22 is C1-C6 alkyl, e.g. C1-C4 alkyl, or C1-C3 alkyl, in particular methyl.
  • R 13 is R 23 R 24 N(CH 2 ) k , k is an integer of from 0 to 4, e.g. from 1 to 4, or from 1 to 3, e.g. k is 2; and R 23 and R 24 are independently selected from H and C1-C6 alkyl; or R 23 and R 24 , together with the nitrogen atom to which they are both attached, form a 4- to 6-membered ring.
  • R 23 and R 24 are independently selected from C1-C6 alkyl; or R 23 and R 24 , together with the nitrogen atom to which they are both attached, form a 4- to 6-membered ring.
  • R 23 and R 24 together with the nitrogen atom to which they are both attached, form a 4- to 6-membered ring.
  • R 23 and R 24 are C1-C6 alkyl
  • said alkyl more e.g. may be selected from C1-C4 alkyl, or from C1-C3 alkyl.
  • R 23 and R 24 together with the nitrogen atom to which they are both attached, form a 4- to 6-membered ring, said ring e.g. may be 5- to 6-membered, or 5-membered. Any such ring in particular may be non-aromatic and saturated, and optionally contain one or more further heteroatoms. In some embodiments, the ring contains no further heteroatoms, e.g. the ring is a 4- to 6-membered saturated ring containing no further heteroatoms, such as a pyrrolidinyl.
  • R 14 when R 14 is H or C1-C6 alkyl, R 14 more particularly is H or C1-C4 alkyl, or H or C1-C3 alkyl, such as H or methyl. In some embodiments, R 14 is H. In some embodiments, R 14 is as defined herein above, but is different from H, e.g. R 14 is methyl.
  • R 13 and R 14 together with the nitrogen atom to which they are both attached, form a 4- to 6-membered ring, e.g. a 5- or 6-membered ring, said ring optionally being substituted by one or more substituents independently selected fromoxo, halogen, C1-C6 alkyl, R 25 C(O), R 26 OC(O), and R 27 O(CH 2 ) m .
  • R 25 is H or C1-C6 alkyl, e.g. H or C1-C4 alkyl, or H or C1-C3 alkyl, such as H or methyl.
  • R 25 is C1-C6 alkyl, e.g. C1-C4 alkyl, or C1-C3 alkyl, in particular methyl.
  • R 26 is H or C1-C6 alkyl, e.g. H or C1-C4 alkyl, or H or C1-C3 alkyl, such as H or methyl.
  • R 26 is C1-C6 alkyl, e.g. C1-C5 alkyl, or C1-C4 alkyl, such as tert-butyl.
  • R 27 O(CH 2 ) m
  • m is an integer of from 0 to 4, e.g. from 1 to 4, or from 1 to 3, e.g. m is 2; and R 27 is H or C1-C6 alkyl, e.g. H or C1-C4 alkyl, or H or C1-C3 alkyl, such as H or methyl, e.g. H.
  • R 27 is C1-C6 alkyl, e.g. C1-C4 alkyl, or C1-C3 alkyl, in particular methyl.
  • R 13 and R 14 together with the nitrogen atom to which they are both attached, form a 4- to 6-membered ring, said ring e.g. may be non-aromatic, e.g. the ring may be a saturated ring.
  • the ring optionally may contain one or more further heteroatoms, e.g. one or more further heteroatoms selected from N and O.
  • said ring optionally contains no or at most one further heteroatom, said heteroatom being selected from N and O.
  • R 13 and R 14 together with the nitrogen atom to which they are both attached, form an optionally substituted 4- to 6-membered ring, said ring is selected from azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl and piperazin-1-yl.
  • R 13 and R 14 together with the nitrogen atom to which they are both attached, form a 4- to 6-membered ring containing a further nitrogen in the ring, this further nitrogen may be substituted by C1-C6 alkyl, R 25 C(O), R 26 OC(O), and R 27 O(CH 2 ) m .
  • the ring is piperazinyl, optionally substituted in 4-position (i.e. at the further ring nitrogen) with a substituent selected from C1-C6 alkyl, R 25 C(O), R 26 OC(O), and R 27 O(CH 2 ) m as defined herein above.
  • R 2 is
  • h is an integer of from 0 to 4, e.g. from 0 to 3, or from 0 to 2, e.g. h is 0 or 1.
  • ring B is 4- to 6-membered, and saturated or unsaturated, e.g. saturated or mono-unsaturated.
  • ring B is selected from azetidinyl, pyrrolidinyl, piperidinyl, and tetrahydropyridinyl, e.g. from azetidinyl, piperidinyl, and tetrahydropyridinyl.
  • ring B is 4-membered, e.g. ring B is azetidinyl.
  • ring B is 6-membered, e.g. ring B is piperidinyl or tetrahydropyridinyl.
  • R 18 is H, C1-C6 alkyl, R 29 OC(O)(CH 2 ) n , or R 30 S(O) 2 (CH 2 ) p .
  • R 18 is H or C1-C6 alkyl, e.g. H or C1-C4 alkyl, or H or C1-C3 alkyl, such as H or methyl, e.g. H.
  • R 18 is C1-C6 alkyl, R 29 OC(O)(CH 2 ) n , or R 30 S(O) 2 (CH 2 ) p , e.g. R 18 is R 29 OC(O)(CH 2 ) n , or R 30 S(O) 2 (CH 2 ) p , or R 18 is R 29 OC(O)(CH 2 ) n .
  • n is an integer of from 0 to 4, e.g. from 0 to 3, or from 0 to 2; e.g. n is 0 or 1, in particular n is 0; and R 29 is H or C1-C6 alkyl, e.g. H or C1-C5 alkyl, or H or C1-C4 alkyl.
  • R 29 is C1-C6 alkyl, e.g. C1-C5 alkyl, or C1-C4 alkyl; e.g. R 29 is tert-butyl.
  • R 30 S(O) 2 (CH 2 ) p p is an integer of from 0 to 4, e.g. from 0 to 3, or from 0 to 2; e.g. p is 0 or 1, in particular p is 0; and R 99 is H or C1-C6 alkyl, e.g. R 30 is H or C1-C4 alkyl, or H or C1-C3 alkyl, such as H or methyl. In some embodiments, R 30 is C1-C6 alkyl, e.g. C1-C4 alkyl, or C1-C3 alkyl, such as methyl.
  • R 2 is R 15 O(CH 2 ) e .
  • e is an integer of from 0 to 4, e.g. from 0 to 3, or from 1 to 3, e.g. e is 1 or 2; or e is 1; and R 15 is H, C1-C6 alkyl or R 28 C(O).
  • R 15 is H or C1-C6 alkyl, e.g. H or C1-C4 alkyl, or H or C1-C3 alkyl, such as H or methyl, in particular H.
  • R 15 is H or R 28 C(O).
  • R 15 is R 28 C(O).
  • R 28 is H or C1-C6 alkyl, e.g. R 28 is H or C1-C4 alkyl, or H or C1-C3 alkyl, such as H or methyl. In some embodiments, R 28 is C1-C6 alkyl, e.g. C1-C4 alkyl, or C1-C3 alkyl, such as methyl.
  • R 2 is R 16 S(CH 2 ) f .
  • f is an integer of from 0 to 4, e.g. from 0 to 3, or from 0 to 2; e.g. f is 0 or 1, in particular f is 0; and R 16 is H or C1-C6 alkyl.
  • R 16 is H or C1-C6 alkyl, e.g. H or C1-C4 alkyl, or H or C1-C3 alkyl, such as H or methyl.
