CONNECTIONS FOR THE TREATMENT OF NEUROMUSCULAR DISEASES

Description

Technical field

[0001] The present disclosure relates to compounds and their use in treating, ameliorating and / or preventing neuromuscular disorders, including the reversal of drug-induced neuromuscular blockade. The compounds as defined herein can inhibit the CIC-1 ion channel. The disclosure further relates to methods of treating, preventing and / or ameliorating neuromuscular disorders, by administering said composition to a person in need thereof.Background

[0002] Walking, breathing, and eye movement are examples of essential everyday physiological activities that are powered by the contractile activity of skeletal muscle. Skeletal muscles are inherently in a resting state and contractile activity occurs exclusively in response to commands from the central nervous system (CNS). Such neuronal commands take the form of action potentials that travel from the brain to the muscle fibres in several steps. The neuromuscular junction (NMJ) is a highly specialized membrane area on muscle fibres where motor neurons come into close contact with the muscle fibres, and it is at the NMJ where neuronal action potentials are transmitted to muscular action potentials in a one-to-one fashion via synaptic transmission.

[0003] Unfortunately, none of the currently employed drug regimens for treating neuromuscular disorders, such as myasthenia gravis, Lambert-Eaton Syndrome, Charcot-Marie Tooth (CMT) disease, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA) and sarcopenia, have been able to fully restore muscle function in compromised patients.

[0004] The CIC-1 ion channel (Pedersen, T.H., Riisager, A., Vincenzo de Paoli, F., Chen, T-Y, Nielsen, O.B. Role of physiological CIC-1 Cl- ion channel regulation for the excitability and function of working skeletal muscle. J. Gen. Physiol. 2016, 147, 291 - 308) is emerging as a target for improving muscle function in patients having a neuromuscular disfunction.Summary

[0005] The present disclosure comprises a series of compounds that can alleviate disorders of the neuromuscular junction through inhibition of CIC-1 channels.

[0006] It has been found that compounds that inhibit CIC-1 ion channels are capable of restoring neuromuscular transmission, as evidenced by the data generated by investigation of the compound set in biological models described herein. These compounds thus constitute a group of potential drugs that can be used to treat and / or ameliorate muscle weakness and / or muscle fatigue in neuromuscular junction disorders caused by disease or by neuromuscular blocking agents.

[0007] The present disclosure is directed to CIC-1 ion channel inhibitors with application in the treatment of a range of conditions, such as reversal of neuromuscular block, SMA, CMT, ALS and myasthenic conditions, in which muscle activation by the nervous system is compromised and symptoms of weakness and fatigue are prominent.

[0008] In one aspect, the disclosure concerns a compound of Formula (I): wherein: M is CR 5< R 6< , NR 7< , O or S; Q is CR 5< R 6< , NR 8< , O or S; T is CR 5< R 6< , NR 8< , O or S; X is absent, CR 5< R 6< , NR 8< , O or S; Z is CR 5< R 6< , NR 9< , O or S; two or more of M, Q, T, X and Z are NR 7< , NR 8< , NR 9< , O or S; R 1< is selected from the group consisting of F; Cl; Br; C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-3 alkenyl optionally substituted with one or more, identical or different, substituents R 10< ; -OC 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; -OC 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; - SC 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< and -SC 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 2< is selected from the group consisting of H; F; Cl; Br; and C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 3< is selected from the group consisting of H, F and Cl; R 4< is selected from the group consisting of H; C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-5 alkenyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-5 alkynyl optionally substituted with one or more, identical or different, substituents R 10< ; C 3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; phenyl optionally substituted with one or more, identical or different, substituents R 11< ; and benzyl optionally substituted with one or more, identical or different, substituents R 11< ; R 5< is independently selected from the group consisting of H, deuterium, F and C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 6< is independently selected from the group consisting of H, deuterium, F and C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 7< is independently selected from the group consisting of H, C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with phenyl optionally substituted with one or more, identical or different, substituents R 11< ; C 1-3 alkyl substituted with C 5 heteroaryl optionally substituted with one or more, identical or different, substituents R 11< ; and C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 8< is independently selected from benzyl optionally substituted with one or more, identical or different, substituents R 11< ; R 9< is independently selected from the group consisting of H, C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with phenyl optionally substituted with one or more, identical or different, substituents R 11< ; C 1-3 alkyl substituted with naphthyl optionally substituted with one or more, identical or different, substituents R 11< ; C 1-3 alkyl substituted with a 5- to 10-membered heteroaryl optionally substituted with one or more, identical or different, substituents R 11< ; and C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 10< is independently selected from the group consisting of H, deuterium, F, Cl and -OC 1-3 alkyl; and R 11< is independently selected from the group consisting of deuterium, methoxy, -OCF 3 , Me, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CD 3 , cyclopropyl, NH 2 , -NHAc, -C(=O)-NH 2 , nitro, cyano, CI, Br, I, and F; when R 5< and R 6< are individually C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< , then R 5< and R 6< are optionally joined together to form a ring; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof provided that: only one of M, Q, T, X and Z is O; and when M is O, Q and T are CH 2 , X is absent, Z is NH, R 1< is Cl, R 2< is H and R 3< is H then R 4< is not H.

[0009] In another aspect, the disclosure concerns a compound as defined herein for use in treating, ameliorating and / or preventing a neuromuscular disorder, and / or for use in reversing and / or ameliorating a neuromuscular blockade. In yet another aspect, the disclosure concerns a composition comprising a compound as defined herein.

[0010] The invention is defined by the claims. Any subject matter falling outside the scope of the claims is provided for information purposes only.Definitions

[0011] The terms "C 1-3 alkyl" and "C 1-5 alkyl" refers to a branched or unbranched alkyl group having from one to three or one to five carbon atoms respectively, including but not limited to methyl, ethyl, prop-1-yl, prop-2-yl, 2-methyl-prop-1-yl, 2-methyl-prop-2-yl, 2,2-dimethyl-prop-1-yl, but-1-yl, but-2-yl, 3-methyl-but-1-yl, 3-methyl-but-2-yl, pent-1-yl, pent-2-yl and pent-3-yl.

[0012] The term "alkanediyl" refers to the corresponding derivative of an alkyl group having two bonding sites. Thus, a C 1-3 alkanediyl refers to -(CH 2 ) n -, wherein n is a positive integer from 1 to 3, i.e. including -CH 2 -, -CH 2 CH 2 -, and -CH 2 CH 2 CH 2 -.

[0013] The term "C 2-3 alkenyl" and "C 2-5 alkenyl" refers to a branched or unbranched alkenyl group having from two to three or two to five carbon atoms respectively, two of which are connected by a double bond, including but not limited to ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl and isopentenyl.

[0014] The term "C 2-5 alkynyl" refers to a branched or unbranched alkynyl group having from two to five carbon atoms, two of which are connected by a triple bond, including but not limited to ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, buta-1,3-diynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, penta-2,4-diynyl and penta-1,3-diynyl.

[0015] The term "C 3-5 cycloalkyl" and "C 3-6 cycloalkyl" refers to a group having three to five or three to six carbon atoms respectively including a monocyclic or bicyclic carbocycle, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0016] The term "heterocycle" as used herein refers to a monocyclic or bicyclic, heterocyclic ring which is either saturated, unsaturated, or aromatic, and which contains from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. The term "C 5 heterocycle" as used herein refers to a 5-membered heterocycle.

[0017] The term "5- to 10-membered heteroaryl" refers to a monovalent, aromatic heterocyclic group having one or more heteroatoms, preferably one to three heteroatoms, selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom. The term "5- to 10-membered heteroaryl" encompasses an aromatic heterocyclic group condensed with an aromatic or non-aromatic carbocyclic ring or an aromatic or non-aromatic heterocyclic ring to form a bicyclic group, and also encompasses an aromatic carbocyclic group condensed with an aromatic or non-aromatic heterocyclic ring to form a bicyclic group. Binding to the heteroaryl may be via a heteroatom or via a carbon atom of the heteroaryl.

[0018] In some embodiments, the 5- to 10-membered heteroaryl is a 5-membered heteroaryl. The term "5-membered heteroaryl" refers to a monovalent, aromatic ring system having 5 ring atoms and which contains at least one heteroatom which may be identical or different, said heteroatom being oxygen, nitrogen or sulfur. 5-membered heteroaryls include but are not limited to oxazolyl, thiazolyl, thiadiazolyl, oxadiazolyl, triazolyl, pyrrolyl, thienyl, furanyl, diazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, and tetrazolyl. In one embodiment, the 5-membered heteroaryl is furanyl, such as furan-2-yl. In one embodiment, the 5-membered heteroaryl is thienyl, such as thien-2-yl or thien-3-yl. In one embodiment, the 5-membered heteroaryl is thiazolyl, such as thiazol-2-yl. In one embodiment, the 5-membered heteroaryl is oxazolyl, such as oxazol-2-yl.

[0019] In some embodiments, the 5- to 10-membered heteroaryl is a 6-membered heteroaryl. The term "6-membered heteroaryl" refers to a monovalent, aromatic ring system having 6 ring atoms and which contains at least one heteroatom which may be identical or different, said heteroatom being oxygen, nitrogen or sulfur. 6-membered heteroaryls include but are not limited to pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl.

[0020] In some embodiments, the 5- to 10-membered heteroaryl is a 8-membered heteroaryl. The term "8-membered heteroaryl" refers to a monovalent, aromatic ring system having 8 ring atoms and which contains at least one heteroatom which may be identical or different, said heteroatom being oxygen, nitrogen or sulfur. 8-membered heteroaryls include but are not limited to groups encompassing an aromatic heterocyclic group condensed with an aromatic or non-aromatic carbocyclic ring or an aromatic or non-aromatic heterocyclic ring to form a bicyclic group, and also groups encompassing an aromatic carbocyclic group condensed with an aromatic or non-aromatic heterocyclic ring to form a bicyclic group. 8-membered heteroaryls include but are not limited to 1,4-dihydropyrrolo[3,2-b]pyrrolyl, 1,6-dihydropyrrolo[2,3-b]pyrrolyl, 6H-furo[2,3-b]pyrrole, 4H-furo[2,3-b]pyrrolyl, 6H-thieno[2,3-b]pyrrolyl and 4H-thieno[2,3-b]pyrrolyl.

[0021] In some embodiments, the 5- to 10-membered heteroaryl is a 9-membered heteroaryl. The term "9-membered heteroaryl" refers to a monovalent, aromatic ring system having 9 ring atoms and which contains at least one heteroatom which may be identical or different, said heteroatom being oxygen, nitrogen or sulfur. 9-membered heteroaryls include but are not limited to groups encompassing an aromatic heterocyclic group condensed with an aromatic or non-aromatic carbocyclic ring or an aromatic or non-aromatic heterocyclic ring to form a bicyclic group, and also groups encompassing an aromatic carbocyclic group condensed with an aromatic or non-aromatic heterocyclic ring to form a bicyclic group. 9-membered heteroaryls include but are not limited to indolyl, isoindolyl, indolizinyl, indazolyl, benzimidazolyl, azaindolyl, azaindazolyl, pyrazolo[1,5-a]pyrimidinyl, purinyl, benzofuranyl, benzo[b]thiophenyl, benzisoxazolyl, benzthiazolyl, benzisothiazolyl, and benzo[c][1,2,5]thiadiazolyl.

[0022] In some embodiments, the 5- to 10-membered heteroaryl is a 10-membered heteroaryl. The term "10-membered heteroaryl" refers to a monovalent, aromatic ring system having 10 ring atoms and which contains at least one heteroatom which may be identical or different, said heteroatom being oxygen, nitrogen or sulfur. 10-membered heteroaryls include but are not limited to groups encompassing an aromatic heterocyclic group condensed with an aromatic or non-aromatic carbocyclic ring or an aromatic or non-aromatic heterocyclic ring to form a bicyclic group, and also groups encompassing an aromatic carbocyclic group condensed with an aromatic or non-aromatic heterocyclic ring to form a bicyclic group. 10-membered heteroaryls include but are not limited to quinolinyl, isoquinolinyl, 4H-quinolizinyl, quinoxalinyl, phthalazinyl, quinazolinyl, cinnolinyl, 1,8-naphthyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, pyrido[3,4-b]pyrazinyl, pyrido[2,3-b]pyrazinyl and pteridinyl.

[0023] The term "spiro compound" as used herein refers to a compound having one atom (usually a quaternary carbon) as the only common member of two rings.

[0024] The term "half-life" as used herein is the time it takes for the compound to lose one-half of its pharmacologic activity. The term "plasma half-life" is the time that it takes the compound to lose one-half of its pharmacologic activity in the blood plasma.

[0025] The term "treatment" refers to the combating of a disease or disorder. "Treatment" or "treating," as used herein, includes any desirable effect on the symptoms or pathology of a disease or condition as described herein, and may include even minimal changes or improvements in one or more measurable markers of the disease or condition being treated. "Treatment" or "treating" does not necessarily indicate complete eradication or cure of the disease or condition, or associated symptoms thereof. In some embodiments, the term "treatment" encompasses amelioration and prevention.

[0026] The term "amelioration" refers to moderation in the severity of the symptoms of a disease or condition. Improvement in a patient's condition, or the activity of making an effort to correct, or at least make more acceptable, conditions that are difficult to endure related to patient's conditions is considered "ameliorative" treatment.

[0027] The term "prevent" or "preventing" refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action.

[0028] The term "reversal" or "reversing" refers to the ability of a compound to restore nerve-stimulated force in skeletal muscle exposed either ex vivo or in vivo to a non-depolarizing neuromuscular blocking agent or another pharmaceutical that is able to depress neuromuscular transmission

[0029] The term "non-depolarizing blockers" refers to pharmaceutical agents that antagonize the activation of acetylcholine receptors at the post-synaptic muscle fibre membrane by blocking the acetylcholine binding site on the receptor. These agents are used to block neuromuscular transmission and induce muscle paralysis in connection with surgery.

[0030] The term "ester hydrolysing reagent" refers to a chemical reagent which is capable of converting an ester functional group to a carboxylic acid with elimination of the alcohol moiety of the original ester, including but not limited to acid, base, a fluoride source, PBr 3 , PCl 3 and lipase enzymes.

[0031] The term "total membrane conductance (Gm)" is the electrophysiological measure of the ability of ions to cross the muscle fibre surface membrane. It reflects the function of ion channels that are active in resting muscle fibres of which CIC-1 is known to contribute around 80 % in most animal species.Detailed description Compounds

[0032] It is within the scope of the present disclosure to provide a compound for use in treating, ameliorating and / or preventing neuromuscular disorders that reduce neuromuscular function. As disclosed herein, inhibition of CIC-1 improves or restores neuromuscular function. The compounds of the present disclosure comprise compounds capable of inhibiting the CIC-1 channel thereby improving or restoring neuromuscular function.

[0033] In one aspect, the disclosure concerns a compound of Formula (I): wherein: M is CR 5< R 6< , NR 7< , O or S; Q is CR 5< R 6< , NR 8< , O or S; T is CR 5< R 6< , NR 8< , O or S; X is absent, CR 5< R 6< , NR 8< , O or S; Z is CR 5< R 6< , NR 9< , O or S; two or more of M, Q, T, X and Z are NR 7< , NR 8< , NR 9< , O or S; R 1< is selected from the group consisting of H; F; Cl; Br; C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-3 alkenyl optionally substituted with one or more, identical or different, substituents R 10< ; -OC 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; -OC 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; - SC 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< and -SC 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 2< is selected from the group consisting of H; F; Cl; Br; C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< and OC 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 3< is selected from the group consisting of H, F and Cl; R 4< is selected from the group consisting of H; C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-5 alkenyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-5 alkynyl optionally substituted with one or more, identical or different, substituents R 10< ; C 3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; phenyl optionally substituted with one or more, identical or different, substituents R 11< ; and benzyl optionally substituted with one or more, identical or different, substituents R 11< ; R 5< is independently selected from the group consisting of H, deuterium, F and C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 6< is independently selected from the group consisting of H, deuterium, F and C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 7< is independently selected from the group consisting of H, C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with phenyl optionally substituted with one or more, identical or different, substituents R 11< ; C 1-3 alkyl substituted with C 5 heteroaryl optionally substituted with one or more, identical or different, substituents R 11< ; and C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 8< is independently selected from benzyl optionally substituted with one or more, identical or different, substituents R 11< ; R 9< is independently selected from the group consisting of H, C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with phenyl optionally substituted with one or more, identical or different, substituents R 11< ; C 1-3 alkyl substituted with naphthyl optionally substituted with one or more, identical or different, substituents R 11< ; C 1-3 alkyl substituted with a 5- to 10-membered heteroaryl optionally substituted with one or more, identical or different, substituents R 11< ; and C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 10< is independently selected from the group consisting of H, deuterium, F, Cl and -OC 1-3 alkyl; and R 11< is independently selected from the group consisting of deuterium, methoxy, -OCF 3 , Me, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CD 3 , cyclopropyl, NH 2 , -NHAc, -C(=O)-NH 2 , nitro, cyano, CI, Br, I, and F; when R 5< and R 6< are individually C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< , then R 5< and R 6< are optionally joined together to form a ring; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0034] In one aspect, the disclosure concerns a compound of Formula (I): wherein: M is CR 5< R 6< , NR 7< , O or S; Q is CR 5< R 6< , NR 8< , O or S; T is CR 5< R 6< , NR 8< , O or S; X is absent, CR 5< R 6< , NR 8< , O or S; Z is CR 5< R 6< , NR 9< , O or S; two or more of M, Q, T, X and Z are NR 7< , NR 8< , NR 9< , O or S; R 1< is selected from the group consisting of H; F; Cl; Br; C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-3 alkenyl optionally substituted with one or more, identical or different, substituents R 10< ; -OC 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; -OC 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; - SC 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< and -SC 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 2< is selected from the group consisting of H; F; Cl; Br; C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< and OC 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 3< is selected from the group consisting of H, F and Cl; R 4< is selected from the group consisting of H; C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-5 alkenyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-5 alkynyl optionally substituted with one or more, identical or different, substituents R 10< ; C 3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; phenyl optionally substituted with one or more, identical or different, substituents R 11< ; and benzyl optionally substituted with one or more, identical or different, substituents R 11< ; R 5< is independently selected from the group consisting of H, deuterium, F and C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 6< is independently selected from the group consisting of H, deuterium, F and C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 7< is independently selected from the group consisting of H, C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with phenyl optionally substituted with one or more, identical or different, substituents R 11< ; C 1-3 alkyl substituted with C 5 heterocycle optionally substituted with one or more, identical or different, substituents R 11< ; and C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 8< is independently selected from benzyl optionally substituted with one or more, identical or different, substituents R 11< ; R 9< is independently selected from the group consisting of H, C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with phenyl optionally substituted with one or more, identical or different, substituents R 11< ; C 1-3 alkyl substituted with C 5 heterocycle optionally substituted with one or more, identical or different, substituents R 11< ; and C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 10< is independently selected from the group consisting of H, deuterium, F, Cl and -OC 1-3 alkyl; and R 11< is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I, and F; when R 5< and R 6< are individually C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< , then R 5< and R 6< are optionally joined together to form a ring; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0035] In one embodiment, only one of M, Q, T, X and Z is O. In one embodiment, when M is O, Q and T are CH 2 , X is absent, Z is NH, R 1< is Cl, R 2< is H and R 3< is H then R 4< is not H. In one embodiment, the compound is not 6-chloro-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid.