  • R 16 is C1-C6 alkyl, e.g. C1-C4 alkyl, or C1-C3 alkyl, such as methyl.
  • R 2 is R 17 C(O)(CH 2 ) g .
  • g is an integer of from 0 to 4, e.g. from 0 to 3, or from 0 to 2; e.g. g is 0 or 1, in particular g is 0; and R 17 is H or C1-C6 alkyl.
  • R 17 is H or C1-C4 alkyl, or H or C1-C3 alkyl, such as H or methyl.
  • R 17 is C1-C6 alkyl, e.g. C1-C4 alkyl, or C1-C3 alkyl, such as methyl.
  • R 2 is phenyl, optionally substituted by R 19 O(CH 2 ) i , e.g. phenyl substituted by one moiety R 19 O(CH 2 ) i , which moiety is attached in either ortho, meta or para position, e.g. in ortho or para position, in particular in para position on the phenyl ring.
  • R 19 O(CH 2 ) i i is an integer of from 0 to 4, e.g. from 0 to 3, or from 0 to 2; e.g. i is 0 or 1, in particular i is 0; and R 19 is H or C1-C6 alkyl.
  • R 19 is H or C1-C4 alkyl, or H or C1-C3 alkyl, such as H or methyl.
  • R 16 is C1-C6 alkyl, e.g. C1-C4 alkyl, or C1-C3 alkyl, such as methyl.
  • R 2 when R 2 is phenyl, optionally substituted by R 19 O(CH 2 ), R 2 is 2-methoxyphenyl or 4-methoxyphenyl.
  • R′ 1 and R′ 2 together form a bond; or R′ 1 is H, C1-C6 alkyl, C3-C6 carbocyclyl-(CH 2 ) q , or R 31 O(CH 2 ) r ; and R′ 2 is H.
  • R′ 1 and R′ 2 together form a bond, i.e. the compound of formula (I) may be represented by formula (In)
  • Q is a direct bond
  • R 1 is R 4 CO
  • R 4 is R 5 O or R 6 NH.
  • Q is a direct bond
  • R 1 is R 4 CO
  • R 4 is R 5 O or R 6 NH
  • R 2 is H or R 13 R 14 N(CH 2 ) d .
  • b is an integer of from 1 to 4,
  • ring A is a 5- or 6-membered carbocycle
  • Q is a direct bond
  • R 1 is R 4 CO
  • R 4 is R 5 O or R 6 NH.
  • b is an integer of from 1 to 4
  • ring A is a 6-membered carbocycle
  • Q is a direct bond
  • R 1 is R 4 CO
  • R 4 is R 5 O or R 6 NH
  • R 2 is H or R 13 R 14 N(CH 2 ) d .
  • b is an integer of from 1 to 4
  • ring A is a 6-membered carbocycle
  • Q is a direct bond
  • R 1 is R 4 CO
  • R 4 is R 5 O
  • R 2 is H or R 13 R 14 N(CH 2 ) d .
  • b is an integer of from 1 to 4
  • ring A is a 6-membered carbocycle
  • Q is a direct bond
  • R 1 is R 4 CO
  • R 4 is R 5 O
  • R 2 is H.
  • b is an integer of from 1 to 4
  • ring A is a 6-membered carbocycle
  • Q is a direct bond
  • R 1 is R 4 CO
  • R 4 is R 6 NH
  • R 2 is H.
  • R′ 1 is H, C1-C6 alkyl, C3-C6 carbocyclyl-(CH 2 ) q , or R 31 O(CH 2 ) r ; and R′ 2 is H, i.e. the compound of formula (I) may be represented by formula (Io)
  • ring A is benzene
  • R 2 is H
  • R′ 1 is H, C1-C6 alkyl, or C3-C6 carbocyclyl-(CH 2 ) q ; e.g. R′ 1 is H, C1-C6 alkyl, non-aromatic C3-C6 carbocyclyl-(CH 2 ) q or phenyl-(CH 2 ) q .
  • R′ 1 is H, C1-C6 alkyl, or C3-C6 cycloalkyl-(CH 2 ) q , e.g. R′ 1 is H or C1-C6 alkyl.
  • R′ 1 is H.
  • R′ 1 is C1-C6 alkyl
  • said alkyl more particularly may be C1-C5 alkyl, or C1-C4 alkyl, e.g. methyl or isobutyl.
  • said alkyl is methyl.
  • R′ is selected from H, methyl and isobutyl, in particular from H and methyl.
  • q is an integer of from 0 to 4, e.g. q is an integer of from 1 to 4, or from 1 to 3, e.g. q is 1 or 2, e.g. q is 1; and the carbocyclyl e.g. is C3-C6 cycloalkyl or phenyl, e.g. C3-C5 cycloalkyl or phenyl, or C3-C4 cycloalkyl or phenyl, such as cyclopropyl or phenyl.
  • q is an integer of from 1 to 3 and the carbocyclyl is C3-C6 cycloalkyl or phenyl, e.g. C3-C5 cycloalkyl or phenyl, or C3-C4 cycloalkyl or phenyl. In some embodiments, q is 1, and the carbocyclyl is C3-C6 cycloalkyl or phenyl, e.g. C3-C5 cycloalkyl or phenyl, or C3-C4 cycloalkyl or phenyl, e.g. cyclopropyl or phenyl.
  • R′ 1 is R 31 O(CH 2 ) r .
  • r is an integer of from 0 to 4, e.g. r is an integer of from 1 to 4, or r is an integer of from 1 to 3, e.g. r is 1 or 2, e.g. r is 1; and R 31 is H or C1-C6 alkyl, e.g. R 31 is H or C1-C4 alkyl, or H or C1-C3 alkyl, such as H or methyl.
  • R 31 is H.
  • the moiety R 31 O(CH 2 ) r is a moiety of formula HO(CH 2 ) r , wherein r is as defined herein.
  • R′ 1 is selected from H, methyl, isobutyl, cyclopropylmethyl, benzyl and hydroxymethyl.
  • b indicating the number of moieties R 3 attached to ring A, is an integer of from 0 to 4. In some embodiments b is 0, 1, 2 or 3. In some other embodiments, b is 0, 1 or 2. In some other embodiments, b is 0 or 1. In some embodiments, b is 0. In some embodiments, b is 1. In some embodiments, b is 2. In some other embodiments, b is an integer of from 1 to 4. In some embodiments, b is 1, 2 or 3. In some embodiments, b is 1 or 2. In some other embodiments, b is an integer of from 2 to 4, e.g. b is 2, or b is 4. In some embodiments, when ring A is benzene, b is not 0.
  • b is an integer of from 1 to 4, and one R 3 is in meta position (position 10 on the benzene ring, i.e. ring A), i.e. the compound is as represented by formula (Ip)
  • R 1 , R 2 , R′ 1 , R′ 2 , each R 3 , and Q are as defined herein and b is an integer of from 1 to 4, e.g. b is 1, 2 or 3, in particular b is 1 or 2, e.g. b is 2.
  • b is an integer of from 1 to 4, and one R 3 is in ortho position (position 9 on the benzene ring, i.e. ring A), i.e. the compound is as represented by formula (Iq)
  • R 1 , R 2 , R′ 1 , R′ 2 , each R 3 , and Q are as defined herein and b is an integer of from 1 to 4, e.g. b is 1, 2 or 3, in particular b is 1 or 2.
  • R 1 , R 2 , R′ 1 , R′ 2 , each R 3 , and Q are as defined herein and b is an integer of from 2 to 4, e.g. b is 2 or 3, in particular b is 2.
  • R 1 , R 2 , R′ 1 , R′ 2 , each R 3 , and Q are as defined herein, Z is a direct bond, CH 2 or a heteroatom, such as 0; and u is an integer of from 0 to 2, e.g. u is 1.
  • u when Z is a direct bond, u is 1 or 2, e.g. u is 1; and when Z is CH 2 or O, u is 0, 1 or 2.
  • u is 1.
  • u is 1 and Z is CH 2 or a direct bond; in particular u is 1 and Z is CH 2 .
  • R 1 , R 2 , R′ 1 , R′ 2 , each R 3 , and Q are as defined herein, u is an integer of from 0 to 2, e.g. u is 0 or 1, or u is 1, and b is an integer of from 1 to 4, e.g. b is 1, 2 or 3, or b is 1 or 2, e.g. b is 1.
  • each moiety R 3 is independently selected from C1-C6 alkyl, C3-C6 carbocyclyl, halogen, oxo, R 32 O, R 33 S, and R 34 R 35 N and, when b is 2, 3 or 4, two R 3 attached to adjacent atoms of ring A, together with the atoms to which they are attached, may form a 3- to 6 membered ring, said ring being optionally substituted by one or more C1-C6 alkyl.
  • each moiety R 3 is independently selected from C1-C6 alkyl, C3-C6 carbocyclyl, halogen, oxo, R 32 O, R 33 S, and R 34 R 35 N.
  • each moiety R 3 is independently selected from C1-C6 alkyl, C3-C6 carbocyclyl, halogen, R 32 O, R 33 S, and R 34 R 35 N.
  • each R 3 is independently selected from C1-C6 alkyl, halogen, R 32 O, R 33 S, and R 34 R 35 N; or from C1-C6 alkyl, C3-C6 carbocyclyl, halogen, R 32 O, and R 34 R 35 N; e.g. from C1-C6 alkyl, halogen, R 32 O, and R 34 R 35 N; or from C1-C6 alkyl, halogen, and R 32 O, in particular from halogen.
  • at least one R 3 is halogen.
  • each moiety R 3 is independently selected from C1-C6 alkyl, C3-C6 carbocyclyl, halogen and R 32 O; e.g. from C1-C6 alkyl.
  • R 3 when a moiety R 3 is C1-C6 alkyl, said alkyl more particularly may be C1-C4 alkyl, or C1-C3 alkyl, in particular methyl. In some embodiments represented by formula (Is), each R 3 is methyl.
  • R 3 when a moiety R 3 is C3-C6 carbocyclyl, said carbocyclyl more particularly is C3-C6 cycloalkyl or phenyl, e.g. C3-C5 cycloalkyl or phenyl, or C3-C4 cycloalkyl or phenyl, such as cyclopropyl or phenyl.
  • the compound when any R 3 is a C3-C6 carbocyclyl, said carbocyclyl is non-aromatic, e.g. it is a cycloalkyl as mentioned herein above.
  • the compound is as represented by formula (Ib), in particular a compound as represented by formula (It), when R 3 is C3-C6 carbocyclyl, said carbocyclyl more particularly is phenyl.
  • any R 3 is halogen
  • said halogen more particularly may be selected from F, Cl, and Br, e.g. from F and Cl, in particular Cl.
  • R 32 is H, C1-C6 alkyl, C3-C6 carbocyclyl-(CH 2 ) s , or R 36 R 37 N(CH 2 ) t .
  • R 32 is H or C1-C6 alkyl, e.g. R 32 is C1-C6 alkyl.
  • R 32 is C1-C6 alkyl, C3-C6 carbocyclyl-(CH 2 ) s , or R 36 R 37 N(CH 2 ) t , e.g.
  • R 32 is C3-C6 carbocyclyl-(CH 2 ) s , or R 36 R 37 N(CH 2 ) t . In some embodiments, R 32 is R 36 R 37 N(CH 2 ) t ; in some other embodiments, R 32 is C1-C6 alkyl or C3-C6 carbocyclyl-(CH 2 ) s , e.g. R 32 is C3-C6 carbocyclyl-(CH 2 ) s . In still other embodiments, R 32 is H.
  • R 32 is C1-C6 alkyl
  • said alkyl e.g. may be selected from C1-C4 alkyl, or from C1-C3 alkyl, e.g. R 32 may be methyl.
  • R 32 is C1-C6 alkyl
  • said alkyl e.g. may be selected from C1-C4 alkyl, or from C1-C3 alkyl, e.g. R 32 may be methyl.
  • any alkyl may be substituted by one or more F. Therefore, in some embodiments, R 32 is methyl or trifluoromethyl.
  • R 32 is C3-C6 carbocyclyl-(CH 2 ) s
  • s is an integer of from 0 to 4, e.g. from 0 to 3, or from 0 to 2, e.g. s is 0 or 1; and the C3-C6 carbocyclyl e.g. is C4-C6 carbocyclyl, or C5-C6 carbocyclyl.
  • the carbocyclyl is C3-C6 cycloalkyl or phenyl, e.g. C4-C6 cycloalkyl or phenyl, such as cyclopentyl or phenyl.
  • any C3-C6 carbocyclyl-(CH 2 ) s is selected from, C3-C6 cycloalkyl and benzyl, e.g. from cyclopentyl and benzyl.
  • R 32 is R 36 R 37 N(CH 2 ) t , t is an integer of from 0 to 4, e.g. from 1 to 4, or from 2 to 4, e.g. t is 2 or 3, in particular 2; and R 36 and R 37 are independently selected from H and C1-C6 alkyl, e.g. from H and C1-C3 alkyl, or from C1-C3 alkyl; or R 36 and R 37 , together with the nitrogen atom to which they are both attached, form a 4- to 6-membered ring, or a 5- to 6-membered ring; optionally substituted by one or more halogen. In some embodiments, R 36 and R 37 , together with the nitrogen atom to which they are both attached, form a 4- to 6-membered ring, e.g. morpholino.
  • R 33 is H or C1-C6 alkyl; in particular C1-C6 alkyl.
  • said alkyl e.g. may be selected from C1-C4 alkyl, or from C1-C3 alkyl, e.g. R 33 may be methyl.
  • any alkyl may be substituted by one or more F. Therefore, in some embodiments, R 33 is methyl or trifluoromethyl.
  • R 34 and R 35 are independently selected from H and C1-C6 alkyl, e.g. from C1-C6 alkyl, or from C1-C3 alkyl; or R 34 and R 35 , together with the nitrogen atom to which they are both attached, form a 4- to 6-membered ring optionally substituted by one or more halogen.
  • R 34 and R 35 together with the nitrogen atom to which they are both attached, form a 4- to 6-membered ring optionally substituted by one or more halogen.
  • said ring is selected from azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl.
  • any halogen attached to the ring is F.
  • two R 3 attached to adjacent atoms of ring A, together with the atoms to which they are attached, may form a 3- to 6 membered ring, said ring being optionally substituted by one or more C1-C6 alkyl, e.g. one or more C1-C4 alkyl, or one or more C1-C3 alkyl, or one or more methyl.
  • Said 3- to 6 membered ring may be non-aromatic or aromatic, and heterocyclic or carbocyclic.
  • the ring formed by the two R 3 is a non-aromatic or aromatic, 3- to 6 membered carbocycle, e.g.
  • a non-aromatic 3- to 6 membered carbocycle e.g. a non-aromatic 3- to 5-membered carbocycle, or a non-aromatic 3- to 4-membered carbocycle, e.g. the ring is cyclopropane; or the ring is benzene.
  • said carbocycle is a cycloalkane.
  • the ring is a cycloalkane.