[0036] In one aspect, the disclosure concerns a compound of Formula (I): wherein: M is CR 5< R 6< , NR 7< , O or S; Q is CR 5< R 6< , NR 8< , O or S; T is CR 5< R 6< , NR 8< , O or S; X is absent, CR 5< R 6< , NR 8< , O or S; Z is CR 5< R 6< , NR 9< , O or S; two or more of M, Q, T, X and Z are NR 7< , NR 8< , NR 9< , O or S; R 1< is selected from the group consisting of F; Cl; Br; C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-3 alkenyl optionally substituted with one or more, identical or different, substituents R 10< ; -OC 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; -OC 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; - SC 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< and -SC 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 2< is selected from the group consisting of H; F; Cl; Br; and C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 3< is selected from the group consisting of H, F and Cl; R 4< is selected from the group consisting of H; C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-5 alkenyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-5 alkynyl optionally substituted with one or more, identical or different, substituents R 10< ; C 3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; phenyl optionally substituted with one or more, identical or different, substituents R 11< ; and benzyl optionally substituted with one or more, identical or different, substituents R 11< ; R 5< is independently selected from the group consisting of H, deuterium, F and C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 6< is independently selected from the group consisting of H, deuterium, F and C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 7< is independently selected from the group consisting of H, C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with phenyl optionally substituted with one or more, identical or different, substituents R 11< ; C 1-3 alkyl substituted with C 5 heteroaryl optionally substituted with one or more, identical or different, substituents R 11< ; and C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 8< is independently selected from benzyl optionally substituted with one or more, identical or different, substituents R 11< ; R 9< is independently selected from the group consisting of H, C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with phenyl optionally substituted with one or more, identical or different, substituents R 11< ; C 1-3 alkyl substituted with naphthyl optionally substituted with one or more, identical or different, substituents R 11< ; C 1-3 alkyl substituted with a 5- to 10-membered heteroaryl optionally substituted with one or more, identical or different, substituents R 11< ; and C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 10< is independently selected from the group consisting of H, deuterium, F, Cl and -OC 1-3 alkyl; and R 11< is independently selected from the group consisting of deuterium, methoxy, -OCF 3 , Me, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CD 3 , cyclopropyl, NH 2 , -NHAc, -C(=O)-NH 2 , nitro, cyano, CI, Br, I, and F; when R 5< and R 6< are individually C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< , then R 5< and R 6< are optionally joined together to form a ring; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof provided that: only one of M, Q, T, X and Z is O; and when M is O, Q and T are CH 2 , X is absent, Z is NH, R 1< is Cl, R 2< is H and R 3< is H then R 4< is not H.

[0037] In one aspect, the disclosure concerns a compound of Formula (I): wherein: M is NR 7< , O or S; Q is CR 5< R 6< ; T is CR 5< R 6< ; X is absent or CR 5< R 6< ; Z is NR 9< , O or S; R 1< is selected from the group consisting of F; Cl; Br; C 1-3 alkyl optionally substituted with one or more, identical or different, substituents7 R 10< ; C 2-3 alkenyl optionally substituted with one or more, identical or different, substituents R 10< ; -OC 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; -OC 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; - SC 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< and -SC 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 2< is selected from the group consisting of H; F; Cl; Br; and C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 3< is selected from the group consisting of H, F and Cl; R 4< is selected from the group consisting of H; C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-5 alkenyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-5 alkynyl optionally substituted with one or more, identical or different, substituents R 10< ; C 3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; phenyl optionally substituted with one or more, identical or different, substituents R 11< ; and benzyl optionally substituted with one or more, identical or different, substituents R 11< ; R 5< is independently selected from the group consisting of H, deuterium, F and C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 6< is independently selected from the group consisting of H, deuterium, F and C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 7< is independently selected from the group consisting of H, C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with phenyl optionally substituted with one or more, identical or different, substituents R 11< ; C 1-3 alkyl substituted with C 5 heteroaryl optionally substituted with one or more, identical or different, substituents R 11< ; and C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 8< is independently selected from benzyl optionally substituted with one or more, identical or different, substituents R 11< ; R 9< is independently selected from the group consisting of H, C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with phenyl optionally substituted with one or more, identical or different, substituents R 11< ; C 1-3 alkyl substituted with naphthyl optionally substituted with one or more, identical or different, substituents R 11< ; C 1-3 alkyl substituted with a 5- to 10-membered heteroaryl optionally substituted with one or more, identical or different, substituents R 11< ; and C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 10< is independently selected from the group consisting of H, deuterium, F, Cl and -OC 1-3 alkyl; and R 11< is independently selected from the group consisting of deuterium, methoxy, -OCF 3 , Me, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CD 3 , cyclopropyl, NH 2 , -NHAc, -C(=O)-NH 2 , nitro, cyano, CI, Br, I, and F; when R 5< and R 6< are individually C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< , then R 5< and R 6< are optionally joined together to form a ring; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof provided that: only one of M, Q, T, X and Z is O; and when M is O, Q and T are CH 2 , X is absent, Z is NH, R 1< is Cl, R 2< is H and R 3< is H then R 4< is not H.

[0038] In one aspect, the disclosure concerns a compound of Formula (II): M is CR 5< R 6< , NR 7< , O or S; Q is CR 5< R 6< , NR 8< , O or S; T is CR 5< R 6< , NR 8< , O or S; Z is CR 5< R 6< , NR 9< , O or S; two or more of M, Q, T and Z are NR 7< , NR 8< , NR 9< , O or S; R 1< is selected from the group consisting of F; Cl; Br; C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-3 alkenyl optionally substituted with one or more, identical or different, substituents R 10< ; -OC 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; -OC 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; - SC 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< and -SC 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 2< is selected from the group consisting of H; F; Cl; Br; and C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 3< is selected from the group consisting of H, F and Cl; R 4< is selected from the group consisting of H; C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-5 alkenyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-5 alkynyl optionally substituted with one or more, identical or different, substituents R 10< ; C 3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; phenyl optionally substituted with one or more, identical or different, substituents R 11< ; and benzyl optionally substituted with one or more, identical or different, substituents R 11< ; R 5< is independently selected from the group consisting of H, deuterium, F and C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 6< is independently selected from the group consisting of H, deuterium, F and C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 7< is independently selected from the group consisting of H, C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with phenyl optionally substituted with one or more, identical or different, substituents R 11< ; C 1-3 alkyl substituted with C 5 heteroaryl optionally substituted with one or more, identical or different, substituents R 11< ; and C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 8< is independently selected from benzyl optionally substituted with one or more, identical or different, substituents R 11< ; R 9< is independently selected from the group consisting of H, C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with phenyl optionally substituted with one or more, identical or different, substituents R 11< ; C 1-3 alkyl substituted with naphthyl optionally substituted with one or more, identical or different, substituents R 11< ; C 1-3 alkyl substituted with a 5- to 10-membered heteroaryl optionally substituted with one or more, identical or different, substituents R 11< ; and C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 10< is independently selected from the group consisting of H, deuterium, F, Cl and -OC 1-3 alkyl; and R 11< is independently selected from the group consisting of deuterium, methoxy, -OCF 3 , Me, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CD 3 , cyclopropyl, NH 2 , -NHAc, -C(=O)-NH 2 , nitro, cyano, CI, Br, I, and F; when R 5< and R 6< are individually C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< , then R 5< and R 6< are optionally joined together to form a ring; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof provided that: only one of M, Q, T and Z is O; and when M is O, Q and T are CH 2 , Z is NH, R 1< is Cl, R 2< is H and R 3< is H then R 4< is not H.

[0039] In one aspect, the disclosure concerns a compound of Formula (II): M is NR 7< , O or S; Q is CR 5< R 6< ; T is CR 5< R 6< ; Z is NR 9< , O or S; R 1< is selected from the group consisting of F; Cl; Br; C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-3 alkenyl optionally substituted with one or more, identical or different, substituents R 10< ; -OC 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; -OC 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; - SC 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< and -SC 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 2< is selected from the group consisting of H; F; Cl; Br; and C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 3< is selected from the group consisting of H, F and Cl; R 4< is selected from the group consisting of H; C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-5 alkenyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-5 alkynyl optionally substituted with one or more, identical or different, substituents R 10< ; C 3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; phenyl optionally substituted with one or more, identical or different, substituents R 11< ; and benzyl optionally substituted with one or more, identical or different, substituents R 11< ; R 5< is independently selected from the group consisting of H, deuterium, F and C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 6< is independently selected from the group consisting of H, deuterium, F and C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 7< is independently selected from the group consisting of H, C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with phenyl optionally substituted with one or more, identical or different, substituents R 11< ; C 1-3 alkyl substituted with C 5 heteroaryl optionally substituted with one or more, identical or different, substituents R 11< ; and C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 8< is independently selected from benzyl optionally substituted with one or more, identical or different, substituents R 11< ; R 9< is independently selected from the group consisting of H, C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with phenyl optionally substituted with one or more, identical or different, substituents R 11< ; C 1-3 alkyl substituted with naphthyl optionally substituted with one or more, identical or different, substituents R 11< ; C 1-3 alkyl substituted with a 5- to 10-membered heteroaryl optionally substituted with one or more, identical or different, substituents R 11< ; and C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 10< is independently selected from the group consisting of H, deuterium, F, Cl and -OC 1-3 alkyl; and R 11< is independently selected from the group consisting of deuterium, methoxy, -OCF 3 , Me, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CD 3 , cyclopropyl, NH 2 , -NHAc, -C(=O)-NH 2 , nitro, cyano, CI, Br, I, and F; when R 5< and R 6< are individually C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< , then R 5< and R 6< are optionally joined together to form a ring; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof provided that: only one of M and Z is O; and when M is O, Q and T are CH 2 , Z is NH, R 1< is Cl, R 2< is H and R 3< is H then R 4< is not H.

[0040] In one aspect, the disclosure concerns a compound of Formula (I): M is CR 5< R 6< , NR 7< , O or S; Q is CR 5< R 6< , NR 8< , O or S; T is CR 5< R 6< , NR 8< , O or S; X is CR 5< R 6< , NR 8< , O or S; Z is CR 5< R 6< , NR 9< , O or S; two or more of M, Q, T, X and Z are NR 7< , NR 8< , NR 9< , O or S; R 1< is selected from the group consisting of F; Cl; Br; C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-3 alkenyl optionally substituted with one or more, identical or different, substituents R 10< ; -OC 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; -OC 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; - SC 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< and -SC 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 2< is selected from the group consisting of H; F; Cl; Br; and C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 3< is selected from the group consisting of H, F and Cl; R 4< is selected from the group consisting of H; C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-5 alkenyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-5 alkynyl optionally substituted with one or more, identical or different, substituents R 10< ; C 3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; phenyl optionally substituted with one or more, identical or different, substituents R 11< ; and benzyl optionally substituted with one or more, identical or different, substituents R 11< ; R 5< is independently selected from the group consisting of H, deuterium, F and C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 6< is independently selected from the group consisting of H, deuterium, F and C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 7< is independently selected from the group consisting of H, C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with phenyl optionally substituted with one or more, identical or different, substituents R 11< ; C 1-3 alkyl substituted with C 5 heteroaryl optionally substituted with one or more, identical or different, substituents R 11< ; and C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 8< is independently selected from benzyl optionally substituted with one or more, identical or different, substituents R 11< ; R 9< is independently selected from the group consisting of H, C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with phenyl optionally substituted with one or more, identical or different, substituents R 11< ; C 1-3 alkyl substituted with naphthyl optionally substituted with one or more, identical or different, substituents R 11< ; C 1-3 alkyl substituted with a 5- to 10-membered heteroaryl optionally substituted with one or more, identical or different, substituents R 11< ; and C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 10< is independently selected from the group consisting of H, deuterium, F, Cl and -OC 1-3 alkyl; and R 11< is independently selected from the group consisting of deuterium, methoxy, -OCF 3 , Me, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CD 3 , cyclopropyl, NH 2 , -NHAc, -C(=O)-NH 2 , nitro, cyano, CI, Br, I, and F; when R 5< and R 6< are individually C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< , then R 5< and R 6< are optionally joined together to form a ring; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof provided that: - - only one of M, Q, T, X and Z is O.

[0041] In one aspect, the disclosure concerns a compound of Formula (I): M is NR 7< , O or S; Q is CR 5< R 6< ; T is CR 5< R 6< ; X is absent, CR 5< R 6< ; Z is NR 9< , O or S; R 1< is selected from the group consisting of F; Cl; Br; C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-3 alkenyl optionally substituted with one or more, identical or different, substituents R 10< ; -OC 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; -OC 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; - SC 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< and -SC 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 2< is selected from the group consisting of H; F; Cl; Br; and C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 3< is selected from the group consisting of H, F and Cl; R 4< is selected from the group consisting of H; C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-5 alkenyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-5 alkynyl optionally substituted with one or more, identical or different, substituents R 10< ; C 3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; phenyl optionally substituted with one or more, identical or different, substituents R 11< ; and benzyl optionally substituted with one or more, identical or different, substituents R 11< ; R 5< is independently selected from the group consisting of H, deuterium, F and C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 6< is independently selected from the group consisting of H, deuterium, F and C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 7< is independently selected from the group consisting of H, C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with phenyl optionally substituted with one or more, identical or different, substituents R 11< ; C 1-3 alkyl substituted with C 5 heteroaryl optionally substituted with one or more, identical or different, substituents R 11< ; and C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 8< is independently selected from benzyl optionally substituted with one or more, identical or different, substituents R 11< ; R 9< is independently selected from the group consisting of H, C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with phenyl optionally substituted with one or more, identical or different, substituents R 11< ; C 1-3 alkyl substituted with naphthyl optionally substituted with one or more, identical or different, substituents R 11< ; C 1-3 alkyl substituted with a 5- to 10-membered heteroaryl optionally substituted with one or more, identical or different, substituents R 11< ; and C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 10< is independently selected from the group consisting of H, deuterium, F, Cl and -OC 1-3 alkyl; and R 11< is independently selected from the group consisting of deuterium, methoxy, -OCF 3 , Me, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CD 3 , cyclopropyl, NH 2 , -NHAc, -C(=O)-NH 2 , nitro, cyano, CI, Br, I, and F; when R 5< and R 6< are individually C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< , then R 5< and R 6< are optionally joined together to form a ring; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof provided that: only one of M and Z is O.

[0042] In one embodiment, M is CR 5< R 6< . In one embodiment, M is NR 7< . In one embodiment, M is O. In one embodiment, M is S.

[0043] In one embodiment, Q is CR 5< R 6< . In one embodiment, Q is C(H) 2 . In one embodiment, Q is NR 8< . In one embodiment, Q is O. In one embodiment, Q is S.

[0044] In one embodiment, T is CR 5< R 6< . In one embodiment, T is C(H) 2 . In one embodiment, T is C(H)(OMe). In one embodiment, T is C(CH 3 )(CH 3 ). In one embodiment, T is

[0045] In one embodiment, T is NR 8< . In one embodiment, T is O. In one embodiment, T is S.

[0046] In one embodiment, X is absent. In one embodiment, X is CR 5< R 6< . In one embodiment, X is C(H) 2 . In one embodiment, X is NR 8< . In one embodiment, X is O. In one embodiment, X is S.

[0047] In one embodiment, Z is CR 5< R 6< . In one embodiment, Z is NR 9< . In one embodiment, Z is O. In one embodiment, Z is S.

[0048] In one embodiment, M is NR 7< ; Q is CR 5< R 6< ; T is CR 5< R 6< ; X is absent; and Z is O. In one aspect, the disclosure concerns a compound of Formula (III): wherein: R 1< is selected from the group consisting of F; Cl; Br; C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-3 alkenyl optionally substituted with one or more, identical or different, substituents R 10< ; -OC 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; -OC 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; - SC 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< and -SC 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 2< is selected from the group consisting of H; F; Cl; Br; and C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 3< is selected from the group consisting of H, F and Cl; R 4< is selected from the group consisting of H; C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-5 alkenyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-5 alkynyl optionally substituted with one or more, identical or different, substituents R 10< ; C 3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; phenyl optionally substituted with one or more, identical or different, substituents R 11< ; and benzyl optionally substituted with one or more, identical or different, substituents R 11< ; R 5Q< and R 5T< are independently selected from the group consisting of H, deuterium, F and C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 6Q< and R 6T< are independently selected from the group consisting of H, deuterium, F and C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 7< is independently selected from the group consisting of H, C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with phenyl optionally substituted with one or more, identical or different, substituents R 11< ; C 1-3 alkyl substituted with C 5 heteroaryl optionally substituted with one or more, identical or different, substituents R 11< ; and C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 10< is independently selected from the group consisting of H, deuterium, F, Cl and -OC 1-3 alkyl; and R 11< is independently selected from the group consisting of deuterium, methoxy, -OCF 3 , Me, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CD 3 , cyclopropyl, NH 2 , -NHAc, -C(=O)-NH 2 , nitro, cyano, CI, Br, I, and F; when R 5< and R 6< are individually C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< , then R 5< and R 6< are optionally joined together to form a ring; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0049] In one embodiment, M is NR 7< ; Q is CR 5< R 6< ; T is CR 5< R 6< ; X is absent; and Z is S. In one aspect, the disclosure concerns a compound of Formula (IV): R 1< is selected from the group consisting of F; Cl; Br; C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-3 alkenyl optionally substituted with one or more, identical or different, substituents R 10< ; -OC 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; -OC 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; - SC 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< and -SC 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 2< is selected from the group consisting of H; F; Cl; Br; and C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 3< is selected from the group consisting of H, F and Cl; R 4< is selected from the group consisting of H; C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-5 alkenyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-5 alkynyl optionally substituted with one or more, identical or different, substituents R 10< ; C 3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; phenyl optionally substituted with one or more, identical or different, substituents R 11< ; and benzyl optionally substituted with one or more, identical or different, substituents R 11< ; R 5Q< and R 5T< are independently selected from the group consisting of H, deuterium, F and C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 6Q< and R 6T< are independently selected from the group consisting of H, deuterium, F and C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 7< is independently selected from the group consisting of H, C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with phenyl optionally substituted with one or more, identical or different, substituents R 11< ; C 1-3 alkyl substituted with C 5 heteroaryl optionally substituted with one or more, identical or different, substituents R 11< ; and C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 10< is independently selected from the group consisting of H, deuterium, F, Cl and -OC 1-3 alkyl; and R 11< is independently selected from the group consisting of deuterium, methoxy, -OCF 3 , Me, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CD 3 , cyclopropyl, NH 2 , -NHAc, -C(=O)-NH 2 , nitro, cyano, CI, Br, I, and F; when R 5Q< and R 6Q< are individually C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< , then R 5Q< and R 6Q< are optionally joined together to form a ring; or when R 5T< and R 6T< are individually C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< , then R 5T< and R 6T< are optionally joined together to form a ring; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0050] In one embodiment, M is NR 7< ; Q is CR 5< R 6< ; T is CR 5< R 6< ; X is absent; and Z is NR 9< . In one aspect, the disclosure concerns a compound of Formula (V): wherein: R 1< is selected from the group consisting of F; Cl; Br; C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-3 alkenyl optionally substituted with one or more, identical or different, substituents R 10< ; -OC 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; -OC 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; - SC 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< and -SC 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 2< is selected from the group consisting of H; F; Cl; Br; and C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 3< is selected from the group consisting of H, F and Cl; R 4< is selected from the group consisting of H; C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-5 alkenyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-5 alkynyl optionally substituted with one or more, identical or different, substituents R 10< ; C 3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; phenyl optionally substituted with one or more, identical or different, substituents R 11< ; and benzyl optionally substituted with one or more, identical or different, substituents R 11< ; R 5Q< and R 5T< are independently selected from the group consisting of H, deuterium, F and C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 6Q< and R 6T< are independently selected from the group consisting of H, deuterium, F and C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 7< is independently selected from the group consisting of H, C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with phenyl optionally substituted with one or more, identical or different, substituents R 11< ; C 1-3 alkyl substituted with C 5 heteroaryl optionally substituted with one or more, identical or different, substituents R 11< ; and C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 9< is independently selected from the group consisting of H, C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with phenyl optionally substituted with one or more, identical or different, substituents R 11< ; C 1-3 alkyl substituted with naphthyl optionally substituted with one or more, identical or different, substituents R 11< ; C 1-3 alkyl substituted with a 5- to 10-membered heteroaryl optionally substituted with one or more, identical or different, substituents R 11< ; and C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 10< is independently selected from the group consisting of H, deuterium, F, Cl and -OC 1-3 alkyl; and R 11< is independently selected from the group consisting of deuterium, methoxy, -OCF 3 , Me, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CD 3 , cyclopropyl, NH 2 , -NHAc, -C(=O)-NH 2 , nitro, cyano, CI, Br, I, and F; when R 5Q< and R 6Q< are individually C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< , then R 5Q< and R 6Q< are optionally joined together to form a ring; or when R 5T< and R 6T< are individually C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< , then R 5T< and R 6T< are optionally joined together to form a ring; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0051] In one embodiment, M is O; Q is CR 5< R 6< ; T is CR 5< R 6< ; X is absent; and Z is NR 9< . In one aspect, the disclosure concerns a compound of Formula (VI): R 1< is selected from the group consisting of F; Cl; Br; C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-3 alkenyl optionally substituted with one or more, identical or different, substituents R 10< ; -OC 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; -OC 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; - SC 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< and -SC 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 2< is selected from the group consisting of H; F; Cl; Br; and C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 3< is selected from the group consisting of H, F and Cl; R 4< is selected from the group consisting of H; C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-5 alkenyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-5 alkynyl optionally substituted with one or more, identical or different, substituents R 10< ; C 3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; phenyl optionally substituted with one or more, identical or different, substituents R 11< ; and benzyl optionally substituted with one or more, identical or different, substituents R 11< ; R 5Q< and R 5T< are independently selected from the group consisting of H, deuterium, F and C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 6Q< and R 6T< are independently selected from the group consisting of H, deuterium, F and C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 9< is independently selected from the group consisting of H, C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with phenyl optionally substituted with one or more, identical or different, substituents R 11< ; C 1-3 alkyl substituted with naphthyl optionally substituted with one or more, identical or different, substituents R 11< ; C 1-3 alkyl substituted with a 5- to 10-membered heteroaryl optionally substituted with one or more, identical or different, substituents R 11< ; and C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 10< is independently selected from the group consisting of H, deuterium, F, Cl and -OC 1-3 alkyl; and R 11< is independently selected from the group consisting of deuterium, methoxy, -OCF 3 , Me, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CD 3 , cyclopropyl, NH 2 , -NHAc, -C(=O)-NH 2 , nitro, cyano, CI, Br, I, and F; when R 5Q< and R 6Q< are individually C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< , then R 5Q< and R 6Q< are optionally joined together to form a ring; or when R 5T< and R 6T< are individually C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< , then R 5T< and R 6T< are optionally joined together to form a ring; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof provided that: when R 1< is Cl, R 2< , R 3< , R 5Q< , R 5T< , R 6Q< , R 6T< and R 9< are H then R 4< is not H.