  • the compound of the invention is as represented by formula (Iu)
  • R 1 , R 2 , R′ 1 , R′ 2 , and Q are as defined herein, v is an integer of from 0 to 3, e.g. from 0 to 2, or from 0 to 1, e.g. v is 0; and w is an integer of from 1 to 3, e.g. w is 1 or 2, and in particular w is 1.
  • R 1 , R 2 , R′ 1 , R′ 2 , Q are as defined herein, and w is an integer of from 1 to 3, e.g. w is 1 or 2, and in particular w is 2.
  • a compound of formula (Ia) may also be a compound of formula (Ic), and may therefore herein be referred to as a compound of formula (Iac)
  • R 1 , R 2 , R′ 1 , R′ 2 , each R 3 and x are as defined herein.
  • a compound of formula (Iac) may also be a compound of formula (Id), i.e. represented by formula (Iacd)
  • a compound of formula (Iacd) may also be a compound of formula (In), i.e. represented by formula (Iacdn)
  • a compound of formula (Iacn) may also be a compound of formula (Ie), i.e. represented by formula (Iacen)
  • a compound of formula (Ib) also is a compound of formula (Ic), and may be represented by formula (Ibc)
  • a compound of formula (Ibc) also is a compound of formula (In), and may be represented by formula (Ibcn)
  • a compound of formula (Ibcn) also is a compound of formula (Id) and may be represented by formula (Ibcdn)
  • a compound of formula (Ic) also is a compound of formula (Id), and also is compound of formula (In), i.e. the compound is as represented by formula (Icdn)
  • a compound of formula (Ic) e.g. a compound of formula (Icd), or a compound of formula (Icdn)
  • ring A is a 5- to 7-membered, aromatic or non-aromatic carbocycle
  • R 2 is H, halogen or R 13 NH
  • R 13 is C1-C6 alkyl or benzyl
  • each R 3 is independently selected from C1-C6 alkyl, halogen, phenyl, and R 32 O,
  • each R 32 is independently selected from H and C1-C6 alkyl
  • R 4 is OH, NC—NH, or R 7 (S(O) 2 NH;
  • R 7 is C1-C6 alkyl, C3-C6 cycloalkyl, or R 8 (CH 2 ) y ;
  • R 8 is R 9 O, R 10 R 11 N, or R 12 OC(O);
  • R 9 is H or C1-C6 alkyl
  • R 10 is H or C1-C6 alkyl
  • R 11 is H or C1-C6 alkyl
  • R 10 and R 11 together with the nitrogen atom to which they are both attached, form a 5- or 6-membered heterocyclic ring;
  • R 12 is H or C1-C6 alkyl
  • y is an integer of from 1 to 4.
  • any alkyl or cycloalkyl is optionally substituted by one or more F.
  • R 4 is OH or R 7 S(O) 2 NH. In some embodiments, R 4 is OH.
  • R 4 is R 7 S(O) 2 NH the moiety R 7 S(O) 2 NH
  • R 7 is C3-C6 cycloalkyl, e.g. C3-C5 cyloalkyl, or C3-C4 cycloalkyl, such as cyclopropyl, or C1-C6 alkyl, e.g. C1-C4 alkyl, or C1-C3 alkyl, wherein any cycloalkyl or alkyl is optionally substituted by one or more F, or R 7 is R 8 (CH 2 ) y .
  • R 7 is C1-C6 alkyl, e.g. C1-C4 alkyl, or C1-C3 alkyl, wherein any alkyl optionally is substituted by one or more F, or R 7 is R 8 (CH 2 ) y .
  • R 7 is C3-C6 cycloalkyl, e.g. C3-C5 cyloalkyl, or C3-C4 cycloalkyl, such as cyclopropyl.
  • R 7 is alkyl, which alkyl is unsubstituted or substituted by one or more F. In some embodiments, when R 7 is alkyl, said alkyl is unsubstituted.
  • R 8 is R 9 O or R 10 R 11 N. In some embodiments, R 8 is R 9 O. In some other embodiments, R 8 is R 10 R 11 N.
  • R 8 is R 9 O and the moiety R 9 is H or C1-C3 alkyl, e.g. H or methyl.
  • R 9 is H.
  • R 9 is C1-C6 alkyl, e.g. C1-C3 alkyl, in particular methyl.
  • R 8 is R 10 R 11 N and R 10 and R 11 are independently selected from H and C1-C6 alkyl. In some other embodiments, R 8 is R 10 R 11 N and R 10 and R 11 , together with the nitrogen atom to which they are both attached, form a 5- or 6-membered heterocyclic ring. In some embodiments of a compound of formula (Icdn), R 8 is R 10 R 11 N and the moieties R 10 and R 11 are independently selected from C1-C6 alkyl, e.g. C1-C3 alkyl; or R 10 and R 11 , together with the nitrogen atom to which they are both attached, form a 5- or 6-membered heterocyclic ring, e.g. a 6-membered heterocyclic ring.
  • R 8 is R 12 OC(O).
  • R 12 is H or C1-C3 alkyl, or H or methyl.
  • R 12 is H.
  • R 12 is C1-C6 alkyl, e.g. C1-C3 alkyl, in particular methyl.
  • R 4 when R 4 is R 7 S(O) 2 NH, R 4 more specifically is selected from
  • R 2 is H or halogen. In some other embodiments, R 2 is H or R 13 NH. In some particular embodiments, R 2 is H.
  • R 2 is R 13 NH.
  • ring A is a 5- to 7-membered, aromatic or non-aromatic carbocycle.
  • ring A is benzene.
  • b is an integer of from 0 to 3, or from 0 to 2, e.g. b is 1 or 2.
  • b is 1.
  • b is 2.
  • any alkyl moiety in a compound of formula (I) may be substituted by one or more F.
  • R 32 is alkyl, said alkyl is substituted by one or more F.
  • R 32 is selected from H, CH 3 and CF 3 , e.g. from CH 3 and CF 3 .
  • R 3 is R 32 O, wherein R 32 is as defined herein above, e.g. R 32 is CH 3 or CF 3 , in particular CF 3 .
  • one R 3 is phenyl.
  • the compound is as represented by formula (Iacen), and
  • x is 0 or 1; e.g. x is 0;
  • b is an integer of from 0 to 4; e.g. b is an integer of from 0 to 3; or b is 1 or 2;
  • R 2 is H, halogen or R 13 NH; e.g. R 2 is H;
  • R 13 is C1-C6 alkyl or benzyl
  • each R 3 is independently selected from C1-C6 alkyl, halogen, phenyl, and R 32 O; e.g. from C1-C6 alkyl, halogen, and R 32 O;
  • each R 32 is independently selected from H and C1-C6 alkyl
  • R 3 are attached to adjacent carbon atoms of the benzene ring and, together with the atoms to which they are attached, form a benzene ring;
  • R 4 is OH, NC—NH, or R 7 S(O) 2 NH; e.g. R 4 is OH, or R 7 S(O) 2 NH;
  • R 7 is C3-C6 cycloalkyl C1-C6 alkyl, or R 8 (CH 2 ) y ;
  • R 8 is R 9 O, R 10 R 11 N, or R 12 OC(O);
  • R 9 is H or C1-C6 alkyl
  • R 10 is H or C1-C6 alkyl; or R 10 is C1-C6 alkyl;
  • R 11 is H or C1-C6 alkyl; or R 11 is C1-C6 alkyl; or
  • R 10 and R 11 together with the nitrogen atom to which they are both attached, form a 5- or 6-membered heterocyclic ring;
  • R 12 is H or C1-C6 alkyl; or R 12 is C1-C6 alkyl;
  • y is an integer of from 1 to 4.
  • any alkyl or cycloalkyl is optionally substituted by one or more F.
  • each R 3 is independently selected from C1-C6 alkyl, halogen, and R 32 O.
  • R 10 is H or C1-C6 alkyl; e.g. R 10 is C1-C6 alkyl; and R 11 is H or C1-C6 alkyl; e.g. R 11 is C1-C6 alkyl.
  • any C1-C6 alkyl more specifically is selected from C1-C4 alkyl, e.g. C1-C3 alkyl.
  • x is 0; b is 1 or 2; R 4 is OH; R 2 is H; and each R 3 is independently selected from CH 3 , CF 3 , F, Cl, Br, CH 3 O, and CF 3 O.
  • x is 1; b is 1 or 2; R 4 is OH; R 2 is H; and each R 3 is independently selected from CH 3 , CF 3 , F, Cl, Br, CH 3 O, and CF 3 O.
  • x is 1; b is 1 or 2; R 4 is R 7 S(O) 2 NH; R 2 is H; each R 3 is independently selected from CH 3 , CF 3 , F, Cl, Br, CH 3 O, and CF 3 O; and R 7 is cyclopropyl, CH 3 , CF 3 , CH 3 CH 2 , CF 3 CH 2 , HOCH 2 CH 2 , CH 3 OCH 2 CH 2 , CH 3 OC(O)CH 2 CH 2 , or (CH 3 CH 2 ) 2 NCH 2 CH 2 CH 2 .
  • halogen selected from F, Cl and Br
  • said halogen more particularly may be selected from F and Cl.
  • ring A is 5, 6- or 7-membered carbocyclyl, e.g. 5- or 6-membered carbocyclyl, in particular 6-membered, mono-unsaturated carbocyclyl; i.e. the compound is a compound of formula (Ibcdn), and
  • x is 0 or 1; or x is 0;
  • b is an integer of from 0 to 4.
  • z is 1, 2 or 3; e.g. z is 1 or 2; or z is 2;
  • R 2 is H, halogen or R 13 NH
  • R 13 is C1-C6 alkyl or benzyl
  • each R 3 is independently selected from C1-C6 alkyl, halogen, phenyl, and R 32 O; e.g. each R 3 is independently selected from C1-C6 alkyl, phenyl, and R 32 O; or each R 3 is independently selected from C1-C6 alkyl and R 32 O; or each R 3 is independently selected from C1-C6 alkyl; each R 32 is independently selected from H and C1-C6 alkyl; e.g. from H and methyl, e.g.
  • each R 32 is H; or two R 3 are attached to adjacent carbon atoms of ring A and, together with the atoms to which they are attached, form a benzene ring;
  • R 4 is OH, NC—NH, or R 7 S(O) 2 NH; preferably R 4 is OH or R 7 S(O) 2 NH;
  • R 7 is C3-C6 cycloalkyl or C1-C6 alkyl, or R 8 (CH 2 ) y ; e.g. R 7 is C1-C6 alkyl or R 8 (CH 2 ) y ;
  • R 8 is R 9 O, R 10 R 11 N, or R 12 OC(O); e.g.
  • R 8 is R 10 R 11 N;
  • R 9 is H or C1-C6 alkyl;
  • R 10 is H or C1-C6 alkyl;
  • R 11 is H or C1-C6 alkyl; or
  • R 10 and R 11 together with the nitrogen atom to which they are both attached, form a 5- or 6-membered heterocyclic ring;
  • R 12 is H or C1-C6 alkyl;
  • y is an integer of from 1 to 4; and any alkyl or cycloalkyl is optionally substituted by one or more F.
  • R 4 is R 7 S(O) 2 NH wherein R 7 is C1-C6 alkyl, in particular C1-C3 alkyl, or R 8 (CH 2 ) y , wherein y e.g. is an integer of from 1 to 3.
  • R 4 is R 7 S(O) 2 NH
  • R 7 is C1-C6 alkyl, in particular C1-C3 alkyl, or R 8 (CH 2 ) y , wherein y e.g. is an integer of from 1 to 3, and R 8 is R 10 R 11 N.
  • R 4 is R 7 S(O) 2 NH
  • R 7 is C1-C6 alkyl, in particular R 8 (CH 2 ) y
  • y e.g. is an integer of from 1 to 3, in particular from 2 to 3
  • R 8 is R 10 R 11 N.
  • R 8 is diethylamino or morpholino.
  • R 4 is R 7 S(O) 2 NH wherein R 7 is C1-C6 alkyl, e.g. C1-C3 alkyl, optionally substituted by one or more F.
  • R 7 is methyl or ethyl, optionally substituted by one or more F, e.g. R 7 is CH 3 or CF 3 CH 2 .
  • each R 3 is independently selected from C1-C6 alkyl, phenyl and R 32 O; e.g. each R 3 is independently selected from C1-C6 alkyl and R 32 O; or each R 3 is independently selected from C1-C6 alkyl.
  • any R 3 is methyl.
  • b is 1.
  • R 3 is C1-C6 alkyl, such as methyl or tert-butyl.
  • a compound of formula (Ia) also should be construed as a reference to a compound of any of the embodiments thereof, e.g. as illustrated in any of the formulas herein above.
  • a compound of formula (Ia) also is a compound of formula (Id) (i.e. a compound of formula (Iad), e.g. a compound of formula (Ie) (i.e.
  • the compound of formula (I) is a compound of formula (Iah), or of formula (Iaj), (Iak), (Iam), (Ian), or (Iao).
  • the compound of formula (I) is a compound of formula (Ibd), (Ibe), (Ibf), (Ibg), (Ibh), (Ibj), (Ibk), (Ibm), (Ibn) or (Ibo).
  • the compound of formula (I) is a compound of formula (Icd), (Ice), (Icf), (Icg), (Ich), (Icj), (Ick), (Icm), (Icn), (Ico), (Icp), (Icq), (Icr), (Ics), (Ict), (Icu), (Icv), (Idj), (Idk), (Idm), (Idn), (Ido), (Idp), (Idq), (Idr), (Ids), (Idt), (Idu), (Idv), (Iej), (Iek), (Iem), (Ien), (Ieo), (Iep), (Ieq), (Ier), (Ies), (Iet), (Ieu), (Iev), (Ifj), (Ifk), (Ifm), (Ifn), (Ifo), (Ifp), (Ifq),
  • the compound of formula (Icdmn) also is a compound of formula (Ib), i.e. a compound of formula (Ibcdmn)
  • the compound of formula (Icdmn) also is a compound of formula (Is), i.e. a compound of formula (Icdmns)
  • the compound of formula (Icdmn) also is a compound of formula (Ia), i.e. a compound of formula (Iacdmn),
  • the compound also is a compound of formula (Ip), or a compound of formula (q), or a compound of formula (Ir).
  • the compound more particularly is a compound of formula (Ie), e.g. a compound of formula (If), in particular a compound of formula (Iep) or (Ifp).
  • x is 0.
  • a compound of formula (Ikn) also is a compound (Icd), i.e. a compound of formula (Icdkn)
  • the compound of formula (Icdkn) also is a compound as represented by formula (Ib), e.g. by formula (It). In some other embodiments, the compound of formula (Icdkn) also is a compound of formula (Is). In some other of those embodiments, the compound of formula (Icdkn) also is as represented by formula (Ia). In some of these embodiments, x is 0.
  • a compound of formula (Iac) also is a compound of formula (Ido), i.e. a compound as represented by formula (Iacdo)
  • the compound of formula (Iacdo) also is a compound of formula (Ij), i.e. wherein R 2 is H.