[0052] In one embodiment, M is NR 7< ; Q is CR 5< R 6< ; T is CR 5< R 6< ; X is CR 5< R 6< ; and Z is O. In one aspect, the disclosure concerns a compound of Formula (VII): wherein: R 1< is selected from the group consisting of F; Cl; Br; C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-3 alkenyl optionally substituted with one or more, identical or different, substituents R 10< ; -OC 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; -OC 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; - SC 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< and -SC 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 2< is selected from the group consisting of H; F; Cl; Br; and C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 3< is selected from the group consisting of H, F and Cl; R 4< is selected from the group consisting of H; C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-5 alkenyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-5 alkynyl optionally substituted with one or more, identical or different, substituents R 10< ; C 3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; phenyl optionally substituted with one or more, identical or different, substituents R 11< ; and benzyl optionally substituted with one or more, identical or different, substituents R 11< ; R 5Q< , R 5T< and R 5X< are independently selected from the group consisting of H, deuterium, F and C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 6Q< , R 6T< and R 6X< are independently selected from the group consisting of H, deuterium, F and C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 7< is independently selected from the group consisting of H, C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with phenyl optionally substituted with one or more, identical or different, substituents R 11< ; C 1-3 alkyl substituted with C 5 heteroaryl optionally substituted with one or more, identical or different, substituents R 11< ; and C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 10< is independently selected from the group consisting of H, deuterium, F, Cl and -OC 1-3 alkyl; and R 11< is independently selected from the group consisting of deuterium, methoxy, -OCF 3 , Me, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CD 3 , cyclopropyl, NH 2 , -NHAc, -C(=O)-NH 2 , nitro, cyano, CI, Br, I, and F; when R 5Q< and R 6Q< are individually C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< , then R 5Q< and R 6Q< are optionally joined together to form a ring; or when R 5T< and R 6T< are individually C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< , then R 5T< and R 6T< are optionally joined together to form a ring; or when R 5X< and R 6X< are individually C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< , then R 5X< and R 6X< are optionally joined together to form a ring; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0053] In one embodiment, M is S; Q is CR 5< R 6< ; T is CR 5< R 6< ; X is absent; and Z is NR 9< . In one aspect, the disclosure concerns a compound of Formula (VIII): wherein: R 1< is selected from the group consisting of F; Cl; Br; C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-3 alkenyl optionally substituted with one or more, identical or different, substituents R 10< ; -OC 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; -OC 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; - SC 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< and -SC 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 2< is selected from the group consisting of H; F; Cl; Br; and C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 3< is selected from the group consisting of H, F and Cl; R 4< is selected from the group consisting of H; C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-5 alkenyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-5 alkynyl optionally substituted with one or more, identical or different, substituents R 10< ; C 3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; phenyl optionally substituted with one or more, identical or different, substituents R 11< ; and benzyl optionally substituted with one or more, identical or different, substituents R 11< ; R 5Q< and R 5T< are independently selected from the group consisting of H, deuterium, F and C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 6Q< and R 6T< are independently selected from the group consisting of H, deuterium, F and C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 9< is independently selected from the group consisting of H, C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with phenyl optionally substituted with one or more, identical or different, substituents R 11< ; C 1-3 alkyl substituted with naphthyl optionally substituted with one or more, identical or different, substituents R 11< ; C 1-3 alkyl substituted with a 5- to 10-membered heteroaryl optionally substituted with one or more, identical or different, substituents R 11< ; and C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 10< is independently selected from the group consisting of H, deuterium, F, Cl and -OC 1-3 alkyl; and R 11< is independently selected from the group consisting of deuterium, methoxy, -OCF 3 , Me, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CD 3 , cyclopropyl, NH 2 , -NHAc, -C(=O)-NH 2 , nitro, cyano, CI, Br, I, and F; when R 5Q< and R 6Q< are individually C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< , then R 5Q< and R 6Q< are optionally joined together to form a ring; or when R 5T< and R 6T< are individually C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< , then R 5T< and R 6T< are optionally joined together to form a ring; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0054] In one embodiment, M is S; Q is CR 5< R 6< ; T is CR 5< R 6< ; X is absent; and Z is S. In one aspect, the disclosure concerns a compound of Formula (IX): wherein: R 1< is selected from the group consisting of F; Cl; Br; C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-3 alkenyl optionally substituted with one or more, identical or different, substituents R 10< ; -OC 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; -OC 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; - SC 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< and -SC 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 2< is selected from the group consisting of H; F; Cl; Br; and C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 3< is selected from the group consisting of H, F and Cl; R 4< is selected from the group consisting of H; C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-5 alkenyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-5 alkynyl optionally substituted with one or more, identical or different, substituents R 10< ; C 3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; phenyl optionally substituted with one or more, identical or different, substituents R 11< ; and benzyl optionally substituted with one or more, identical or different, substituents R 11< ; R 5Q< and R 5T< are independently selected from the group consisting of H, deuterium, F and C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 6Q< and R 6T< are independently selected from the group consisting of H, deuterium, F and C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 10< is independently selected from the group consisting of H, deuterium, F, Cl and -OC 1-3 alkyl; and R 11< is independently selected from the group consisting of deuterium, methoxy, -OCF 3 , Me, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CD 3 , cyclopropyl, NH 2 , -NHAc, -C(=O)-NH 2 , nitro, cyano, Cl, Br, I, and F; when R 5Q< and R 6Q< are individually C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< , then R 5Q< and R 6Q< are optionally joined together to form a ring; or when R 5T< and R 6T< are individually C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< , then R 5T< and R 6T< are optionally joined together to form a ring; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0055] In one embodiment, M is NR 7< ; Q is CR 5< R 6< ; T is CR 5< R 6< ; X is CR 5< R 6< ; and Z is S. In one aspect, the disclosure concerns a compound of Formula (X): wherein: R 1< is selected from the group consisting of F; Cl; Br; C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-3 alkenyl optionally substituted with one or more, identical or different, substituents R 10< ; -OC 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; -OC 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; - SC 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< and -SC 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 2< is selected from the group consisting of H; F; Cl; Br; and C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 3< is selected from the group consisting of H, F and Cl; R 4< is selected from the group consisting of H; C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-5 alkenyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-5 alkynyl optionally substituted with one or more, identical or different, substituents R 10< ; C 3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; phenyl optionally substituted with one or more, identical or different, substituents R 11< ; and benzyl optionally substituted with one or more, identical or different, substituents R 11< ; R 5Q< , R 5T< and R 5X< are independently selected from the group consisting of H, deuterium, F and C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 6Q< , R 6T< and R 6X< are independently selected from the group consisting of H, deuterium, F and C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 7< is independently selected from the group consisting of H, C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with phenyl optionally substituted with one or more, identical or different, substituents R 11< ; C 1-3 alkyl substituted with C 5 heteroaryl optionally substituted with one or more, identical or different, substituents R 11< ; and C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 10< is independently selected from the group consisting of H, deuterium, F, Cl and -OC 1-3 alkyl; and R 11< is independently selected from the group consisting of deuterium, methoxy, -OCF 3 , Me, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CD 3 , cyclopropyl, NH 2 , -NHAc, -C(=O)-NH 2 , nitro, cyano, CI, Br, I, and F; when R 5Q< and R 6Q< are individually C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< , then R 5Q< and R 6Q< are optionally joined together to form a ring; or when R 5T< and R 6T< are individually C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< , then R 5T< and R 6T< are optionally joined together to form a ring; or when R 5X< and R 6X< are individually C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< , then R 5X< and R 6X< are optionally joined together to form a ring; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0056] In one embodiment, M is NR 7< ; Q is CR 5< R 6< ; T is CR 5< R 6< ; X is CR 5< R 6< ; and Z is NR 9< . In one aspect, the disclosure concerns a compound of Formula (XI): wherein: R 1< is selected from the group consisting of F; Cl; Br; C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-3 alkenyl optionally substituted with one or more, identical or different, substituents R 10< ; -OC 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; -OC 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; - SC 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< and -SC 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 2< is selected from the group consisting of H; F; Cl; Br; and C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 3< is selected from the group consisting of H, F and Cl; R 4< is selected from the group consisting of H; C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-5 alkenyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-5 alkynyl optionally substituted with one or more, identical or different, substituents R 10< ; C 3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; phenyl optionally substituted with one or more, identical or different, substituents R 11< ; and benzyl optionally substituted with one or more, identical or different, substituents R 11< ; R 5Q< , R 5T< and R 5X< are independently selected from the group consisting of H, deuterium, F and C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 6Q< , R 6T< and R 6X< are independently selected from the group consisting of H, deuterium, F and C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 7< is independently selected from the group consisting of H, C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with phenyl optionally substituted with one or more, identical or different, substituents R 11< ; C 1-3 alkyl substituted with C 5 heteroaryl optionally substituted with one or more, identical or different, substituents R 11< ; and C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 9< is independently selected from the group consisting of H, C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with phenyl optionally substituted with one or more, identical or different, substituents R 11< ; C 1-3 alkyl substituted with naphthyl optionally substituted with one or more, identical or different, substituents R 11< ; C 1-3 alkyl substituted with a 5- to 10-membered heteroaryl optionally substituted with one or more, identical or different, substituents R 11< ; and C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 10< is independently selected from the group consisting of H, deuterium, F, Cl and -OC 1-3 alkyl; and R 11< is independently selected from the group consisting of deuterium, methoxy, -OCF 3 , Me, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CD 3 , cyclopropyl, NH 2 , -NHAc, -C(=O)-NH 2 , nitro, cyano, CI, Br, I, and F; when R 5Q< and R 6Q< are individually C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< , then R 5< ° and R 6Q< are optionally joined together to form a ring; or when R 5T< and R 6T< are individually C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< , then R 5T< and R 6T< are optionally joined together to form a ring; or when R 5X< and R 6X< are individually C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< , then R 5X< and R 6X< are optionally joined together to form a ring; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0057] In one embodiment, M is O; Q is CR 5< R 6< ; T is CR 5< R 6< ; X is CR 5< R 6< ; and Z is NR 9< . In one aspect, the disclosure concerns a compound of Formula (XII): wherein: R 1< is selected from the group consisting of F; Cl; Br; C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-3 alkenyl optionally substituted with one or more, identical or different, substituents R 10< ; -OC 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; -OC 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; - SC 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< and -SC 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 2< is selected from the group consisting of H; F; Cl; Br; and C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 3< is selected from the group consisting of H, F and Cl; R 4< is selected from the group consisting of H; C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-5 alkenyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-5 alkynyl optionally substituted with one or more, identical or different, substituents R 10< ; C 3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; phenyl optionally substituted with one or more, identical or different, substituents R 11< ; and benzyl optionally substituted with one or more, identical or different, substituents R 11< ; R 5Q< , R 5T< and R 5X< are independently selected from the group consisting of H, deuterium, F and C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 6Q< , R 6T< and R 6X< are independently selected from the group consisting of H, deuterium, F and C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 9< is independently selected from the group consisting of H, C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with phenyl optionally substituted with one or more, identical or different, substituents R 11< ; C 1-3 alkyl substituted with naphthyl optionally substituted with one or more, identical or different, substituents R 11< ; C 1-3 alkyl substituted with a 5- to 10-membered heteroaryl optionally substituted with one or more, identical or different, substituents R 11< ; and C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 10< is independently selected from the group consisting of H, deuterium, F, Cl and -OC 1-3 alkyl; and R 11< is independently selected from the group consisting of deuterium, methoxy, -OCF 3 , Me, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CD 3 , cyclopropyl, NH 2 , -NHAc, -C(=O)-NH 2 , nitro, cyano, CI, Br, I, and F; when R 5Q< and R 6Q< are individually C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< , then R 5Q< and R 6Q< are optionally joined together to form a ring; or when R 5T< and R 6T< are individually C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< , then R 5T< and R 6T< are optionally joined together to form a ring; or when R 5X< and R 6X< are individually C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< , then R 5X< and R 6X< are optionally joined together to form a ring; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0058] In one embodiment, M is S; Q is CR 5< R 6< ; T is CR 5< R 6< ; X is CR 5< R 6< ; and Z is NR 9< . In one aspect, the disclosure concerns a compound of Formula (XIII): wherein: R 1< is selected from the group consisting of F; Cl; Br; C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-3 alkenyl optionally substituted with one or more, identical or different, substituents R 10< ; -OC 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; -OC 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; - SC 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< and -SC 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 2< is selected from the group consisting of H; F; Cl; Br; and C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 3< is selected from the group consisting of H, F and Cl; R 4< is selected from the group consisting of H; C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-5 alkenyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-5 alkynyl optionally substituted with one or more, identical or different, substituents R 10< ; C 3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; phenyl optionally substituted with one or more, identical or different, substituents R 11< ; and benzyl optionally substituted with one or more, identical or different, substituents R 11< ; R 5Q< , R 5T< and R 5X< are independently selected from the group consisting of H, deuterium, F and C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 6Q< , R 6T< and R 6X< are independently selected from the group consisting of H, deuterium, F and C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 9< is independently selected from the group consisting of H, C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with phenyl optionally substituted with one or more, identical or different, substituents R 11< ; C 1-3 alkyl substituted with naphthyl optionally substituted with one or more, identical or different, substituents R 11< ; C 1-3 alkyl substituted with a 5- to 10-membered heteroaryl optionally substituted with one or more, identical or different, substituents R 11< ; and C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 10< is independently selected from the group consisting of H, deuterium, F, Cl and -OC 1-3 alkyl; and R 11< is independently selected from the group consisting of deuterium, methoxy, -OCF 3 , Me, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CD 3 , cyclopropyl, NH 2 , -NHAc, -C(=O)-NH 2 , nitro, cyano, CI, Br, I, and F; when R 5Q< and R 6Q< are individually C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< , then R 5Q< and R 6Q< are optionally joined together to form a ring; or when R 5T< and R 6T< are individually C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< , then R 5T< and R 6T< are optionally joined together to form a ring; or when R 5X< and R 6X< are individually C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< , then R 5X< and R 6X< are optionally joined together to form a ring; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0059] In one embodiment, M is CR 5< R 6< ; Q is NR 8Q< ; T is CR 5< R 6< ; X is CR 5< R 6< ; and Z is O. In one aspect, the disclosure concerns a compound of Formula (XIV): wherein: R 1< is selected from the group consisting of F; Cl; Br; C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-3 alkenyl optionally substituted with one or more, identical or different, substituents R 10< ; -OC 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; -OC 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; - SC 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< and -SC 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 2< is selected from the group consisting of H; F; Cl; Br; and C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 3< is selected from the group consisting of H, F and Cl; R 4< is selected from the group consisting of H; C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-5 alkenyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-5 alkynyl optionally substituted with one or more, identical or different, substituents R 10< ; C 3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; phenyl optionally substituted with one or more, identical or different, substituents R 11< ; and benzyl optionally substituted with one or more, identical or different, substituents R 11< ; R 5M< , R 5T< and R 5X< are independently selected from the group consisting of H, deuterium, F and C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 6M< , R 6T< and R 6X< are independently selected from the group consisting of H, deuterium, F and C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 8Q< is independently selected from benzyl optionally substituted with one or more, identical or different, substituents R 11< ; R 10< is independently selected from the group consisting of H, deuterium, F, Cl and -OC 1-3 alkyl; and R 11< is independently selected from the group consisting of deuterium, methoxy, -OCF 3 , Me, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CD 3 , cyclopropyl, NH 2 , -NHAc, -C(=O)-NH 2 , nitro, cyano, CI, Br, I, and F; when R 5M< and R 6M< are individually C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< , then R 5M< and R 6M< are optionally joined together to form a ring; or when R 5T< and R 6T< are individually C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< , then R 5T< and R 6T< are optionally joined together to form a ring; or when R 5X< and R 6X< are individually C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< , then R 5X< and R 6X< are optionally joined together to form a ring; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0060] In one embodiment, M is O; Q is CR 5< R 6< ; T is CR 5< R 6< ; X is NR 8X< ; and Z is CR 5< R 6< . In one aspect, the disclosure concerns a compound of Formula (XV): wherein: R 1< is selected from the group consisting of F; Cl; Br; C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-3 alkenyl optionally substituted with one or more, identical or different, substituents R 10< ; -OC 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; -OC 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; - SC 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< and -SC 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 2< is selected from the group consisting of H; F; Cl; Br; and C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 3< is selected from the group consisting of H, F and Cl; R 4< is selected from the group consisting of H; C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-5 alkenyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-5 alkynyl optionally substituted with one or more, identical or different, substituents R 10< ; C 3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; phenyl optionally substituted with one or more, identical or different, substituents R 11< ; and benzyl optionally substituted with one or more, identical or different, substituents R 11< ; R 5Q< , R 5T< and R 5Z< are independently selected from the group consisting of H, deuterium, F and C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 6Q< , R 6T< and R 6Z< are independently selected from the group consisting of H, deuterium, F and C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 8X< is independently selected from benzyl optionally substituted with one or more, identical or different, substituents R 11< ; R 10< is independently selected from the group consisting of H, deuterium, F, Cl and -OC 1-3 alkyl; and R 11< is independently selected from the group consisting of deuterium, methoxy, -OCF 3 , Me, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CD 3 , cyclopropyl, NH 2 , -NHAc, -C(=O)-NH 2 , nitro, cyano, CI, Br, I, and F; when R 50< and R 6Q< are individually C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< , then R 5Q< and R 6Q< are optionally joined together to form a ring; or when R 5T< and R 6T< are individually C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< , then R 5T< and R 6T< are optionally joined together to form a ring; or when R 5Z< and R 6Z< are individually C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< , then R 5Z< and R 6Z< are optionally joined together to form a ring; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

[0061] In one embodiment, R 5M< is R 5< . In one embodiment, R 50< is R 5< . In one embodiment, R 5T< is R 5< . In one embodiment, R 5X< is R 5< . In one embodiment, R 5Z< is R 5< . In one embodiment, R 6M< is R 6< . In one embodiment, R 6Q< is R 6< . In one embodiment, R 6T< is R 6< . In one embodiment, R 6X< is R 6< . In one embodiment, R 6Z< is R 6< . In one embodiment, R 8Q< is R 8< . In one embodiment, R 8X< is R 8< .

[0062] In one embodiment, R' is F. In one embodiment, R 1< is Cl. In one embodiment, R 1< is Br. In one embodiment, R 1< is C 1-3 alkyl such as Me or Et. In one embodiment, R 1< is C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< , wherein R 10< is independently selected from the group consisting of deuterium, F, Cl and -OC 1-3 alkyl. In one embodiment, R 1< is C 2-3 alkenyl. In one embodiment, R 1< is C 2-3 alkenyl optionally substituted with one or more, identical or different, substituents R 10< , wherein R 10< is independently selected from the group consisting of deuterium, F, Cl and -OC 1-3 alkyl. In one embodiment, R 1< is -OC 1-3 alkyl, such as OMe, OEt or OiPr. In one embodiment, R 1< is -OC 1-3 alkyl, such as OMe. In one embodiment, R 1< is -OC 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< , wherein R 10< is independently selected from the group consisting of deuterium, F, Cl and -OC 1-3 alkyl. In one embodiment, R 1< is -OC 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R'°, wherein R 10< is independently selected from the group consisting of deuterium, F, Cl and -OC 1-3 alkyl. In one embodiment, R 1< is -SC 1-3 alkyl, such as SMe. In one embodiment, R 1< is -SC 1-3 alkyl optionally substituted with one or more, identical or different, substituents R'°, wherein R 10< is independently selected from the group consisting of deuterium, F, Cl and -OC 1-3 alkyl. In one embodiment, R 1< is -SC 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< , wherein R 10< is independently selected from the group consisting of deuterium, F, Cl and -OC 1-3 alkyl. In one embodiment, R 1< is selected from the group consisting of F, Cl, Me, OMe, OEt, OCHMe 2 and SMe. In one embodiment, R 1< is selected from the group consisting of F, Cl and OMe.

[0063] In one embodiment, R 2< is H. In one embodiment, R 2< is F. In one embodiment, R 2< is CI. In one embodiment, R 2< is Br. In one embodiment, R 2< is C 1-3 alkyl, such as Me. In one embodiment, R 2< is C 1-3 alkyl substituted with one or more, identical or different substituents R'°, wherein R 10< is independently selected from the group consisting of deuterium, F, Cl and -OC 1-3 alkyl. In one embodiment, R 2< is selected from the group consisting of H, F, Cl and Me. In one embodiment, R 2< is selected from the group consisting of F and CI.

[0064] In one embodiment, R 1< is OMe and R 2< is F or Cl. In one embodiment, R 1< is F and R 2< is Cl.

[0065] In one embodiment, R 3< is H. In one embodiment, R 3< is F. In one embodiment, R 3< is CI.

[0066] In one embodiment, R 4< is H. In one embodiment, R 4< is C 1-5 alkyl. In one embodiment, R 4< is C 1-5 alkyl substituted with one or more, identical or different substituents R 10< , wherein R 10< is independently selected from the group consisting of deuterium, F, Cl and -OC 1-3 alkyl. In one embodiment, R 4< is C 2-5 alkenyl. In one embodiment, R 4< is C 2-5 alkenyl substituted with one or more, identical or different substituents R 10< , wherein R 10< is independently selected from the group consisting of deuterium, F, Cl and -OC 1-3 alkyl. In one embodiment, R 4< is C 2-5 alkynyl. In one embodiment, R 4< is C 2-5 alkynyl substituted with one or more, identical or different substituents R'°, wherein R 10< is independently selected from the group consisting of deuterium, F, Cl and -OC 1-3 alkyl. In one embodiment, R 4< is C 3-6 cycloalkyl. In one embodiment, R 4< is C 3-6 cycloalkyl substituted with one or more, identical or different substituents R'°, wherein R 10< is independently selected from the group consisting of deuterium, F, Cl and -OC 1-3 alkyl. In one embodiment, R 4< is phenyl. In one embodiment, R 4< is phenyl substituted with one or more, identical or different substituents R 11< , wherein R 11< is independently selected from the group consisting of deuterium, methoxy, -OCF 3 , Me, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CD 3 , cyclopropyl, NH 2 , -NHAc, -C(=O)-NH 2 , nitro, cyano, Cl, Br, I, and F. In one embodiment, R 4< is benzyl. In one embodiment, R 4< is benzyl substituted with one or more, identical or different substituents R 11< , wherein R 11< is independently selected from the group consisting of deuterium, methoxy, -OCF 3 , Me, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CD 3 , cyclopropyl, NH 2 , -NHAc, -C(=O)-NH 2 , nitro, cyano, CI, Br, I, and F.

[0067] In one embodiment, R 5< is H. In one embodiment, R 5< is deuterium. In one embodiment, R 5< is F. In one embodiment, R 5< is C 1-5 alkyl, such as Me, Et or "Pr. In one embodiment, R 5< is C 1-5 alkyl substituted with one or more, identical or different, substituents R 10< , wherein R 10< is independently selected from the group consisting of deuterium, F, Cl and -OC 1-3 alkyl.

[0068] In one embodiment, R 6< is H. In one embodiment, R 6< is deuterium. In one embodiment, R 6< is F. In one embodiment, R 6< is C 1-5 alkyl, such as Me, Et or "Pr. In one embodiment, R 6< is C 1-5 alkyl substituted with one or more, identical or different, substituents R 10< , wherein R 10< is independently selected from the group consisting of deuterium, F, Cl and -OC 1-3 alkyl.

[0069] In one embodiment, R 5< is C 1-5 alkyl substituted with one or more, identical or different, substituents R'°, and R 6< is C 1-5 alkyl substituted with one or more, identical or different, substituents R 10< , and R 5< and R 6< are joined together to form a ring. When R 5< and R 6< are joined together to form a ring, R 5< and R 6< are C 1-5 alkanediyls, substituted with one or more, identical or different, substituents R 10< .

[0070] In one embodiment, R 5< is C 1 alkyl substituted with one or more, identical or different, substituents R'°, and R 6< is C 1 alkyl substituted with one or more, identical or different, substituents R 10< , and R 5< and R 6< are joined together to form a ring. In one embodiment, -R 5< -R 6< - is -C(R 10< ) 2 C(R 10< ) 2 -, such as -CH 2 CH 2 -.

[0071] In one embodiment, R 5< is C 2 alkyl substituted with one or more, identical or different, substituents R'°, and R 6< is C 1 alkyl substituted with one or more, identical or different, substituents R 10< , and R 5< and R 6< are joined together to form a ring. In one embodiment, -R 5< -R 6< - is -C(R 10< ) 2 C(R 10< ) 2 C(R 10< ) 2 -, such as -CH 2 CH 2 CH 2 -.

[0072] In one embodiment, R 5< is C 2 alkyl substituted with one or more, identical or different, substituents R'°, and R 6< is C 2 alkyl substituted with one or more, identical or different, substituents R 10< , and R 5< and R 6< are joined together to form a ring. In one embodiment, -R 5< -R 6< - is -C(R 10< ) 2 C(R 10< ) 2 C(R 10< ) 2 C(R 10< ) 2 -, such as -CH 2 CH 2 CH 2 CH 2 -.

[0073] In one embodiment, R 5< and R 6< are bound to the same carbon atom and joined together to form a ring, thus forming a spirocyclic ring of Formula (XVI):

[0074] In one embodiment, M is CR 5< R 6< wherein said R 5< and R 6< are joined together to form a spriocyclic ring, and -R 5< -R 6< - is -C(R 10< ) 2 C(R 10< ) 2 -, such as -CH 2 CH 2 -, -C(R 10< ) 2 C(R 10< ) 2 C(R 10< ) 2 -, such as -CH 2 CH 2 CH 2 -, or -C(R 10< ) 2 C(R 10< ) 2 C(R 10< ) 2 C(R 10< ) 2 -, such as -CH 2 CH 2 CH 2 CH 2 -.

[0075] In one embodiment, R 5M< and R 6M< are joined together to form a spriocyclic ring, and - R 5m< -R 6M< - is -C(R 10< ) 2 C(R 10< ) 2 -, such as -CH 2 CH 2 -. In one embodiment, R 5M< and R 6M< are joined together to form a spriocyclic ring, and -R 5M< -R 6M< - is -C(R 10< ) 2 C(R 10< ) 2 C(R 10< ) 2 -, such as -CH 2 CH 2 CH 2 -. In one embodiment, R 5M< and R 6M< are joined together to form a spriocyclic ring, and -R 5m< -R 6M< - is -C(R 10< ) 2 C(R 10< ) 2 C(R 10< ) 2 C(R 10< ) 2 -, such as -CH 2 CH 2 CH 2 CH 2 -.

[0076] In one embodiment, Q is CR 5< R 6< wherein said R 5< and R 6< are joined together to form a spriocyclic ring, and -R 5< -R 6< - is -C(R 10< ) 2 C(R 10< ) 2 -, such as -CH 2 CH 2 -, -C(R 10< ) 2 C(R 10< ) 2 C(R 10< ) 2 -, such as -CH 2 CH 2 CH 2 -, or -C(R 10< ) 2 C(R 10< ) 2 C(R 10< ) 2 C(R 10< ) 2 -, such as -CH 2 CH 2 CH 2 CH 2 -.

[0077] In one embodiment, R 5Q< and R 6Q< are joined together to form a spriocyclic ring, and - R 5Q< -R 6Q< - is -C(R 10< ) 2 C(R 10< ) 2 -, such as -CH 2 CH 2 -. In one embodiment, R 5Q< and R 6Q< are joined together to form a spriocyclic ring, and -R 5Q< -R 6Q< - is -C(R 10< ) 2 C(R 10< ) 2 C(R 10< ) 2 -, such as -CH 2 CH 2 CH 2 -. In one embodiment, R 5Q< and R 6Q< are joined together to form a spriocyclic ring, and -R 5Q< -R 6Q< - is -C(R 10< ) 2 C(R 10< ) 2 C(R 10< ) 2 C(R 10< ) 2 -, such as -CH 2 CH 2 CH 2 CH 2 -.

[0078] In one embodiment, T is CR 5< R 6< wherein said R 5< and R 6< are joined together to form a spriocyclic ring, and -R 5< -R 6< - is -C(R 10< ) 2 C(R 10< ) 2 -, such as -CH 2 CH 2 -, -C(R 10< ) 2 C(R 10< ) 2 C(R 10< ) 2 -, such as -CH 2 CH 2 CH 2 -, or -C(R 10< ) 2 C(R 10< ) 2 C(R 10< ) 2 C(R 10< ) 2 -, such as -CH 2 CH 2 CH 2 CH 2 -.

[0079] In one embodiment, R 5T< and R 6T< are joined together to form a spriocyclic ring, and -R 5T< -R 6T< - is -C(R 10< ) 2 C(R 10< ) 2 -, such as -CH 2 CH 2 -. In one embodiment, R 5T< and R 6T< are joined together to form a spriocyclic ring, and -R 5T< -R 6T< - is -C(R 10< ) 2 C(R 10< ) 2 C(R 10< ) 2 -, such as -CH 2 CH 2 CH 2 -. In one embodiment, R 5T< and R 6T< are joined together to form a spriocyclic ring, and -R 5T< -R 6T< - is -C(R 10< ) 2 C(R 10< ) 2 C(R 10< ) 2 C(R 10< ) 2 -, such as -CH 2 CH 2 CH 2 CH 2 -.

[0080] In one embodiment, X is CR 5< R 6< wherein said R 5< and R 6< are joined together to form a spriocyclic ring, and -R 5< -R 6< - is -C(R 10< ) 2 C(R 10< ) 2 -, such as -CH 2 CH 2 -, -C(R 10< ) 2 C(R 10< ) 2 C(R 10< ) 2 -, such as -CH 2 CH 2 CH 2 -, or -C(R 10< ) 2 C(R 10< ) 2 C(R 10< ) 2 C(R 10< ) 2 -, such as -CH 2 CH 2 CH 2 CH 2 -.

[0081] In one embodiment, R 5X< and R 6X< are joined together to form a spriocyclic ring, and - R 5X< -R 6X< - is -C(R 10< ) 2 C(R 10< ) 2 -, such as -CH 2 CH 2 -. In one embodiment, R 5X< and R 6X< are joined together to form a spriocyclic ring, and -R 5X< -R 6X< - is -C(R 10< ) 2 C(R 10< ) 2 C(R 10< ) 2 -, such as -CH 2 CH 2 CH 2 -. In one embodiment, R 5X< and R 6X< are joined together to form a spriocyclic ring, and -R 5X< -R 6X< - is -C(R 10< ) 2 C(R 10< ) 2 C(R 10< ) 2 C(R 10< ) 2 -, such as -CH 2 CH 2 CH 2 CH 2 -.

[0082] In one embodiment, Z is CR 5< R 6< wherein said R 5< and R 6< are joined together to form a spriocyclic ring, and -R 5< -R 6< - is -C(R 10< ) 2 C(R 10< ) 2 -, such as -CH 2 CH 2 -, -C(R 10< ) 2 C(R 10< ) 2 C(R 10< ) 2 -, such as -CH 2 CH 2 CH 2 -, or -C(R 10< ) 2 C(R 10< ) 2 C(R 10< ) 2 C(R 10< ) 2 -, such as -CH 2 CH 2 CH 2 CH 2 -.

[0083] In one embodiment, R 5Z< and R 6Z< are joined together to form a spriocyclic ring, and -R 5Z< -R 6Z< - is -C(R 10< ) 2 C(R 10< ) 2 -, such as -CH 2 CH 2 -. In one embodiment, R 5Z< and R 6Z< are joined together to form a spriocyclic ring, and -R 5Z< -R 6Z< - is -C(R 10< ) 2 C(R 10< ) 2 C(R 10< ) 2 -, such as -CH 2 CH 2 CH 2 -. In one embodiment, R 5Z< and R 6Z< are joined together to form a spriocyclic ring, and -R 5Z< -R 6Z< - is -C(R 10< ) 2 C(R 10< ) 2 C(R 10< ) 2 C(R 10< ) 2 -, such as -CH 2 CH 2 CH 2 CH 2 -.

[0084] In one embodiment, R 7< is H. In one embodiment, R 7< is C 1-5 alkyl, such as Me, Et or "Pr. In one embodiment, R 7< is C 1-5 alkyl substituted with one or more, identical or different, substituents R'°, wherein R 10< is independently selected from the group consisting of F; Cl; and -OC 1-3 alkyl.

[0085] In one embodiment, R 7< is C 1-3 alkyl substituted with phenyl. In one embodiment, R 7< is benzyl. In one embodiment, R 7< is phenylethyl. In one embodiment, R 7< is phenylpropyl. In one embodiment, R 7< is C 1-3 alkyl substituted with phenyl, wherein the phenyl is substituted with one or more, identical or different, substituents R 11< wherein R 11< is independently selected from the group consisting of deuterium, methoxy, -OCF 3 , Me, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CD 3 , cyclopropyl, NH 2 , -NHAc, -C(=O)-NH 2 , nitro, cyano, Cl, Br, I, and F. In one embodiment, R 7< is C 1 alkyl substituted with phenyl, wherein the phenyl is substituted with one or more, identical or different, substituents R 11< wherein R 11< is independently selected from the group consisting of deuterium, methoxy, -OCF 3 , Me, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CD 3 , cyclopropyl, NH 2 , -NHAc, -C(=O)-NH 2 , nitro, cyano, Cl, Br, I, and F. In one embodiment, R 7< is benzyl substituted with one or more, identical or different, substituents R 11< wherein R 11< is independently selected from the group consisting of deuterium, methoxy, -OCF 3 , Me, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CD 3 , cyclopropyl, NH 2 , -NHAc, -C(=O)-NH 2 , nitro, cyano, CI, Br, I, and F. In one embodiment, R 7< is C 2 alkyl substituted with phenyl, wherein the phenyl is substituted with one or more, identical or different, substituents R 11< wherein R 11< is independently selected from the group consisting of deuterium, methoxy, -OCF 3 , Me, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CD 3 , cyclopropyl, NH 2 , -NHAc, -C(=O)-NH 2 , nitro, cyano, CI, Br, I, and F. In one embodiment, R 7< is phenylethyl substituted with one or more, identical or different, substituents R 11< , wherein R 11< is independently selected from the group consisting of deuterium, methoxy, -OCF 3 , Me, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CD 3 , cyclopropyl, NH 2 , -NHAc, -C(=O)-NH 2 , nitro, cyano, CI, Br, I, and F. In one embodiment, R 7< is C 3 alkyl substituted with phenyl, wherein the phenyl is substituted with one or more, identical or different, substituents R 11< wherein R 11< is independently selected from the group consisting of deuterium, methoxy, -OCF 3 , Me, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CD 3 , cyclopropyl, NH 2 , -NHAc, -C(=O)-NH 2 , nitro, cyano, CI, Br, I, and F. In one embodiment, R 7< is phenylpropyl substituted with one or more, identical or different, substituents R 11< wherein R 11< is independently selected from the group consisting of deuterium, methoxy, -OCF 3 , Me, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CD 3 , cyclopropyl, NH 2 , -NHAc, -C(=O)-NH 2 , nitro, cyano, CI, Br, I, and F.