  • the compound of formula (Iacdo) or formula (Iacdjo) more particularly is a compound of formula (Iaceo), i.e.a compound wherein R 4 is R 5 O.
  • the compound of formula (Iacdo) or (Iaceo) also is a compound of formula (Ip) or (Iq), or a compound of formula (Ijp) or (Ijq). In some of these embodiments, x is 0.
  • a compound of formula (Iacen) in particular wherein R 2 is H, b is not 0, and when b is 1 and R 3 is attached in position 10 on ring A, R 3 is not halogen, methyl, methoxy, trifluoromethyl or ethyl.
  • a compound of formula (Iacen) in particular wherein R 2 is H, b is not 0, and when b is 1 and R 3 is attached in position 10 on ring A, R 3 is not halogen, C1-C6 alkyl optionally substituted by F, or C1-C6 alkoxy, optionally substituted by F.
  • a compound of formula (Iacen) in particular wherein R 2 is H, b is not 0, and when b is 1, R 3 is not attached in position 10 or 12 on ring A, and when b is 2, ring A is not 10,11-dialkylsubstituted.
  • a compound of formula (Iacen) in particular wherein R 2 is H, b is not 0, and when b is 1 and R 3 is halogen, C1-C6 alkyl or C1-C6 alkoxy, R 3 is not attached in position 10 or 12 on ring A, and when b is 2 and each R 3 is halogen, C1-C6 alkyl or C1-C6 alkoxy, ring A is not 10,11-disubstituted.
  • a compound of formula (I) e.g. when ring A is benzene, Q is a direct bond or (CH 2 ), R 1 is R 5 OC(O), and R′ 1 and R′ 2 form a bond, b is not 0.
  • a compound of formula (I) e.g. when ring A is benzene, Q is a direct bond or (CH 2 ), R 1 is R 5 OC(O), and R′, and R′ 2 form a bond, b is an integer of from 1 to 4 and one R 3 is attached in position 9 on ring A.
  • a compound of formula (I) e.g. when ring A is benzene, Q is a direct bond or (CH 2 ), R 1 is R 5 OC(O), and R′, and R′ 2 form a bond, b is not 0, and when b is 1, R 3 is not attached in position 12 on ring A.
  • a compound of formula (I) e.g. when ring A is benzene, Q is a direct bond or (CH 2 ), R 1 is R 5 OC(O), and R′ 1 and R′ 2 form a bond, b is not 0, and when b is 1 and R 3 is attached in position 10 on ring A, R 3 is not halogen, methyl, methoxy, trifluoromethyl or ethyl.
  • a compound of formula (I) e.g. when ring A is benzene, Q is a direct bond or (CH 2 ), R 1 is R 5 OC(O), and R′, and R′ 2 form a bond, b is not 0, and when b is 1 and R 3 is attached in position 10 on ring A, R 3 is not halogen, C1-C6 alkyl optionally substituted by F, or C1-C6 alkoxy, optionally substituted by F.
  • a compound of formula (I) e.g. when ring A is benzene, Q is a direct bond or (CH 2 ), R 1 is R 5 OC(O), and R′ 1 and R′ 2 form a bond, b is not 0, and when b is 1, R 3 is not attached in position 10 on ring A.
  • ring A is benzene
  • Q is a direct bond or (CH 2 )
  • R 1 is R 5 OC(O)
  • R′ 1 and R′ 2 form a bond
  • b is not 0, and when b is 1, and R 3 is halogen, C1-C6 alkyl or C1-C6 alkoxy, R 3 is not attached in position 10 or 12 on ring A.
  • a compound of formula (I) e.g. when ring A is benzene, Q is a direct bond or (CH 2 ), R 1 is R 5 OC(O), and R′, and R′ 2 form a bond, b is not 0, and when b is 1, R 3 is not attached in position 10 or 12 on ring A.
  • a compound of formula (I) e.g. when ring A is benzene, Q is a direct bond or (CH 2 ), R 1 is R 5 OC(O), and R′, and R′ 2 form a bond, b is not 0, and when b is 1, R 3 is not attached in position 10 or 12 on ring A, and when b is 2 and each R 3 is methyl, ring A is not 10,11-disubstituted.
  • ring A when ring A is benzene, Q is a direct bond or (CH 2 ), R 1 is R 5 OC(O), and R′ 1 and R′ 2 form a bond, b is not 0, and when b is 1, R 3 is not attached in position 10 or 12 on ring A, and when b is 2 and each R 3 is C1-C6 alkyl, ring A is not 10,11-disubstituted.
  • a compound of formula (I) e.g. when ring A is benzene, Q is a direct bond or (CH 2 ), R 1 is R 5 OC(O), and R′ 1 and R′ 2 form a bond, b is not 0, and when b is 1 and R 3 is halogen, C1-C6 alkyl or C1-C6 alkoxy, R 3 is not attached in position 10 or 12 on ring A, and when b is 2 and each R 3 is halogen, C1-C6 alkyl or C1-C6 alkoxy, ring A is not 10,11-disubstituted.
  • a compound of formula (I) e.g. when ring A is benzene, Q is a direct bond or (CH 2 ), R 1 is R 5 OC(O), and R′ 1 and R′ 2 form a bond, b is not 0 or 1, and when b is 2, one R 3 is in position 9 on ring A.
  • a compound of formula (I) e.g. when ring A is benzene, Q is a direct bond or (CH 2 ), R 1 is R 5 OC(O), and R′, and R′ 2 form a bond, b is not 0, and when b is 1 or 2, one R 3 is in position 9 on ring A.
  • a compound of formula (I) e.g. when ring A is benzene, Q is a direct bond or (CH 2 ), R 1 is HC(O), R 5 OC(O) or tetrazolyl, and R′ 1 and R′ 2 form a bond, b is not 0, and when b is 1 and R 3 is attached in position 10 on ring A, R 3 is not halogen, C1-C6 alkyl optionally substituted by F, or C1-C6 alkoxy, optionally substituted by F.
  • a compound of formula (I) e.g. when ring A is benzene, Q is a direct bond or (CH 2 ), R 1 is HC(O), R 5 OC(O) or tetrazolyl, and R′ 1 and R′ 2 form a bond, b is not 0, and when b is 1, R 3 is not attached in position 10 on ring A.
  • ring A is benzene
  • Q is a direct bond or (CH 2 )
  • R 1 is HC(O), R 5 OC(O) or tetrazolyl
  • R′ 1 and R′ 2 form a bond
  • b is not 0, and when b is 1, and R 3 is halogen, C1-C6 alkyl or C1-C6 alkoxy, R 3 is not attached in position 10 or 12 on ring A.
  • a compound of formula (I) e.g. when ring A is benzene, Q is a direct bond or (CH 2 ), R 1 is HC(O), R 5 OC(O) or tetrazolyl, and R′ 1 and R′ 2 form a bond, b is not 0, and when b is 1, R 3 is not attached in position 10 or 12 on ring A.
  • a compound of formula (I) e.g. when ring A is benzene, Q is a direct bond or (CH 2 ), R 1 is HC(O), R 5 OC(O) or tetrazolyl, and R′ 1 and R′ 2 form a bond, b is not 0, and when b is 1, R 3 is not attached in position 10 or 12 on ring A, and when b is 2 and each R 3 is methyl, ring A is not 10,11-disubstituted.
  • ring A when ring A is benzene, Q is a direct bond or (CH 2 ), R 1 is HC(O), R 5 OC(O) or tetrazolyl, and R′ 1 and R′ 2 form a bond, b is not 0, and when b is 1, R 3 is not attached in position 10 or 12 on ring A, and when b is 2 and each R 3 is C1-C6 alkyl, ring A is not 10,11-disubstituted.