[0086] In one embodiment, R 7< is C 1-3 alkyl substituted with a C 5 heteroaryl. In one embodiment, R 7< is C 1-3 alkyl substituted with a C 5 heteroaryl wherein the C 5 heteroaryl is substituted with one or more, identical or different, substituents R 11< wherein R 11< is independently selected from the group consisting of deuterium, methoxy, -OCF 3 , Me, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CD 3 , cyclopropyl, NH 2 , -NHAc, -C(=O)-NH 2 , nitro, cyano, Cl, Br, I, and F. In one embodiment, R 7< is (thiophen-2-yl)meth-1-yl. In one embodiment, R 7< is (thiophen-3-yl)meth-1-yl. In one embodiment, R 7< is (furan-2-yl)meth-1-yl. In one embodiment R 7< is (furan-3-yl)meth-1-yl. In one embodiment, R 7< is (1,3-thiazol-2-yl)meth-1-yl. In one embodiment, R 7< is(1,3-oxazol-2-yl)meth-1-yl. In one embodiment, R 7< is (thiophen-2-yl)eth-2-yl. In one embodiment, R 7< is (thiophen-3-yl)eth-2-yl. In one embodiment, R 7< is (furan-2-yl)eth-2-yl. In one embodiment, R 7< is (furan-3-yl)eth-2-yl. In one embodiment, R 7< is (1,3-thiazol-2-yl)eth-2-yl. In one embodiment, R 7< is (1,3-oxazol-2-yl)eth-2-yl. In one embodiment, R 7< is (thiophen-2-yl)prop-3-yl. In one embodiment, R 7< is (thiophen-3-yl)prop-3-yl. In one embodiment, R 7< is (furan-2-yl)prop-3-yl. In one embodiment, R 7< is (furan-3-yl)prop-3-yl. In one embodiment, R 7< is (1,3-thiazol-2-yl)prop-3-yl. In one embodiment, R 7< is (1,3-oxazol-2-yl)prop-3-yl.

[0087] In one embodiment, R 7< is C 1-3 alkyl substituted with C 3-5 cycloalkyl. In one embodiment, R 7< is C 1-3 alkyl substituted with C 3-5 cycloalkyl substituted with one or more, identical or different, substituents R 10< , wherein R 10< is independently selected from the group consisting of F; Cl; and -OC 1-3 alkyl. In one embodiment, R 7< is cyclopropylmethyl. In one embodiment, R 7< is cyclopropylethyl. In one embodiment, R 7< is cyclobutylmethyl.

[0088] In one embodiment, R 7< is C 3-5 cycloalkyl. In one embodiment, R 7< is C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R'°, wherein R 10< is independently selected from the group consisting of deuterium, F, Cl and -OC 1-3 alkyl. In one embodiment, R 7< is cyclopropyl. In one embodiment, R 7< is cyclobutyl. In one embodiment, R 7< is cyclopentyl.

[0089] In one embodiment, R 3< is benzyl. In one embodiment, R 8< is benzyl substituted with one or more, identical or different, substituents R 11< , wherein R 11< is independently selected from the group consisting of deuterium, methoxy, -OCF 3 , Me, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CD 3 , cyclopropyl, NH 2 , -NHAc, -C(=O)-NH 2 , nitro, cyano, Cl, Br, I, and F.

[0090] In one embodiment, R 9< is H. In one embodiment, R 9< is C 1-5 alkyl, such as Me, Et or "Pr. In one embodiment, R 9< is C 1-5 alkyl substituted with one or more, identical or different, substituents R'°, wherein R 10< is independently selected from the group consisting of F; Cl; and -OC 1-3 alkyl.

[0091] In one embodiment, R 9< is C 1-3 alkyl substituted with C 3-5 cycloalkyl. In one embodiment, R 9< is C 1-3 alkyl substituted with C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R'°, wherein R 10< is independently selected from the group consisting of F; Cl; and -OC 1-3 alkyl. In one embodiment, R 9< is cyclopropylmethyl. In one embodiment, R 9< is cyclopropylethyl. In one embodiment, R 7< is cyclobutylmethyl.

[0092] In one embodiment, R 9< is C 1-3 alkyl substituted with phenyl, such as benzyl, phenylethyl or phenylpropyl. In one embodiment, R 9< is C 1-3 alkyl substituted with phenyl, wherein the phenyl is substituted with one or more, identical or different, substituents R 11< wherein R 11< is independently selected from the group consisting of deuterium, methoxy, -OCF 3 , Me, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CD 3 , cyclopropyl, NH 2 , -NHAc, -C(=O)-NH 2 , nitro, cyano, Cl, Br, I, and F. In one embodiment, R 9< is C 1 alkyl substituted with phenyl, wherein the phenyl is substituted with one or more, identical or different, substituents R 11< wherein R 11< is independently selected from the group consisting of deuterium, methoxy, -OCF 3 , Me, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CD 3 , cyclopropyl, NH 2 , -NHAc, -C(=O)-NH 2 , nitro, cyano, Cl, Br, I, and F. In one embodiment, R 9< is benzyl substituted with one or more, identical or different, substituents R 11< wherein R 11< is independently selected from the group consisting of deuterium, methoxy, -OCF 3 , Me, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CD 3 , cyclopropyl, NH 2 , -NHAc, -C(=O)-NH 2 , nitro, cyano, Cl, Br, I, and F. In one embodiment, R 9< is C 2 alkyl substituted with phenyl, wherein the phenyl is substituted with one or more, identical or different, substituents R 11< wherein R 11< is independently selected from the group consisting of deuterium, methoxy, -OCF 3 , Me, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CD 3 , cyclopropyl, NH 2 , -NHAc, -C(=O)-NH 2 , nitro, cyano, Cl, Br, I, and F. In one embodiment, R 9< is phenylethyl substituted with one or more, identical or different, substituents R 11< , wherein R 11< is independently selected from the group consisting of deuterium, methoxy, -OCF 3 , Me, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CD 3 , cyclopropyl, NH 2 , -NHAc, -C(=O)-NH 2 , nitro, cyano, CI, Br, I, and F. In one embodiment, R 9< is C 3 alkyl substituted with phenyl, wherein the phenyl is substituted with one or more, identical or different, substituents R 11< wherein R 11< is independently selected from the group consisting of deuterium, methoxy, -OCF 3 , Me, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CD 3 , cyclopropyl, NH 2 , -NHAc, -C(=O)-NH 2 , nitro, cyano, CI, Br, I, and F. In one embodiment, R 9< is phenylpropyl substituted with one or more, identical or different, substituents R 11< wherein R 11< is independently selected from the group consisting of deuterium, methoxy, -OCF 3 , Me, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CD 3 , cyclopropyl, NH 2 , -NHAc, -C(=O)-NH 2 , nitro, cyano, CI, Br, I, and F.

[0093] In one embodiment, R 9< is C 1-3 alkyl substituted with naphthyl, such as (1-naphthyl)methyl, (2-naphthyl)methyl, (1-naphthyl)ethyl, (2-naphthyl)ethyl, (1-naphthyl)propyl, (2-naphthyl)propyl. In one embodiment, R 9< is C 1-3 alkyl substituted with naphthyl, wherein the naphthyl is substituted with one or more, identical or different, substituents R 11< wherein R 11< is independently selected from the group consisting of deuterium, methoxy, -OCF 3 , Me, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CD 3 , cyclopropyl, NH 2 , -NHAc, -C(=O)-NH 2 , nitro, cyano, Cl, Br, I, and F. In one embodiment, R 9< is (1-naphthyl)methyl substituted with one or more, identical or different, substituents R 11< wherein R 11< is independently selected from the group consisting of deuterium, methoxy, -OCF 3 , Me, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CD 3 , cyclopropyl, NH 2 , -NHAc, -C(=O)-NH 2 , nitro, cyano, Cl, Br, I, and F. In one embodiment, R 9< is (2-naphthyl)methyl substituted with one or more, identical or different, substituents R 11< wherein R 11< is independently selected from the group consisting of deuterium, methoxy, -OCF 3 , Me, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CD 3 , cyclopropyl, NH 2 , -NHAc, -C(=O)-NH 2 , nitro, cyano, Cl, Br, I, and F. In one embodiment, R 9< is (1-naphthyl)ethyl substituted with one or more, identical or different, substituents R 11< , wherein R 11< is independently selected from the group consisting of deuterium, methoxy, -OCF 3 , Me, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CD 3 , cyclopropyl, NH 2 , -NHAc, -C(=O)-NH 2 , nitro, cyano, CI, Br, I, and F. In one embodiment, R 9< is (2-naphthyl)ethyl substituted with one or more, identical or different, substituents R 11< wherein R 11< is independently selected from the group consisting of deuterium, methoxy, -OCF 3 , Me, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CD 3 , cyclopropyl, NH 2 , -NHAc, -C(=O)-NH 2 , nitro, cyano, Cl, Br, I, and F. In one embodiment, R 9< is (1-naphthyl)propyl substituted with one or more, identical or different, substituents R 11< wherein R 11< is independently selected from the group consisting of deuterium, methoxy, -OCF 3 , Me, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CD 3 , cyclopropyl, NH 2 , -NHAc, -C(=O)-NH 2 , nitro, cyano, Cl, Br, I, and F. In one embodiment, R 9< is (2-naphthyl)propyl substituted with one or more, identical or different, substituents R 11< wherein R 11< is independently selected from the group consisting of deuterium, methoxy, -OCF 3 , Me, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CD 3 , cyclopropyl, NH 2 , -NHAc, -C(=O)-NH 2 , nitro, cyano, Cl, Br, I, and F.

[0094] In one embodiment, R 9< is C 1-3 alkyl substituted with a C 5 heterocycle. In one embodiment, R 9< is C 1-3 alkyl substituted with a C 5 heterocycle wherein the C 5 heterocycle is substituted with one or more, identical or different, substituents R 11< wherein R 11< is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, CI, Br, I, and F. In one embodiment, R 9< is C 1-3 alkyl substituted with a 5- to 10-membered heteroaryl. In one embodiment, R 9< is C 1-3 alkyl substituted with a 5- to 10-membered heteroaryl wherein the 5- to 10-membered heteroaryl is substituted with one or more, identical or different, substituents R 11< wherein R 11< is independently selected from the group consisting of deuterium, methoxy, -OCF 3 , Me, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CD 3 , cyclopropyl, NH 2 , -NHAc, -C(=O)-NH 2 , nitro, cyano, Cl, Br, I, and F. In one embodiment, R 9< is C 1-3 alkyl substituted with a 5- to 10-membered heteroaryl selected from the group consisting of oxazolyl, thiazolyl, thiadiazolyl, oxadiazolyl, triazolyl, pyrrolyl, thienyl, furanyl, diazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, and tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, 1,4-dihydropyrrolo[3,2-b]pyrrolyl, 1,6-dihydropyrrolo[2,3-b]pyrrolyl, 6H-furo[2,3-b]pyrrole, 4H-furo[2,3-b]pyrrolyl, 6H-thieno[2,3-b]pyrrolyl, 4H-thieno[2,3-b]pyrrolyl, indolyl, isoindolyl, indolizinyl, indazolyl, benzimidazolyl, azaindolyl, azaindazolyl, pyrazolo[1,5-a]pyrimidinyl, purinyl, benzofuranyl, benzo[b]thiophenyl, benzisoxazolyl, benzthiazolyl, benzisothiazolyl, benzo[c][1,2,5]thiadiazolyl, quinolinyl, isoquinolinyl, 4H-quinolizinyl, quinoxalinyl, phthalazinyl, quinazolinyl, cinnolinyl, 1,8-naphthyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, pyrido[3,4-b]pyrazinyl, pyrido[2,3-b]pyrazinyl and pteridinyl. In one embodiment, R 9< is C 1-3 alkyl substituted with a 5-membered heteroaryl wherein the 5-membered heteroaryl is substituted with one or more, identical or different, substituents R 11< wherein R 11< is independently selected from the group consisting of deuterium, methoxy, -OCF 3 , Me, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CD 3 , cyclopropyl, NH 2 , -NHAc, -C(=O)-NH 2 , nitro, cyano, CI, Br, I, and F. In one embodiment, R 9< is (thiophen-2-yl)meth-1-yl. In one embodiment, R 9< is (thiophen-3-yl)meth-1-yl. In one embodiment, R 9< is (furan-2-yl)meth-1-yl. In one embodiment, R 9< is (furan-3-yl)meth-1-yl. In one embodiment, R 9< is (1,3-thiazol-2-yl)meth-1-yl. In one embodiment, R 9< is (1,3-oxazol-2-yl)meth-1-yl. In one embodiment, R 9< is (thiophen-2-yl)eth-2-yl. In one embodiment, R 9< is (thiophen-3-yl)eth-2-yl. In one embodiment, R 9< is (furan-2-yl)eth-2-yl. In one embodiment, R 9< is (furan-3-yl)eth-2-yl. In one embodiment, R 9< is (1,3-thiazol-2-yl)eth-2-yl. In one embodiment, R 9< is (1,3-oxazol-2-yl)eth-2-yl. In one embodiment, R 9< is (thiophen-2-yl)prop-3-yl. In one embodiment, R 9< is (thiophen-3-yl)prop-3-yl. In one embodiment, R 9< is (furan-2-yl)prop-3-yl. In one embodiment, R 9< is (furan-3-yl)prop-3-yl. In one embodiment, R 9< is (1,3-thiazol-2-yl)prop-3-yl. In one embodiment, R 9< is (1,3-oxazol-2-yl)prop-3-yl.

[0095] In one embodiment, R 9< is C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R'°, wherein R 10< is independently selected from the group consisting of deuterium, F, Cl and -OC 1-3 alkyl. In one embodiment, R 9< is C 3-5 cycloalkyl. In one embodiment, R 9< is cyclopropyl. In one embodiment, R 9< is cyclobutyl. In one embodiment, R 9< is cyclopentyl.

[0096] In one embodiment, R 10< is deuterium. In one embodiment, R 10< is F. In one embodiment, R 10< is CI. In one embodiment, R 10< is -OC 1-3 alkyl such as OMe.

[0097] In one embodiment, R 11< is deuterium. In one embodiment, R 11< is methoxy. In one embodiment, R 11< is -OCF 3 . In one embodiment, R 11< is Me. In one embodiment, R 11< is CF 3 . In one embodiment, R 11< is CF 2 Cl. In one embodiment, R 11< is CF 2 H. In one embodiment, R 11< is CFH 2 . In one embodiment, R 11< is CD 3 . In one embodiment, R 11< is cyclopropyl. In one embodiment, R 11< is NH 2 . In one embodiment, R 11< is -NHAc. In one embodiment, R 11< is -C(=O)-NH 2 . In one embodiment, R 11< is nitro. In one embodiment, R 11< is cyano. In one embodiment, R 11< is Cl. In one embodiment, R 11< is Br. In one embodiment, R 11< is I. In one embodiment, R 11< is F.

[0098] In one embodiment, the compound is selected from the group consisting of: 6-chloro-7-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 7-chloro-6-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid; 7-chloro-6-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 5-chloro-7-fluoro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-fluoro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 7-chloro-6-fluoro-1,4-dimethyl-1,2,3,4-tetrahydroquinoxaline-5-carboxylic acid; 6-chloro-7-fluoro-2,2,4-trimethyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 7-chloro-6-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid; 7-chloro-6-fluoro-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid; 7-chloro-8-methoxy-5-methyl-2,3,4,5-tetrahydro-1,5-benzoxazepine-9-carboxylic acid; 7-chloro-8-fluoro-5-methyl-2,3,4,5-tetrahydro-1,5-benzoxazepine-9-carboxylic acid; 6-chloro-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 7-chloro-8-fluoro-2,3,4,5-tetrahydro-1,5-benzoxazepine-9-carboxylic acid; 7-chloro-8-ethoxy-5-methyl-2,3,4,5-tetrahydro-1,5-benzoxazepine-9-carboxylic acid; 6-chloro-7-fluoro-4-(3-methylbutyl)-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-4-ethyl-7-fluoro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzothiazine-8-carboxylic acid; 6-chloro-4-(cyclopropylmethyl)-7-fluoro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-fluoro-4-propyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 4-benzyl-6-chloro-7-fluoro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-fluoro-4-[3-(4-fluorophenyl)propyl]-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-4-methyl-7-(propan-2-yloxy)-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-fluoro-4-[2-(4-fluorophenyl)ethyl]-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-4-methyl-7-(methylsulfanyl)-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-fluoro-4-(3-methoxypropyl)-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-4-ethyl-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzothiazine-8-carboxylic acid; 6-fluoro-7-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 7-methoxy-4,6-dimethyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-4-(propan-2-yl)-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-4-(2-phenylethyl)-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-4-[2-(4-methoxyphenyl)ethyl]-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-2-(methoxymethyl)-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-4-[(thiophen-3-yl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-2,2,4-trimethyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-fluoro-4-(2-methoxyethyl)-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-4-methyl-3,4-dihydrospiro[1,4-benzoxazine-2,1'-cyclobutane]-8-carboxylic acid; 6-chloro-4-[3-(furan-2-yl)propyl]-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-4-[(thiophen-2-yl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-4-[(thiophen-2-yl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-4-[(1,3-thiazol-2-yl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-5-fluoro-7-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 4-benzyl-7-chloro-6-fluoro-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid; 6-chloro-4-(cyclobutylmethyl)-7-fluoro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-4-[3-(1,3-thiazol-2-yl)propyl]-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-4,7-dimethyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-4-[(4-methoxyphenyl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-4-[(1,3-oxazol-2-yl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 7-chloro-6-fluoro-4-(3-methylbutyl)-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid; 4-benzyl-6-chloro-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-4-[2-(3,5-difluorophenyl)ethyl]-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 7-chloro-6-fluoro-4-[(thiophen-3-yl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid; 4-benzyl-6-fluoro-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; methyl 6-chloro-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate; ethyl 6-chloro-7-fluoro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate; methyl 7-chloro-6-fluoro-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylate; methyl 6-chloro-7-fluoro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate; 7-chloro-6-fluoro-4-propyl-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid; 7-chloro-6-fluoro-4-methyl-1,2,3,4-tetrahydro-5-quinoxalinecarboxylic acid; 7-chloro-6-fluoro-4-[(p-methoxyphenyl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid; 1-benzyl-7-chloro-6-fluoro-4-methyl-1,2,3,4-tetrahydro-5-quinoxalinecarboxylic acid; 7-chloro-6-fluoro-4-[(p-tolyl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid; 7-chloro-6-fluoro-4-[(1-naphthyl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid; 7-chloro-6-fluoro-4-[(o-tolyl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid; and 4-benzyl-6,7-dichloro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid.

[0099] In one embodiment, the compound or the compound for use according to the present disclosure has been modified in order to increase its half-life when administered to a patient, in particular its plasma half-life. In one embodiment, the compound or the compound for use according to the present disclosure further comprises a moiety conjugated to said compound, thus generating a moiety-conjugated compound. In one embodiment, said moiety-conjugated compound has a plasma and / or serum half-life being longer than the plasma and / or serum half-life of the non-moiety conjugated compound. In one embodiment, the moiety conjugated to the compound or compound for use according to the present disclosure, is one or more type(s) of moieties selected from the group consisting of albumin, fatty acids, polyethylene glycol (PEG), acylation groups, antibodies and antibody fragments.

[0100] In one embodiment, the compound has activity on the CIC-1 receptor. In one embodiment, the compound is an inhibitor of the CIC-1 ion channel.

[0101] In one embodiment, the compound is capable of improving the recovered force in isolated rat soleus muscles after exposure to tubocurarine. In one embodiment, the recovery of force in muscles with neuromuscular dysfunction is >5%, for example >10%, for example >15%, for example >20%, for example >25%, for example >30% and for example >35%.Neuromuscular disorders

[0102] The compound or compound for use of the present disclosure may be used for treating, ameliorating and / or preventing a neuromuscular disorder, or reversing neuromuscular blockade.

[0103] The inventors of the present disclosure have shown that inhibition of CIC-1 channels strengthens neuromuscular transmission. CIC-1 function may therefore contribute to muscle weakness in conditions of compromised neuromuscular transmission.

[0104] Thus, in one embodiment of the present disclosure, the compound or the compound for use as described herein inhibits CIC-1 channels. Thus, it is appreciated that compounds and / or compounds for use of Formula (I) inhibit CIC-1 channels.

[0105] The neuromuscular disorder may also include neuromuscular dysfunctions.

[0106] Neuromuscular disorders include for example disorders with symptoms of muscle weakness and fatigue. Such disorders may include conditions with reduced neuromuscular transmission safety factor. In one embodiment the neuromuscular disorders are motor neuron disorders. Motor neuron disorders are disorders with reduced safety in the neuromuscular transmission. In one embodiment motor neuron disorders are selected from the group consisting of amyotrophic lateral sclerosis (ALS) (Killian JM, Wilfong AA, Burnett L, Appel SH, Boland D. Decremental motor responses to repetitive nerve stimulation in ALS. Muscle Nerve, 1994, 17, 747-754), spinal muscular atrophy (SMA) (Wadman RI, Vrancken AF, van den Berg LH, van der Pol WL. Dysfunction of the neuromuscular junction in spinal muscular atrophy types 2 and 3. Neurology, 2012, 79, 2050-2055), Charcot-Marie Tooth disease (Bansagi B, Griffin H, Whittaker RG, Antoniadi T, Evangelista T, Miller J, Greenslade M, Forester N, Duff J, Bradshaw A, Kleinle S, Boczonadi V, Steele H, Ramesh V, Franko E, Pyle A, Lochmüller H, Chinnery PF, Horvath R. Genetic heterogeneity of motor neuropathies. Neurology, 2017, 28;88(13):1226-1234), X-linked spinal and bulbar muscular atrophy (Yamada, M., Inaba, A., Shiojiri, T. X-linked spinal and bulbar muscular atrophy with myasthenic symptoms. Journal of the Neurological Sciences, 1997, 146, 183-185), Kennedy's disorder (Stevic, Z., Peric, S., Pavlovic, S., Basta, I., Lavrnic, D., Myasthenic symptoms in a patient with Kennedy's disorder. Acta Neurologica Belgica, 2014, 114, 71-73), multifocal motor neuropathy (Roberts, M., Willison, H.J., Vincent, A., Newsom-Davis, J. Multifocal motor neuropathy human sera block distal motor nerve conduction in mice. Ann Neurol. 1995, 38, 111-118), Guillain-Barré syndrome (Ansar, V., Valadi, N. Guillain-Barré Syndrome Prim. Care, 2015, 42, 189-193); poliomyelitis (Trojan, D.A., Gendron, D., Cashman, N.R. Electrophysiology and electrodiagnosis of the post-polio motor unit. Orthopedics, 1991, 14, 1353-1361, and Birk T.J. Poliomyelitis and the post-polio syndrome: exercise capacities and adaptation - current research, future directions, and widespread applicability. Med. Sci. Sports Exerc., 1993, 25, 466-472), post-polio syndrome (Garcia, C.C., Potian, J.G., Hognason, K., Thyagarajan, B., Sultatos, L.G., Souayah, N., Routh, V.H., McArdle, J.J. Acetylcholinesterase deficiency contributes to neuromuscular junction dysfunction in type 1 diabetic neuropathy. Am. J. Physiol. Endocrinol. Metab., 2012, 15, E551 - 561) and sarcopenia (Gilmore K.J., Morat T., Doherty T.J., Rice C.L., Motor unit number estimation and neuromuscular fidelity in 3 stages of sarcopenia. 2017 55(5):676-684). In one embodiment, the neuromuscular disorder is diabetic polyneuropathy. In one embodiment, the neuromuscular disorder is sarcopenia. In one embodiment, the neuromuscular disorder is Kennedy's disorder. In one embodiment, the neuromuscular disorder is multifocal motor neuropathy.

[0107] Thus, in one embodiment of the present disclosure the neuromuscular disorder is amyotrophic lateral sclerosis (ALS). In another embodiment the neuromuscular disorder is spinal muscular atrophy (SMA). In another embodiment the neuromuscular disorder is Charcot-Marie tooth disease (CMT). In another embodiment the neuromuscular disorder is sarcopenia. In yet another embodiment, the neuromuscular disorder is critical illness myopathy (CIM).

[0108] As stated above the neuromuscular disorders include for example disorders with symptoms of muscle weakness and fatigue. Such disorder may for example include diabetes (Am. J. Physiol. Endocrinol. Metab., 2012, 15, E551 - 561).

[0109] In another embodiment the neuromuscular disorders is chronic fatigue syndrome. Chronic fatigue syndrome (CFS) (Fletcher, S.N., Kennedy, D.D., Ghosh, I.R., Misra, V.P., Kiff, K., Coakley, J.H., Hinds, C.J. Persistent neuromuscular and neurophysiologic abnormalities in long-term survivors of prolonged critical illness. Crit. Care Med. 2003, 31, 1012 - 1016) is the common name for a medical condition characterized by debilitating symptoms, including fatigue that lasts for a minimum of six months in adults. CFS may also be referred to as systemic exertion intolerance disorder (SEID), myalgic encephalomyelitis (ME), post-viral fatigue syndrome (PVFS), chronic fatigue immune dysfunction syndrome (CFIDS), or by several other terms. Symptoms of CFS include malaise after exertion; unrefreshing sleep, widespread muscle and joint pain, physical exhaustion, and muscle weakness.

[0110] In a further embodiment the neuromuscular disorder is a critical illness polyneuropathy (Angelini C. Spectrum of metabolic myopathies. Biochim. Biophys. Acta., 2015, 1852, 615 - 621) or CIM (Latronico, N., Bolton, C.F. Critical illness polyneuropathy and myopathy: a major cause of muscle weakness and paralysis. Lancet Neurol. 2011, 10, 931-941). Critical illness polyneuropathy and CIM are overlapping syndromes of widespread muscle weakness and neurological dysfunction developing in critically ill patients.

[0111] The neuromuscular disorder may also include metabolic myopathy (Milone, M., Wong, L.J. Diagnosis of mitochondrial myopathies. Mol. Genet. Metab., 2013, 110, 35 - 41) and mitochondrial myopathy (Srivastava, A., Hunter, J.M. Reversal of neuromuscular block. Br. J. Anaesth. 2009, 103, 115 - 129). Metabolic myopathies result from defects in biochemical metabolism that primarily affects muscle. These may include glycogen storage disorders, lipid storage disorder and 3-phosphocreatine stores disorder. Mitochondrial myopathy is a type of myopathy associated with mitochondrial disorder. Symptoms of mitochondrial myopathies include muscular and neurological problems such as muscle weakness, exercise intolerance, hearing loss and trouble with balance and coordination. Thus, in one embodiment of the present disclosure the neuromuscular disorder is metabolic myopathy.

[0112] In another embodiment the neuromuscular disorder is periodic paralysis, in particular hypokalemic periodic paralysis which is a disorder of skeletal muscle excitability that presents with recurrent episodes of weakness, often triggered by exercise, stress, or carbohydrate-rich meals (Wu, F., Mi, W., Cannon, S.C., Neurology, 2013, 80, 1110-1116 and Suetterlin, K. et at, Current Opinion Neurology, 2014, 27, 583-590) or hyperkalemic periodic paralysis which is an inherited autosomal dominant disorder that affects sodium channels in muscle cells and the ability to regulate potassium levels in the blood (Ammat, T. et at, Journal of General Physiology, 2015, 146, 509-525).

[0113] In an embodiment the neuromuscular disorder is a myasthenic condition. Myasthenic conditions are characterized by muscle weakness and neuromuscular transmission failure. Congenital myasthenic syndromes (Finlayson, S., Beeson, D., Palace, J. Congenital myasthenic syndromes: an update. Pract. Neurol., 2013, 13, 80 - 91) is an inherited neuromuscular disorder caused by defects of several types at the neuromuscular junction.

[0114] Myasthenia gravis and Lambert-Eaton syndrome (Titulaer MJ, Lang B, Verschuuren JJ. Lambert-Eaton myasthenic syndrome: from clinical characteristics to therapeutic strategies. Lancet Neurol. 2011, 10, 1098-107) are examples of myasthenic conditions. Myasthenia gravis is either an autoimmune or congenital neuromuscular disorder that leads to fluctuating muscle weakness and fatigue. In the most common cases, muscle weakness is caused by circulating antibodies that block ACh receptors at the postsynaptic neuromuscular junction, inhibiting the excitatory effects of the neurotransmitter ACh on nicotinic ACh-receptors at neuromuscular junctions (Gilhus, N.E., Owe, J.F., Hoff, J.M., Romi, F., Skeie, G.O., Aarli, J.A. Myasthenia Gravis: A Review of Available Treatment Approaches, Autoimmune Diseases, 2011, Article ID 84739). Lambert-Eaton myasthenic syndrome (also known as LEMS, Lambert-Eaton syndrome, or Eaton-Lambert syndrome) is a rare autoimmune disorder that is characterized by muscle weakness of the limbs. It is the result of an autoimmune reaction in which antibodies are formed against presynaptic voltage-gated calcium channels, and likely other nerve terminal proteins, in the neuromuscular junction. Thirty to fifty percent of patients with acetylcholine receptor (AChR) antibody-negative myasthenia gravis (MG) have antibodies to muscle specific kinase (MuSK) and are referred to as having MuSK-MG (Borges, L.S., Richman, D.P., Muscle-Specific Kinase Myasthenia Gravis, Frontiers in Immunology, 2020, 11:707). . In one embodiment of the present disclosure the neuromuscular disorder is myasthenia gravis. In another embodiment the neuromuscular disorder is autoimmune myasthenia gravis. In another embodiment the neuromuscular disorder is MuSK-MG. In another embodiment the neuromuscular disorder is Lambert-Eaton syndrome. In another embodiment the neuromuscular disorder is seronegative myasthenia gravis. In another embodiment the neuromuscular disorder is congenital myasthenia gravis. In one embodiment the neuromuscular disorder is congenital myasthenic syndrome.

[0115] X-linked myotubular myopathy is a part of a group of centronuclear myopathies where cell nuclei are abnormally located in the centre of muscle cells instead of their normal location at the periphery. It is one of the severest congenital muscle diseases and is characterized by marked muscle weakness, hypotonia and feeding and breathing difficulties (Dowling JJ, Lawlor MW, Das S. X-Linked Myotubular Myopathy. 2002 Feb 25 [Updated 2018 Aug 23]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from: https: / / www.ncbi.nlm.nih.gov / books / NBK1432 / ). In one embodiment the neuromuscular disorder is myotubular myopathy.

[0116] Duchenne muscular dystrophy is a severe type of muscular dystrophy that primarily affects boys resulting initially in fatigue and muscle weakness (Angelini C, Tasca E, Fatigue in muscular dystrophies, Neuromuscular Disorders, 2012, 22 Suppl 3: S214-20. doi:10.1016 / j.nmd.2012.10.010). In one embodiment the neuromuscular disorder is Duchenne muscular dystrophy.

[0117] Multiple sclerosis (MS) is the most common demyelinating disease, in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This damage disrupts the ability of parts of the nervous system to transmit signals, resulting in a range of signs and symptoms, including physical, mental, and sometimes psychiatric problems. It has been shown that people with multiple sclerosis typically experience greater levels of exercise-induced fatigue compared with healthy individuals (Brotherton et al, J. Neuorophysiol. 2022, 128, 105-117). There are four types of MS in what is known as the Lublin classification: clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), primary progressive MS (PPMS) and secondary progressive MS (SPMS). In one embodiment, the neuromuscular disorder is selected from the group consisting of multiple sclerosis (MS), clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), primary progressive MS (PPMS) and secondary progressive MS (SPMS).

[0118] Neuromuscular blockade is used in connection with surgery under general anaesthesia. Reversing agents are used for more rapid and safer recovery of muscle function after such blockade. Complications with excessive muscle weakness after blockade during surgery can result in delayed weaning from mechanical ventilation and respiratory complications after the surgery. These complications can have pronounced effects on outcome of the surgery and future quality of life of patients, there is a need for improved reversing agents (Murphy GS, Brull SJ. Residual neuromuscular block: lessons unlearned. Part I: definitions, incidence, and adverse physiologic effects of residual neuromuscular block. Anesth Analg. 2010 111(1):120-8). Thus, in one embodiment, the neuromuscular disorder has been induced by a neuromuscular blocking agent. In one particular embodiment the neuromuscular disorder is muscle weakness caused by neuromuscular blockade after surgery. In another embodiment of the present disclosure the compound or the compound for use is used for reversing and / or ameliorating neuromuscular blockade after surgery. In one embodiment, the neuromuscular blockade is drug induced. In one embodiment, the neuromuscular blockade is caused by non-depolarizing neuromuscular blocker or antibiotic agent. In one embodiment the neuromuscular blockade is induced by an antibiotic. In one embodiment the neuromuscular blockade is induced by a non-depolarizing neuromuscular blocker.

[0119] In one embodiment the compound or the compound for use of the present disclosure is used to prevent a neuromuscular disorder. The compound or the compound for use may for example be used prophylactically against nerve gas that is known to cause symptoms of muscle weakness and fatigue (Kawamura, Y., Kihara, M., Nishimoto, K., Taki, M. Efficacy of a half dose of oral pyridostigmine in the treatment of chronic fatigue syndrome: three case reports. Pathophysiology, 2003, 9, 189-194). In one embodiment the compound or the compound for use of the present disclosure may be used in the treatment of muscle weakness (such as drooping eyelids, loss of facial expression, constipation, muscle weakness in arms, muscle weakness in legs and dyspnoea) caused by botulism poisoning. In one embodiment the compound or the compound for use of the present disclosure may be used in the treatment of snake bites where the snake toxin, such as α-neurotoxin or myotoxin, is known to cause symptoms of muscle weakness and fatigue.

[0120] In one embodiment, the neuromuscular disorder is selected from the group consisting of myasthenia gravis, autoimmune myasthenia gravis, congenital myasthenic syndrome, seronegative myasthenia gravis, muscle specific kinase myasthenia gravis (MuSK-MG), Lambert-Eaton Syndrome, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), critical illness myopathy (CIM), Charcot-Marie Tooth disease, diabetic polyneuropathy, periodic paralysis, hypokalemic periodic paralysis, hyperkalemic periodic paralysis, myotubular myopathy, Duchenne muscular dystrophy, Guillain-Barré syndrome, poliomyelitis, post-polio syndrome, chronic fatigue syndrome, critical illness polyneuropathy, metabolic myopathy, Kennedy's disorder, multiple sclerosis and multifocal motor neuropathy.Pharmaceutical formulations

[0121] In one aspect, the present invention relates to a composition comprising the compound as disclosed herein. The composition according to the present disclosure may be used for treating, ameliorating and / or preventing a neuromuscular disorder, and / or for use in reversing and / or ameliorating a neuromuscular blockade. Thus, the compositions and compounds described herein can be pharmaceutically acceptable. In one embodiment the composition as described herein is in the form of a pharmaceutical formulation. In one embodiment, the composition as described herein further comprises a pharmaceutically acceptable carrier. In one aspect, the present invention concerns a composition comprising the compound as defined herein and a pharmaceutically acceptable carrier.Combination therapy

[0122] The composition of the present disclosure may comprise further active ingredients / agents or other components to increase the efficiency of the composition. Thus, in one embodiment the composition further comprises at least one further active agent. It is appreciated that the active agent can be suitable for treating, preventing or ameliorating said neuromuscular disorder.

[0123] The active agent in certain embodiments can be an acetylcholine esterase inhibitor. Said acetylcholine esterase inhibitor may for example be selected from the group consisting of delta-9-tetrahydrocannabinol, carbamates, physostigmine, neostigmine, pyridostigmine, ambenonium, demecarium, rivastigmine, phenanthrene derivatives, galantamine, piperidines, donepezil, tacrine, edrophonium, huperzine, ladostigil, ungeremine and lactucopicrin.

[0124] In certain embodiments, the acetylcholine esterase inhibitor is selected from the group consisting of neostigmine, physostigmine and pyridostigmine. In certain embodiments, the acetylcholine esterase inhibitor is neostigmine or pyridostigmine.

[0125] The active agent may also be an immunosuppressive drug. Immunosuppressive drugs are drugs that suppress or reduce the strength of the body's immune system. Immunosuppressive drugs include but are not limited to glucocorticoids, corticosteroids, cytostatics, antibodies and drugs acting on immunophilins. In one embodiment the active agent is prednisone.

[0126] The active agent may also be an agent that is used in anti-myotonic treatment. Such agents include for example blockers of voltage gated Na +< channels, and aminoglycosides.

[0127] The active agent may also be an agent for reversing a neuromuscular blockade after surgery. Such agents include for example neostigmine or sugammadex (Org 25969, tradename Bridion).

[0128] The active agent may also be an agent for increasing ACh release by blocking voltage-gated K +< channels in the pre-synaptic terminal. Such agent includes 3,4-diaminopyridine (Amifampridine; tradename Firdapse).

[0129] The active agent may also be an agent for increasing the levels of survival motor neuron (SMN) protein that are produced. For example, by alternating the splicing of the SMN2 gene in order to increase the expression of full-length SMN protein from SMN2 (Zanetta C, Nizzardo M, Simone C, Monguzzi E, Bresolin N, Comi GP, Corti S, "Molecular therapeutic strategies for spinal muscular atrophies: current and future clinical trials". Clinical Therapeutics, 2014, 36 (1): 128-40). Such agents include antisense oligonucleotides such as Nusinersen (tradename Spinraza) or small molecules such as Risdiplam (tradename Evrysdi).

[0130] The active agent may be a gene therapy, for example by using viral vectors to deliver the SMN1 transgene to the affected motor neurons, where it leads to an increase in SMN protein production. Such gene therapies include onasemnogene abeparvovec (tradename Zolgensma). Such gene therapies include nusinersen (tradename Spinraza), risdiplam (tradename Evrysdi) and Branaplam.

[0131] The active agent may be a small molecule that increases expression of the SMN2 gene, thus increasing the amount of full-length SMN protein available. Such therapies include salbutamol (also, called albuterol; tradename Ventolin),

[0132] The active agent may also be an agent for increasing muscle reactivity. Such agents include skeletal troponin activators such as Tirasemtiv and Reldesemtiv (CK-2127107) (Hwee, D.T., Kennedy, A.R., Hartman, J.J., Ryans, J., Durham, N., Malik, F.I., Jasper, J.R. The small-molecule fast skeletal troponin activator, CK-2127107, improves exercise tolerance in a rat model of heart failure. Journal of Pharmacology and Experimental Therapeutics, 2015, 353, 159 - 168). Such agents may also be antibodies that block the activation of the skeletal muscle protein myostatin, such as Apitegromab (SRK-015) or GYM329 (RO7204239),

[0133] The active agent may also be an agent that disrupts or blocks the IgG-FcRn interaction thereby reducing the overall IgG recycling. Such agents may be antibodies, such as the aglycosylated immunoglobulin (Ig)G1 monoclonal antibody Nipocalimab, or IgG1 Fc fragment such as Efgartigimod alfa (tradename Vyvgart).

[0134] The active agent may also be an agent that is an inhibitor of the complement component C5a. The active agent may also be an agent that downregulates the overexpression of PMP22 protein, leading to improvement of neuronal signalling in dysfunctional peripheral nerves. Such agents may be combination drugs such as PXT3003. Alternatively, the active agent may also be an agent that binds to the protein complement component 5 (C5) and inhibits its cleavage into C5a and C5b. Such agents may be Zilucoplan (RA101495).Methods

[0135] In one aspect, the present invention relates to a compound as defined herein for use as a medicament.

[0136] In one aspect, the present invention relates to a compound as defined herein for use in treating, ameliorating and / or preventing a neuromuscular disorder.