  • a compound of formula (I) e.g. when ring A is benzene, Q is a direct bond or (CH 2 ), R 1 is HC(O), R 5 OC(O) or tetrazolyl, and R′, and R′ 2 form a bond, b is not 0, and when b is 1 and R 3 is halogen, C1-C6 alkyl or C1-C6 alkoxy, R 3 is not attached in position 10 or 12 on ring A, and when b is 2 and each R 3 is halogen, C1-C6 alkyl or C1-C6 alkoxy, ring A is not 10,11-disubstituted.
  • a compound of formula (I) e.g. when ring A is benzene, Q is a direct bond or (CH 2 ), R 1 is HC(O), R 5 OC(O) or tetrazolyl, and R′ 1 and R′ 2 form a bond, b is not 0 or 1, and when b is 2, one R 3 is in position 9 on ring A.
  • a compound of formula (I) e.g. when ring A is benzene, Q is a direct bond or (CH 2 ), R 1 is HC(O), R 5 OC(O) or tetrazolyl, and R′ 1 and R′ 2 form a bond, b is not 0, and when b is 1 or 2, one R 3 is in position 9 on ring A.
  • the present invention therefore relates to compounds as defined herein, as S100 protein inhibitors, mainly as S100A9 inhibitors and to their use in treatment or prevention of S100-protein related diseases, in particular diseases related to the activity of S100A9 protein.
  • the present invention relates to the compounds of formula (I) as defined herein, to pharmaceutical compositions comprising said compounds, to the use of such compositions in the therapeutic treatment of conditions selected from in particular cancer, but also automimmune diseases, inflammatory diseases and neurodegenerative diseases, to a method of treatment of such conditions, and to said compounds for use in the treatment of conditions selected from in particular cancer, but also automimmune diseases, inflammatory diseases and neurodegenerative diseases, as well as the use of said compounds in the manufacture of pharmaceutical compositions for the treatment of such conditions.
  • the present invention includes pharmaceutical compositions comprising at least one compound according to formula (I), or an individual isomer, racemic or non-racemic mixture of isomers or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable excipient, e.g. a carrier, and optionally other therapeutic and/or prophylactic ingredients.
  • pharmaceutically acceptable excipient e.g. a carrier, and optionally other therapeutic and/or prophylactic ingredients.
  • a pharmaceutical composition according to the invention may be for topical (local) or systemic administration, e.g. for enteral administration, such as rectal or oral administration, or for parenteral administration to a mammal (especially a human), and comprises a therapeutically effective amount of a compound according to the invention or a pharmaceutically acceptable salt thereof, as active ingredient, in association with a pharmaceutically acceptable excipient, e.g. a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable excipient e.g. a pharmaceutically acceptable carrier.
  • the therapeutically effective amount of the active ingredient is as defined herein above and depends e.g. on the species of mammal, the body weight, the age, the individual condition, individual pharmacokinetic data, the disease to be treated and the mode of administration.
  • the compounds of the invention may be formulated in a wide variety of dosage forms.
  • the pharmaceutical compositions and dosage forms may comprise a compound or compounds of the present invention or pharmaceutically acceptable salt(s) thereof as the active component.
  • the pharmaceutically acceptable carriers may be either solid or liquid. Solid form preparations include powders, tablets, pills, lozenges, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier may be one or more substances which may also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component.
  • the active component In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.
  • Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatine, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • the formulation of the active compound may comprise an encapsulating material as carrier, providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is in association with it.
  • liquid form preparations including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations which are intended to be converted shortly before use to liquid form preparations.
  • Emulsions may be prepared in solutions, for example, in aqueous propylene glycol solutions or may contain emulsifying agents, for example, such as lecithin, sorbitan monooleate, or acacia.
  • Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents.
  • Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents.
  • Solid form preparations include solutions, suspensions, and emulsions, and may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • compositions for rectal administration include suppositories which can contain, for example, a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.
  • a suitable non-irritating excipient such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.
  • the compounds of the invention also may be administered parenterally, e.g. by inhalation, injection or infusion, e.g. by intravenous, intraarterial, intraosseous, intramuscular, intracerebral, intracerebroventricular, intrasynovial, intrasternal, intrathecal, intralesional, intracranial, intratumoral, intracutaneous and subcutaneous injection or infusion.
  • parenterally e.g. by inhalation, injection or infusion, e.g. by intravenous, intraarterial, intraosseous, intramuscular, intracerebral, intracerebroventricular, intrasynovial, intrasternal, intrathecal, intralesional, intracranial, intratumoral, intracutaneous and subcutaneous injection or infusion.
  • the pharmaceutical compositions of the invention may be in the form of a sterile injectable or infusible preparation, for example, as a sterile aqueous or oleaginous suspension.
  • This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (e.g., Tween 80), and suspending agents.
  • the sterile injectable or infusible preparation may also be a sterile injectable or infusible solution or suspension in a non-toxic parenterally acceptable diluent or solvent.
  • the pharmaceutical composition may be a solution in 1,3-butanediol.
  • acceptable vehicles and solvents include, but are not limited to, mannitol, water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant.
  • Suitable stabilizing agents include antioxidizing agents, such as sodium bisulfate, sodium sulfite or ascorbic acid, either alone or combined, citric acid and its salts and sodium EDTA.
  • Suitable stabilizing agents may also contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and cholorobutanol.
  • suitable pharmaceutical formulations are as particles, aerosols, powders, mists or droplets, e.g. with an average size of about 10 ⁇ m in diameter or less.
  • compositions for inhalation may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
  • compositions of the invention also may be administered topically, to the skin or to a mucous membrane.
  • the pharmaceutical composition may be e.g. a lotion, a gel, a paste, a tincture, a transdermal patch, a gel for transmucosal delivery.
  • the composition may be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier.
  • Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.
  • the pharmaceutical composition may be formulated as a suitable lotion or cream containing the active compound suspended or dissolved in a carrier.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetaryl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation.
  • Suitable pharmaceutical excipients e.g. carriers, and methods of preparing pharmaceutical dosage forms are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in art of drug formulation.
  • the pharmaceutical compositions may comprise from approximately 1% to approximately 95%, preferably from approximately 20% to approximately 90% of a compound of formula (I), together with at least one pharmaceutically acceptable excipient.
  • the compounds of the invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities.
  • Suitable daily dosages typically ranges from 1 to 1000 mg, e.g. 1-500 mg daily, or 1-50 mg daily, depending upon numerous factors such as the severity of the disease to be treated, the age and relative health of the patient, the potency of the compound used, the route and form of administration, and the indication towards which the administration is directed, etc.
  • Compounds of the invention may be administered as pharmaceutical formulations including those suitable for enteral or parenteral administration.
  • the preferred manner of administration is generally oral using a convenient daily dosage regimen which can be adjusted according to the degree of affliction.
  • the present invention relates to a method of treatment of a disease that responds to inhibition of a member of the S100 protein family, e.g. S100A9, e.g. a cancer, an autoimmune disease, an inflammatory disease, or a neurodegenerative disease, which method comprises administering a therapeutically effective amount of a compound of formula (I), or pharmaceutically acceptable salt thereof, to a warm-blooded animal, e.g., a human, in need of such treatment.
  • a member of the S100 protein family e.g. S100A9
  • a cancer e.g. a cancer
  • an autoimmune disease e.g. a autoimmune disease
  • an inflammatory disease e.g. a neurodegenerative disease
  • HPLC methods were as follows:
  • Low pH Method refers to HPLC purification using a mobile phase consisting of 0.1% formic acid in a gradient of 0-100% MeCN in water.