[0137] In one aspect, the present invention relates to a compound as defined herein for use in the treatment of an indication selected from the group consisting of myasthenia gravis, autoimmune myasthenia gravis, congenital myasthenic syndrome, seronegative myasthenia gravis, muscle specific kinase myasthenia gravis (MuSK-MG), Lambert-Eaton Syndrome, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), critical illness myopathy (CIM), Charcot-Marie Tooth disease, diabetic polyneuropathy, periodic paralysis, hypokalemic periodic paralysis, hyperkalemic periodic paralysis, myotubular myopathy, Duchenne muscular dystrophy, Guillain-Barré syndrome, poliomyelitis, post-polio syndrome, chronic fatigue syndrome, critical illness polyneuropathy, metabolic myopathy, Kennedy's disorder, multiple sclerosis and multifocal motor neuropathy. In one aspect, the present invention relates to a compound as defined herein for use in the symptomatic treatment of sarcopenia.

[0138] In one aspect, the present invention relates to a compound as defined herein for use in reversing and / or ameliorating a neuromuscular blockade.

[0139] In one aspect, the disclosure concerns a compound of Formula (I): wherein: M is CR 5< R 6< , NR 7< , O or S; Q is CR 5< R 6< , NR 8< , O or S; T is CR 5< R 6< , NR 8< , O or S; X is absent, CR 5< R 6< , NR 8< , O or S; Z is CR 5< R 6< , NR 9< , O or S; two or more of M, Q, T, X and Z are NR 7< , NR 8< , NR 9< , O or S; R' is selected from the group consisting of H; F; Cl; Br; C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-3 alkenyl optionally substituted with one or more, identical or different, substituents R 10< ; -OC 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; -OC 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; - SC 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< and -SC 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 2< is selected from the group consisting of H; F; Cl; Br; C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< and -OC 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 3< is selected from the group consisting of H, F and Cl; R 4< is selected from the group consisting of H; C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-5 alkenyl optionally substituted with one or more, identical or different, substituents R 10< ; C 2-5 alkynyl optionally substituted with one or more, identical or different, substituents R 10< ; C 3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; phenyl optionally substituted with one or more, identical or different, substituents R 11< ; and benzyl optionally substituted with one or more, identical or different, substituents R 11< ; R 5< is independently selected from the group consisting of H, deuterium, F and C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 6< is independently selected from the group consisting of H, deuterium, F and C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 7< is independently selected from the group consisting of H, C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with phenyl optionally substituted with one or more, identical or different, substituents R 11< ; C 1-3 alkyl substituted with C 5 heteroaryl optionally substituted with one or more, identical or different, substituents R 11< ; and C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 8< is independently selected from benzyl optionally substituted with one or more, identical or different, substituents R 11< ; R 9< is independently selected from the group consisting of H, C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; C 1-3 alkyl substituted with phenyl optionally substituted with one or more, identical or different, substituents R 11< ; C 1-3 alkyl substituted with naphthyl optionally substituted with one or more, identical or different, substituents R 11< ; C 1-3 alkyl substituted with a 5- to 10-membered heteroaryl optionally substituted with one or more, identical or different, substituents R 11< ; and C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 10< ; R 10< is independently selected from the group consisting of H, deuterium, F, Cl and -OC 1-3 alkyl; and R 11< is independently selected from the group consisting of deuterium, methoxy, -OCF 3 , Me, CF 3 , CF 2 Cl, CF 2 H, CFH 2 , CD 3 , cyclopropyl, NH 2 , -NHAc, -C(=O)-NH 2 , nitro, cyano, CI, Br, I, and F; when R 5< and R 6< are individually C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 10< , then R 5< and R 6< are optionally joined together to form a ring; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof for use in treating, ameliorating and / or preventing a neuromuscular disorder, and / or for use in reversing and / or ameliorating a neuromuscular blockade.

[0140] In one embodiment, the compound for use is selected from the group consisting of: 7-chloro-2,3-dihydro-1,4-benzodioxine-5-carboxylic acid; 7-chloro-6-methoxy-2,3-dihydro-1,4-benzodioxine-5-carboxylic acid; 7-chloro-6-methyl-2,3-dihydro-1,4-benzodioxine-5-carboxylic acid; 7,8-dichloro-6-methyl-2,3-dihydro-1,4-benzodioxine-5-carboxylic acid; 6-chloro-7-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 7-chloro-6-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid; 7-chloro-6-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 5-chloro-7-fluoro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-fluoro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 7-chloro-6-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 7-chloro-6-fluoro-1,4-dimethyl-1,2,3,4-tetrahydroquinoxaline-5-carboxylic acid; 6-chloro-7-fluoro-2,2,4-trimethyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 7-chloro-6-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid; 7-chloro-6-fluoro-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid; 7-chloro-8-methoxy-5-methyl-2,3,4,5-tetrahydro-1,5-benzoxazepine-9-carboxylic acid; 7-chloro-8-fluoro-5-methyl-2,3,4,5-tetrahydro-1,5-benzoxazepine-9-carboxylic acid; 6-chloro-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 7-chloro-8-fluoro-2,3,4,5-tetrahydro-1,5-benzoxazepine-9-carboxylic acid; 7-chloro-8-ethoxy-5-methyl-2,3,4,5-tetrahydro-1,5-benzoxazepine-9-carboxylic acid; 6-chloro-7-fluoro-4-(3-methylbutyl)-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-4-ethyl-7-fluoro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzothiazine-8-carboxylic acid; 6-chloro-4-(cyclopropylmethyl)-7-fluoro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-fluoro-4-propyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 4-benzyl-6-chloro-7-fluoro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 7-fluoro-6-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-fluoro-4-[3-(4-fluorophenyl)propyl]-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-4-methyl-7-(propan-2-yloxy)-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-fluoro-4-[2-(4-fluorophenyl)ethyl]-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-4-methyl-7-(methylsulfanyl)-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-fluoro-4-(3-methoxypropyl)-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-4-ethyl-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzothiazine-8-carboxylic acid; 6-fluoro-7-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 7-methoxy-4,6-dimethyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-4-(propan-2-yl)-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-4-(2-phenylethyl)-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-4-[2-(4-methoxyphenyl)ethyl]-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-2-(methoxymethyl)-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-4-[(thiophen-3-yl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-2,2,4-trimethyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-2-(methoxymethyl)-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid; 6-chloro-7-fluoro-4-(2-methoxyethyl)-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-4-methyl-3,4-dihydrospiro[1,4-benzoxazine-2,1'-cyclobutane]-8-carboxylic acid; 6-chloro-4-[3-(furan-2-yl)propyl]-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-4-[(thiophen-2-yl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-4-[(thiophen-2-yl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-4-[(1,3-thiazol-2-yl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-5-fluoro-7-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 4-benzyl-7-chloro-6-fluoro-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid; 6-chloro-4-(cyclobutylmethyl)-7-fluoro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-4-[3-(1,3-thiazol-2-yl)propyl]-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-4,7-dimethyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-4-[(4-methoxyphenyl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-4-[(1,3-oxazol-2-yl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 7-chloro-6-fluoro-4-(3-methylbutyl)-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid; 4-benzyl-6-chloro-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-4-[2-(3,5-difluorophenyl)ethyl]-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 7-chloro-6-fluoro-4-[(thiophen-3-yl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid; 4-benzyl-6-fluoro-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; methyl 6-chloro-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate; ethyl 6-chloro-7-fluoro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate; methyl 7-chloro-6-fluoro-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylate; methyl 6-chloro-7-fluoro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate; 7-chloro-6-fluoro-4-propyl-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid; 7-chloro-6-fluoro-4-methyl-1,2,3,4-tetrahydro-5-quinoxalinecarboxylic acid; 7-chloro-6-fluoro-4-[(p-methoxyphenyl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid; 1-benzyl-7-chloro-6-fluoro-4-methyl-1,2,3,4-tetrahydro-5-quinoxalinecarboxylic acid; 7-chloro-6-fluoro-4-[(p-tolyl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid; 7-chloro-6-fluoro-4-[(1-naphthyl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid; 7-chloro-6-fluoro-4-[(o-tolyl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid; and 4-benzyl-6,7-dichloro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid.

[0141] The references to methods of treatment in this description are to be interpreted as references to the compounds, pharmaceutical compositions and medicaments of the present invention for use in a method for the treatment of the human (or animal) body by therapy (or for diagnosis).

[0142] In one aspect, the present disclosure relates to a method of treating, preventing and / or ameliorating a neuromuscular disorder, said method comprising administering a therapeutically effective amount of the compound or the compound for use as defined herein to a person in need thereof.

[0143] In one aspect, the present disclosure relates to a method of reversing and / or ameliorating a neuromuscular blockade, said method comprising administering a therapeutically effective amount of the compound or the compound for use as defined herein to a person in need thereof.

[0144] In one aspect, the present disclosure relates to a method for recovery of neuromuscular transmission, said method comprising administering a therapeutically effective amount of the compound or the compound for use as defined herein to a person in need thereof.

[0145] The person in need thereof may be a person having a neuromuscular disorder or a person at risk of developing a neuromuscular disorder or a person having symptoms of muscle weakness and / or fatigue. In another embodiment the person in need thereof is a person with reduced neuromuscular transmission safety with prolonged recovery after neuromuscular blockade. Types of neuromuscular disorders are defined herein above. In an embodiment the person has amyotrophic lateral sclerosis, spinal muscular atrophy, myasthenia gravis or Lambert-Eaton syndrome.

[0146] A therapeutically effective amount is an amount that produces a therapeutic response or desired effect in the person taking it. Administration routes, formulations and dosages can be optimized by persons of skill in the art.

[0147] The method of treatment may be combined with other methods that are known to treat, prevent and / or ameliorate neuromuscular disorders. The treatment method may for example be combined with administration of any of the agents mentioned herein above. In one embodiment the treatment is combined with administration of acetylcholine esterase inhibitor such as for example neostigmine or pyridostigmine.

[0148] In one aspect, the invention relates to a method for recovery of force in muscles with neuromuscular dysfunction, said method comprising administering a compound or a composition as defined herein to a subject in need thereof. The term "recovery of force in muscles with neuromuscular dysfunction" as used herein refers to the ability of a compound to recover contractile force in nerve-stimulated healthy rat muscle after exposure to submaximal concentration (115 nM) of tubocurarine for 90 minutes. Recovery of force is quantified as the percentage of the force prior to tubocurarine that is recovered after addition of the compound. In one embodiment, said recovery of force is >5%, such as >10%, such as >15%, such as >20%, such as >25%, such as >30%, such as >35%.

[0149] In one aspect, the present invention relates to a method of treating botulism poisoning, snake bites or nerve gas poisoning or preventing nerve gas poisoning, said method comprising administering a therapeutically effective amount of the compound as defined herein to a person in need thereof.

[0150] Another aspect of the disclosure relates to use of a compound as defined herein, for the manufacture of a medicament for the treatment, prevention and / or amelioration of a neuromuscular disorder.

[0151] Another aspect relates to use of a compound as defined herein, for the manufacture of a medicament or a reversal agent for reversing and / or ameliorating a neuromuscular blockade after surgery.

[0152] In one aspect, the present invention related to use of a compound as defined herein for the manufacture of a medicament for the treatment of botulism poisoning, snake bites or nerve gas poisoning or prevention of nerve gas poisoning.Method of manufacturing

[0153] In one aspect, the present disclosure relates to methods of manufacturing compounds or compounds for use according to formula (I).

[0154] Compounds according to the present invention may be prepared according to any conventional methods of chemical synthesis known by the skilled person, e.g. those described in the working examples. The starting materials for the processes described in the present application are known or may readily be prepared by conventional methods known by the skilled artisan from commercially available chemicals.

[0155] The end products of the reactions described herein may be isolated by conventional technique such as extraction, crystallisation, distillation, chromatography etc.

[0156] The compounds of this invention may exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of this invention.Examples General synthetic strategies

[0157] General methods for the synthesis of carboxylic acids and substitution on aromatic rings are featured in literature sources such as: March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 8th Edition, Michael B. Smith, Ed.; ISBN: 978-1-119-37179-3; John Wiley, 2020.Materials and methods Chemicals

[0158] Compounds for testing were obtained from different suppliers including Enamine, Vitas, and CanAm Bioresearch. For synthesis of particular compounds please see below.NMR Spectra

[0159] 1< H-NMR and 19< F-NMR spectra were either recorded on a Bruker AM-300 spectrometer and were calibrated using residual nondeuterated solvent as internal reference. Spectra were processed using Spinworks version 4.0 (developed by Dr. Kirk Marat, Department of Chemistry, University of Manitoba).

[0160] Otherwise 1< H, 13< C and 19< F NMR analyses were conducted Jeol 400 using deuterated chloroform or deuterated dimethyl sulfoxide as solvent. The shift (d) of each signal was measured in parts per million (ppm) relative the residual solvent peak, and the multiplicity reported together with the associated coupling constant (J), where applicable.LC / MS System

[0161] Samples were analysed my direct inject on a Waters Acquity QDa Mass Detector with a Waters 2695 HPLC. Mass spectra were recorded in ESI scan mode (negative / positive).HPLC method

[0162] The product was analysed by Waters 2695 HPLC consisting of a Waters 996 photodiode array detector, Kromasil Eternity C18, 5 µm, 4.6 X 150 mm column. Flow rate: 1 mL / minute, run time 20 minutes. Solvent A: methanol; solvent B: 0.1% formic acid in water. Gradient 0-100 % Solvent B over 15 minutes with monitoring at 280 nm.UPLC-MS method

[0163] UPLC-MS analysis was carried out on a Waters Acquity UPLC system consisting of an Acquity I-Class Sample Manager-FL, Acquity I-Class Binary Solvent Manager and an Acquity UPLC Column Manager. UV detection was afforded using an Acquity UPLC PDA detector (scanning from 210 to 400 nm), whilst mass detection was achieved using an Acquity QDa detector (mass scanning from 100-1250 Da; positive and negative modes simultaneously), and ELS detection was achieved using an Acquity UPLC ELS Detector.

[0164] Samples were prepared by dissolution (with or without sonication) into 1 mL of 50% (v / v) MeCN in water. The resulting solutions were then filtered through a 0.2 □m syringe filter before submitting for analysis. All of the solvents, including formic acid and 36% ammonia solution, were purchased as HPLC grade.Acidic 2 min UPLC-MS method

[0165] Eluent A: 0.1% v / v formic acid in 10mM ammonium formate Eluent B: 0.1% v / v formic acid in MeCN Flow rate 0.8mL / min; column oven 50°C; sample manager 20°C; injection volume 2 µL. 1.5 minutes equilibration time between samples on a Waters Acquity UPLC BEH C18 column (2.1 × 50 mm, 1.7 µm). Gradient as given in table below. Time (min) Eluent A (%) Eluent B (%) 0.009550.259551.255951.555951.659552.00955 Acidic 4 min UPLC-MS method

[0166] Eluent A: 0.1% v / v formic acid in 10mM ammonium formate Eluent B: 0.1% v / v formic acid in MeCN Flow rate 0.8mL / min; column oven 50°C; sample manager 20°C; injection volume 2 µL. 1.5 minutes equilibration time between samples on a Waters Acquity UPLC BEH C18 column (2.1 × 50 mm, 1.7 µm). Gradient as given in table below. Time (min) Eluent A (%) Eluent B (%) 0.009550.259552.755953.255953.359554.00955 Acidic 6 min UPLC-MS method

[0167] Eluent A: 0.1% v / v formic acid in 10mM ammonium formate Eluent B: 0.1% v / v formic acid in MeCN Flow rate 0.8mL / min; column oven 50°C; sample manager 20°C; injection volume 2 µL. 1.5 minutes equilibration time between samples on a Waters Acquity UPLC BEH C18 column (2.1 × 50 mm, 1.7 µm). Gradient as given in table below. Time (min) Eluent A (%) Eluent B (%) 0.009550.309556.005956.109557.00955 Basic 2 min UPLC-MS method

[0168] Eluent A: 0.1% ammonia in water Eluent B: 0.1% ammonia in MeCN Flow rate 0.8mL / min; column oven 50°C; sample manager 20°C; injection volume 2 µL. 1.5 minutes equilibration time between samples on a Waters Acquity UPLC BEH C18 column (2.1 × 50 mm, 1.7 µm). Gradient as given in table below. Time (min) Eluent A (%) Eluent B (%) 0.009550.259551.255951.555951.659552.00955 Basic 4 min UPLC-MS method

[0169] Eluent A: 0.1% ammonia in water Eluent B: 0.1% ammonia in MeCN Flow rate 0.8mL / min; column oven 50°C; sample manager 20°C; injection volume 2 µL. 1.5 minutes equilibration time between samples on a Waters Acquity UPLC BEH C18 column (2.1 × 50 mm, 1.7 µm). Gradient as given in table below. Time (min) Eluent A (%) Eluent B (%) 0.009550.259552.755953.255953.359554.00955 Basic 6 min UPLC-MS method

[0170] Eluent A: 0.1% ammonia in water Eluent B: 0.1% ammonia in MeCN Flow rate 0.8mL / min; column oven 50°C; sample manager 20°C; injection volume 2 µL. 1.5 minutes equilibration time between samples on a Waters Acquity UPLC BEH C18 column (2.1 × 50 mm, 1.7 µm). Gradient as given in table below. Time (min) Eluent A (%) Eluent B (%) 0.009550.309556.005956.109557.00955 Preparative HPLC purification

[0171] Preparative HPLC purification was carried out either on a Teledyne ISCO ACCQPrep ®< HP150 system or on a Waters Mass-directed PrepLC system. All masses were detected with electrospray ionisation (ESI).

[0172] Prep HPLC Columns: C1 XBridge BEH C18. Dimensions: 19 mm x 150 mm 5 µm. C2 XBridge BEH C18. Dimensions: 19 mm x 150 mm 5 µm.

[0173] Solvents: A: [10 mM NH 4 HCO 3 in H 2 O + 0.1% NH 3 ] or [H 2 O + 0.1% NH 3 ] B: [10 mM NH 4 HCO 3 in MeCN + 0.1% NH 3 ] or [MeCN + 0.1% NH 3 ]

[0174] Flow rate: 21.0 mL / minExample 1: 7-Chloro-6-methoxy-2,3-dihydro-1,4-benzodioxine-5-carboxylic acid (A-1)

[0175] Step 1: 5-Bromo-6-methoxy-2,3-dihydrobenzo[b][1,4]dioxine

[0176] To a stirred solution of 6-methoxy-2,3-dihydrobenzo[b][1,4]dioxine (3.32 g, 20 mmol) in anhydrous THF (20 mL), TMEDA (18.1 mL, 120 mmol) and n-BuLi (2.5 M in hexane, 24 mL, 60 mmol) were added at -50°C under an nitrogen atmosphere. The mixture was stirred at the same temperature for 2 h and 1,2-dibromotetrafluoroethane (7.15 mL, 60 mmol) was added. Stirring at -50°C was continued for 1 h and then the reaction was allowed to warm to ambient temperature. The reaction mixture was quenched with water (25 mL), extracted with EtOAc (2 x 50 mL) then the combined extracts were washed with brine (50 mL), dried (Na 2 SO 4 ) and evaporated. The residue was purified by chromatography on silica gel eluting with hexane / EtOAc (0-20%) to provide the title compound (4.7 g, 96%) as a yellow oil.