  • the stationary phase consisted of a Waters Sunfire C18 column, 5 ⁇ m particle size, 19 ⁇ 100 mm.
  • “High pH method” refers to HPLC purification using a mobile phase consisting of 0.2% aqueous ammonia in a gradient of 5-100% MeCN in water.
  • the stationary phase consisted of a Waters X-bridge C18 column, 10 ⁇ m particle size, 30 ⁇ 100 mm.
  • “Neutral method” refers to HPLC purification using a mobile phase (without modifier) consisting of a gradient of 10-100% MeCN in water.
  • the stationary phase consisted of a Waters Sunfire C18 column, 10 ⁇ m particle size, 30 ⁇ 100 mm.
  • Microwave reactions were carried out using a CEM Discover or Activent microwave apparatus.
  • Ethyl 9-chloro-10-fluoro-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 ]dodeca-1(8),3,5,9,11-pentaene-4-carboxylate (53 mg, 0.18 mmol) was suspended in EtOH (3 mL), 1M NaOH in water (1.51 mL, 1.51 mmol) was added and the mixture was stirred at 75° C. for 45 min. The reaction was allowed to cool to room temperature. The EtOH was removed in vacuo and the resulting white suspension was adjusted to pH 1 by the addition of 1M HCl. The white suspension was sonicated for 2 min then filtered over glass fibre filter paper.
  • Ethyl 10-chloro-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 ]dodeca-1(8),3,5,9,11-pentaene-4-carboxylate (310 mg, 1.10 mmol) was dissolved in EtOH (10 mL) and water. NaOH (221 mg, 5.52 mmol) was added and the reaction mixture stirred at room temperature for 30 min. The mixture was then acidified with 6N HCl and the aqueous phase extracted with EtOAc (3 ⁇ 30 mL).
  • the reaction was treated with more EDC (153 mg, 0.99 mmol) and DMAP (145 mg, 1.18 mmol) and stirred at room temperature for a further 18 h.
  • the reaction was quenched by the addition of 1M HCl (10 mL), then diluted with DCM (60 mL) and the phases were separated. The organic phase was washed with 1M HCl (2 ⁇ 10 mL), water (10 mL) and brine (20 mL) then concentrated in vacuo.
  • reaction mixture was diluted with EtOAc (30 mL), washed with 1M HCl (5 mL), water (5 mL), brine (5 mL) then concentrated in vacuo.
  • the residue was purified by FCC over silica (eluent: DCM:MeOH 98:2 to 92:8) to afford approximately 50 mg of product which was triturated with heptane:EtOAc:DCM 2:2:1 (2 ⁇ 4 mL).
  • the reaction was stirred at 80° C. for 1 h.
  • the reaction was retreated with LiBH 4 (3 mg, 0.14 mmol) and methanol (6 ⁇ L, 0.14 mmol) and then stirred at 80° C. for a further 60 min.
  • the reaction was diluted with EtOAc (20 mL) and extracted with saturated aqueous NaHCO 3 (3 ⁇ 3 mL).
  • the combined aqueous extracts were washed with DCM (3 mL) and then brought to pH 1 by the addition of 3N HCl (aq).
  • the resulting suspension was washed with DCM (2 ⁇ 5 mL) then filtered over glass fibre filter paper.
  • Ethyl 10-tert-butyl-3-(tert-butylamino)-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 ]dodeca-1(8),3,5-triene-4-carboxylate (190 mg, 75%, 0.377 mmol) and LiOH.H 2 O (31 mg, 0.755 mmol) were stirred in MeOH/water (5 mL/0.5 mL) at room temp for 16 h. Extra LiOH.H 2 O (31 mg, 0.755 mmol) was added and the reaction heated at 40° C. for 2 days and then stirred at room temperature for 2 days.
  • the racemic mixture was resolved using chiral HPLC.
  • the stationary phase used was a YMC AMY-C (20 mm ⁇ 250 mm, 5 m) column.
  • the mobile phase was heptane:isopropanol 70:30 containing some diethylamine, added as a modifier).
  • Enantiomer 1 The procedure and chiral separation used to obtain Enantiomer 1 was used.
  • reaction mixture was evaporated to dryness, dissolved in DCM (50 mL) and washed with water (25 mL), 1M HCl (25 mL) and brine (25 mL). The organic layer was dried over MgSO 4 and evaporated to dryness to afford a brown oil which was purified by automated reverse phase HPLC (low pH method).
  • N-methanesulfonyl-4,4,5,5-tetramethyl-7-thia-1,9-diazatricyclo[6.3.0.0 2,6 ]undeca-2(6),8,10-triene-10-carboxamide was used except that 9,9,11,11-tetramethyl-7-thia-2,5-diazatricyclo[6.4.0.0 2,6 ]dodeca-1(8),3,5-triene-4-carboxylic acid was substituted for 4,4,5,5-tetramethyl-7-thia-1,9-diazatricyclo[6.3.0.0 2,6 ]undeca-2(6),8,10-triene-10-carboxylic acid and triethylamine substituted for DIPEA.
  • Ethyl 3-bromo-2-oxopropanoate (150 ⁇ L, 1.18 mmol) was added to a solution of 7-chloro-6-fluoro-1,3-benzothiazol-2-amine (120 mg, 0.59 mmol) in DME (3 mL) in a pressure tube. The reaction was sealed and stirred at 75° C. for 18 h. The reaction was allowed to cool to room temperature and re-treated with ethyl 3-bromo-2-oxopropanoate (50 ⁇ L, 0.39 mmol) then stirred at 80° C. for a further 6 h. The reaction was allowed to cool to room temperature then filtered over glass fibre filter paper and the filtrate was concentrated in vacuo.
  • 6-Chloro-7-fluoro-1,3-benzothiazol-2-amine (90%, 430 mg, 1.91 mmol), ethyl 3-bromo-2-oxopropanoate (603 ⁇ L, 4.77 mmol) and DME (6 mL) were charged in a pressure tube.
  • the reaction mixture was sealed and stirred at 75° C. for 2 h.
  • the reaction mixture was allowed to cool to room temperature then diluted with MeCN (5 mL).
  • the reaction was sealed and stirred at 75° C. for 18 h.
  • the reaction was allowed to cool to room temperature then filtered over glass fibre filter paper and the filter pad was washed with MeCN (3 ⁇ 3 mL).
  • Ethyl 3-bromo-2-oxopropanoate (3.85 mL, 30.5 mmol) was added dropwise to a solution of 2-amino-4,5,6,7-tetrahydro-1,3-benzothiazol-7-one (4.27 g, 25.4 mmol) in anhydrous DMF (90 mL) and stirred at 75-80° C. for 60 min. The solution was cooled to room temperature and about half of the solvent was removed under reduced pressure. The remaining solution was diluted with EtOAc (100 mL) and washed with water (5 ⁇ 100 mL).
  • a pressure tube was charged with ethyl 3-bromo-10-tert-butyl-7-thia-2,5-diazatricyclo[6.4.0.026]dodeca-1(8),3,5-triene-4-carboxylate (100 mg, 0.260 mmol), methanesulfonamide (30 mg, 0.31 mmol), Pd 2 (dba) 3 (24 mg, 0.026 mmol), Xantphos (30 mg, 0.052 mmol) and caesium carbonate (118 mg, 0.363 mmol) and 1,4-dioxane (0.5 mL). The reaction was degassed with nitrogen for 10 min. The tube was sealed and stirred at 95° C. for 18 h.

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