[0177] 1< H NMR (300 MHz, CDCl 3 ) δ ppm 6.85 (d, 1H); 6.49 (d, 1H); 4.43-4.37 (m, 2H); 4.29-4.22 (m, 2H); 3.88 (s, 3H); ES-MS: 246 [M+1].Step 2: 5-Bromo-7-chloro-6-methoxy-2,3-dihydrobenzo[b][1,4]dioxine

[0178] A mixture of 5-bromo-6-methoxy-2,3-dihydrobenzo[b][1,4]dioxine (380 mg, 1.55 mmol) and NCS (207 mg, 1.55 mmol) in DMF (5 mL) was stirred at ambient temperature for 24 h. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (2 x 100 mL). the combined extracts were washed with brine (50 mL), dried (Na 2 SO 4 ) and evaporated. The residue was purified by chromatography on silica gel eluting with hexane / EtOAc (0-10%) to provide the title compound (373 mg, 86%) as an oil.

[0179] 1< H NMR (300 MHz, CDCl 3 ) δ ppm 6.91 (s, 1H); 4.38-4.32 (m, 2H); 4.26-4.20 (m, 2H); 3.83 (s, 3H); ES-MS: 280 [M+1].Step 3: 7-Chloro-6-methoxy-2,3-dihydro-1,4-benzodioxine-5-carboxylic acid

[0180] To a solution of 5-bromo-7-chloro-6-methoxy-2,3-dihydrobenzo[b][1,4]dioxine (373 mg, 1.33 mmol) in THF (7 mL) at -78°C, n-BuLi (0.58 mL, 1.46 mmol, [1.6 M]) was added, and the mixture was stirred at ambient temperature for 1 h. The reaction mixture was cooled to 0°C and CO 2 gas was bubbled through it for 45 min. followed by quenching with water (25 mL) and washing with EtOAc (2 x 25 mL). The aqueous layer was acidified to pH ~2 with 1.0 N HCl and extracted with EtOAc (2 x 25 mL). The combined extracts were dried (Na 2 SO 4 ), concentrated under reduced pressure and the crude product was purified by semi-prep HPLC (10 to100% acetonitrile / 0.1% formic acid in water) to afford the title acid (250 mg, 76%) as an off-white solid.

[0181] 1< H NMR (300 MHz, CDCl 3 ) δ ppm 7.26 (s, 1H); 4.65-4.45 (m, 4H); 4.16 (s, 3H) ES-MS: 243 [M-1].

[0182] HPLC Retention Time: 8.62 min., purity >98% at 280 nm.Example 2: 6-Chloro-7-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid (A-2)

[0183] Step 1: 6-Chloro-7-methoxy-4-methyl-2,4-dihydro-1,4-benzoxazin-3-one

[0184] A mixture of 7-methoxy-4-methyl-2,4-dihydro-1,4-benzoxazin-3-one (1240 mg, 6.42 mmol) and NCS (900 mg, 6.74 mmol) in DMF (5 mL) was stirred at 65°C for 16 h. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (2 x 30 mL). The combined extracts were washed with brine (30 mL), dried (Na 2 SO 4 ) and concentrated. The resultant residue was purified by chromatography on silica gel eluting with hexane / EtOAc (0-5%) to provide the title compound (1.40 g, 95%).

[0185] 1< H NMR (300 MHz, CDCl 3 ) δ 7.26 (s, 1H), 6.90 (s, 1H), 4.80 (s, 2H), 3.14 (s, 3H), 3.60 (s, 3H) ppm.Step 2: 6-Chloro-7-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazine

[0186] A mixture of 6-chloro-7-methoxy-4-methyl-2,4-dihydro-1,4-benzoxazin-3-one (1.00 g, 4.393 mmol) and 1N BH 3 -THF solution (17.6 mL, 17.572 mmol) was stirred at 80°C for 16 h. The reaction mixture was quenched with MeOH (20 mL), evaporated, then 1N NaOH (50 mL) was added and the product was extracted with DCM (3 x 50 mL). The combined extracts were washed with brine (30 mL), dried (Na 2 SO 4 ) and concentrated. The resultant residue was purified by chromatography on silica gel eluting with hexane / EtOAc (0-5%) to provide the title compound (840 mg, 89%).

[0187] 1< H NMR (300 MHz, CDCl 3 ) δ 6.45 (s, 1H), 6.90 (s, 1H), 4.37 (m, 2H), 3.79 (s, 3H), 3.18 (m, 2H), 2.80 (s, 3H) ppm.Step 3: 6-Chloro-7-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid

[0188] To a solution of 6-chloro-7-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazine (200 mg, 0.936 mmol) in THF (4 mL) and TMEDA (0.9 mL, 5.616 mmol) at -78°C and n-BuLi (2.5 M in hexane) (1.12 mL, 2.808 mmol) was introduced. The reaction mixture was stirred at that temperature for 2 h and and CO 2 (g) was bubbled through it for 10 min. The reaction mixture was gradually brought to 0°C and quenched with 1NNaOH to pH ~11. Following washing with EtOAc (2 x 10 mL) the aqueous layer was separated and acidified with 1N HCl to pH ~1 prior to extraction with EtOAc (3 x 50 mL). The combined extracts were dried (Na 2 SO 4 ) and concentrated to afford the title compound (162 mg, 76%).

[0189] 1< H NMR (300 MHz, CD 3 OD) δ 6.73 (s, 1H), 4.31 (t, 2H), 3.81 (s, 3H), 3.37 (t, 2H), 2.80 (t, 2H),) ppm.

[0190] ES-MS: m / z 256.9 (M-1).

[0191] HPLC: Retention time 9.26 min., purity >98 % at 280 nm.Example 3: 7-Chloro-6-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid (A-3)

[0192] Step 1: 2-Amino-5-chloro-4-fluorophenol

[0193] To a solution of 5-chloro-4-fluoro-2-nitrophenol (10.0 g, 52.2 mmol) in EtOAc (120 mL), 5% Pt / C (1.00 g) was added. The reaction mixture was hydrogenated at 20 psi for 16 h. The reaction mixture was filtered through a pad of celite, washed with EtOAc (120 mL) and concentrated under reduced pressure to obtain the title compound (8.28 g, 98%) as a dark brown solid.

[0194] 1< H NMR (300 MHz, DMSO-d 6 ) δ 9.40 (s, 1H), 6.65 (d, 1H), 6.52 (d, 1H), 4.90 (br s, 2H).Step 2: 7-Chloro-6-fluoro-2,4-dihydro-1,4-benzoxazin-3-one

[0195] To a solution of 2-amino-5-chloro-4-fluorophenol (8.40 g, 52.0 mmol) in acetonitrile (125 mL) at 0°C, Cs 2 CO 3 (42.4 g, 130 mmol) was introduced, followed by the addition of 2-chloroacetyl chloride (4.4 mL, 54.2 mmol). The mixture was stirred at ambient temperature for 16 h before filtration through a celite pad, and the filter pad was washed with EtOAc (150 mL). The solvent was removed under reduced pressure and the residue treated with EtOAc (250 mL) and water (250 mL). The layers were separated, the aqueous layer was extracted with EtOAc (2 x 150 mL). The combined organic layers were dried (Na 2 SO 4 ), concentrated under reduced pressure and triturated with diethyl ether (3 x 40 mL) to obtain the title compound (4.92 g, 47%).

[0196] 1< H NMR (300 MHz, DMSO-d 6 ) δ 10.9 (s, 1H), 7.23 (d, 1H), 6.86 (d, 1H), 4.60 (s, 2H).Step 3: 7-Chloro-6-fluoro-2,3-dihydro-1,4-benzoxazine

[0197] To a solution of 7-chloro-6-fluoro-2,4-dihydro-1,4-benzoxazin-3-one (6.00g, 29.8 mmol) in THF (100 mL), at 0°C 1M BH 3 .THF (60 mL, 59.3 mmol) was added. The reaction mixture was stirred at ambient temperature for 24 h. The reaction mixture was cooled to 0 °C and carefully quenched with 1.0 N NaOH (120 mL). The reaction mixture was then diluted with water (120 mL) and the solvent was removed under reduced pressure. The residue was extracted with EtOAc (2 x 250 mL). The combined organic layers were dried (Na 2 SO 4 ) and concentrated under reduced pressure to provide the title compound (4.92 g, 97%).

[0198] 1< H NMR (300 MHz, CDCl 3 ) δ 6.77 (d, 1H), 6.36 (d, 1H), 4.19 (t, 2H), 3.84 (br s, 1H), 3.40 (t, 2H).Step 4: 5-Bromo-7-chloro-6-fluoro-2,3-dihydro-1,4-benzoxazine

[0199] NBS (0.59 g, 3.31 mmol) was added to a solution of 7-chloro-6-fluoro-3,4-dihydro-2H-1,4-benzoxazine (0.59 g, 3.14 mmol) in DMF (6.0 mL) and the reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were dried (Na 2 SO 4 ) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with EtOAc / hexane (0-50%) to obtain the title compound (0.30 g, 36%).

[0200] 1< H NMR (300 MHz, CDCl 3 ) δ 6.79 (d, 1H), 4.37 (br s, 1H), 4.19 (t, 2H), 3.52 - 3.48 (m, 2H).Step 5: 5-Bromo-7-chloro-6-fluoro-4-methyl-2,3-dihydro-1,4-benzoxazine

[0201] To a solution of 5-bromo-7-chloro-6-fluoro-3,4-dihydro-2H-1,4-benzoxazine (300 mg, 1.13 mmol) in THF (12 mL) at 0°C, NaH (60% dispersion in mineral oil) (180 mg, 4.50 mmol) was added and the mixture was stirred for 1 h. At that temperature, CH 3 I (0.84 mL, 13.5 mmol) was added, and the reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was cooled to 0°C, quenched with water (10 mL) and extracted with EtOAc (2 x 25 mL). The combined organic layers were dried (Na 2 SO 4 ) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with EtOAc / hexane (0-20%) to obtain the title compound (200 mg, 63%).

[0202] 1< H NMR (300 MHz, CDCl 3 ) δ 6.91 (d, 1H), 4.13 (t, 2H), 3.12 (t, 2H), 2.17 (s, 3H).Step 6: 7-Chloro-6-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid

[0203] n-BuLi (2.5 M in hexane) (0.32 mL, 0.78 mmol) was added to a solution of 5-bromo-7-chloro-6-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazine (200 mg, 0.71 mmol) in THF (7.0 mL) at -78°C and the reaction mixture was stirred at that temperature for 1 h. CO 2 gas was bubbled for 40 min. The reaction mixture was slowly brought to ambient temperature, quenched with water (15 mL) and extracted with EtOAc (2 x 20 mL). The aqueous layer was acidified to pH ~2.0 using 1.0 N HCl and extracted with EtOAc (2 x 25 mL). The combined organic layers were dried (Na 2 SO 4 ) and concentrated under reduced pressure to afford the title compound (102 mg, 58%).

[0204] 1< H NMR (300 MHz, CDCl 3 ) δ 7.08 (d, J H-F = 6.9 Hz, 1H), 4.31 (t, 2H), 3.28 (t, 2H), 2.87 (s, 3H).

[0205] ES-MS: m / z 246.0 (M+H).

[0206] HPLC: Retention time 9.27 min., purity: 95.6% at 280 nm.Example 4: 7-Chloro-6-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid (A-4)

[0207] Step 1: 7-Chloro-6-fluoro-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one

[0208] To a solution of 2-amino-5-chloro-4-fluorophenol (0.997 g, 6.2 mmol) in acetonitrile (25 mL), Cs 2 CO 3 (6.1 g, 18.6 mmol) was added, followed by 2-chloroacetyl chloride (0.732 g, 6.5 mmol) at 0°C. The reaction mixture was stirred at ambient temperature for 16 h. The solvent was removed under reduced pressure and the crude product was filtered through a celite pad with CH 2 Cl 2 / CH 3 OH (5 / 1) and concentrated. The residue was dissolved in DMF (10 mL) then Cs 2 CO 3 (6.1 g, 18.6 mmol) and methyl iodide (2.2 g, 15.5 mmol) was added. The reaction mixture was stirred at ambient temperature for 16 h., solvent was removed under reduced pressure, purified by column chromatography on silica gel eluting with CH 2 Cl 2 / CH 3 OH (0 - 2%) to provide the title compound (0.8 g, 60%) as a gum.

[0209] 1< H NMR (300 MHz, CD 3 OD) δ 7.17 - 7.09 (m, 2H), 4.87 (s, 2H), 3.35 (s, 3H).

[0210] 19< F NMR (300 MHz, CD 3 OD) δ -124.21 ppm.Step 2: 7-Chloro-6-fluoro-4-methyl-2,3-dihydro-1,4-benzoxazine

[0211] A mixture of 7-chloro-6-fluoro-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (0.800 g, 3.71 mmol), and 1M BH 3 .THF (14.84 mL, 14.84 mmol) was heated at reflux for 16 h. The reaction mixture was cooled, carefully quenched with CH 3 OH and evaporated. The residue was purified by column chromatography on silica gel eluting with hexane / EtOAc (0-20%) to afford the title compound (0.24 g, 32%) as a brown solid.

[0212] 1< H NMR (300 MHz, CDCl 3 ) δ 6.72 (d, 1H), 6.38 (d, 1H), 4.22 (t, 2H), 3.25 (t, 2H), 2.84 (s, 3H).

[0213] 19< F NMR (300 MHz, CDCl 3 ) δ -125.12 ppm.Step 3: 7-Chloro-6-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid

[0214] TMEDA (76 mg, 0.655 mmol) and n-BuLi (2.5 M in hexane) (0.262 mL, 0.655 mmol) were added to a solution of 7-chloro-6-fluoro-4-methyl-2,3-dihydro-1,4-benzoxazine (20 mg, 0.595 mmol) in THF (12 mL) at -78°C. The reaction mixture was stirred at that temperature for 1.5 h. and CO 2 gas was bubbled for 10 min. The reaction mixture was stirred at -78°C for 1 h., slowly brought to ambient temperature and quenched with 1M NaOH (5 mL). The reaction mixture was washed with EtOAc (2 x 10 mL), the aqueous layer was acidified to pH ~2.0 using 1.0 N HCl and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried (Na 2 SO 4 ), concentrated, and crystallised from CH2Cl2 / hexane to provide the title compound (55 mg, 38%) as an off-white solid. 1< H NMR (300 MHz, CDCl 3 ) δ 11.28- 10.06 (br s, 1H), 6.46 (d, J H-F =11.3 Hz, 1H), 4.31(t, 2H), 3.33 (t, 2H), 2.89 (s, 3H).

[0215] 19< F NMR (300 MHz, CDCl 3 ) δ -122.83 ppm.

[0216] ES-MS: m / z 244.2 (M-H).

[0217] HPLC Retention Time: 9.10 min.; purity >98% at 280 nm.Example 5: 5-Chloro-7-fluoro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid (A-5)

[0218] Step 1: Methyl 7-fluoro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate

[0219] Cs 2 CO 3 (5.266 g, 16.20 mmol) and 1,2-dibromoethane (0.57 mL, 6.48 mmol) were added to a solution of methyl 3-amino-6-fluoro-2-hydroxybenzoate (1.0 g, 5.41 mmol) in DMF (10 mL). The reaction mixture was heated at 70°C for 16 h, cooled to ambient temperature, quenched with water (30 mL) and extracted with EtOAc (3 x 50 mL). The combined extracts were dried (Na 2 SO 4 ) evaporated, and the residue purified by column chromatography on silica gel eluting with hexane / EtOAc (10 - 30%) to give the title compound, which was utilised directly in the next step.

[0220] 1< H NMR (300 MHz, CDCl 3 ); δ 6.70 (d, 1H), 6.51 (m, 1H), 4.32 (t, 2H), 3.87 (s, 3H), 3.43 (t, 2H) ppm.Step 2: 8-Methyl 4-tert-butyl 7-fluoro-3,4-dihydro-2H-1,4-benzoxazine-4,8-dicarboxylate

[0221] Di-tert-butyl dicarbonate (1.136 g, 5.21 mmol) and DMAP (0.029 g, 0.24 mmol) were added to a solution of methyl 7-fluoro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate (1.0 g, 4.74 mmol) in THF (15 mL). The reaction mixture was stirred at ambient temperature for 16 h, evaporated, and purified by column chromatography on silica gel eluting with EtOAc / hexane (10-20%) to provide the title compound (230 mg, 16 %) as an oil.

[0222] 1< H NMR (300 MHz, CDCl 3 ); δ 7.75 (d, 1H), 6.65 (t 1H), 4.26 (t, 2H), 3.89(s, 3H), 3.82 (t, 2H), 1.49 (s, 9H) ppm.

[0223] 19< F NMR (300 MHz, CDCl 3 ); δ -119.15 ppm.Step 3: Methyl 5-chloro-7-fluoro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate and methyl 6-chloro-7-fluoro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate

[0224] NCS (0.118 g, 0.89 mmol) was added to a solution of 8-methyl 4-tert-butyl 7-fluoro-3,4-dihydro-2H-1,4-benzoxazine-4,8-dicarboxylate (0.230 g, 0.74 mmol) in CH 3 CN (8 mL) and stirred at ambient temperature for 16 h. The reaction mixture was quenched with 2N HCl (5 mL), stirred for 15 min, neutralized with saturated Na 2 CO 3 solution, and extracted with EtOAc (2 x 30 mL). The combined extracts were washed with brine (30 mL), dried (Na 2 SO 4 ) and evaporated. The residue was purified by column chromatography on silica gel eluting with hexane / EtOAc (10 - 30%) to give methyl 5-chloro-7-fluoro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate (15 mg 16%) and methyl 6-chloro-7-fluoro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate both as oilsMethyl 5-chloro-7-fluoro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate

[0225] 1< H NMR (300 MHz, CDCl 3 ) δ 6.63 (d, 1H), 4.27 (t, 2H), 3.92 1(s, 3H), 3.40 (t, 2H) ppm. 19< F NMR (300 MHz, CD 3 OD) δ -129.13.Methyl 6-chloro-7-fluoro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate

[0226] 1< H NMR (300 MHz, CDCl 3 ) δ 6.52 (d, J H-F =7.4 Hz, 1H), 4.11 (t, 2H), 3.98 (s, 3H), 3.23(m, 2H) ppm.Step 4: 5-Chloro-7-fluoro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid

[0227] 1N NaOH (0.06 mL, 0.06 mmol) was added to a solution of methyl 6-chloro-7-fluoro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate (15 mg, 0.06 mmol) in MeOH (1 mL) and water (2 mL). The reaction mixture was subjected to microwave conditions at 150°C for 50 min., cooled and evaporated. The product was neutralised with 0.1% formic acid in water and extracted with a mixture of CH 2 Cl 2 / CH 3 OH (20 : 1) (3 x 10 mL), dried (Na 2 SO 4 ) and evaporated to obtain the title acid (13 mg, 91%).

[0228] 1< H NMR (300 MHz, CD 3 OD) δ 7.23 (d, 1H), 4.34 (t, 2H), 3.53 (t, 2H) ppm.

[0229] 19< F NMR (300 MHz, CD 3 OD) δ -121.79.

[0230] ES-MS: 230.5 [M-1].

[0231] HPLC: Retention time: 7.58 min., purity 97.2 % at 254 nm.Example 6: 6-Chloro-7-fluoro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid (A-6)

[0232] Step 1: 6-Chloro-7-fluoro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid

[0233] A 1N solution of NaOH (0.136 mL, 0.163 mmol) was added to a solution of methyl 6-chloro-7-fluoro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate (0.020 g, 0.0814 mmol) in MeOH (1 mL) and water (2 mL). The reaction mixture was subjected to microwave conditions at 150°C for 50 min., cooled and evaporated. The residue was purified by semi-prep HPLC eluting with 10-100% acetonitrile / 0.1% formic acid in water to provide the title compound (5 mg, 26 %) as a solid.

[0234] 1< H NMR (300 MHz, CDCl 3 ) δ 6.56 (d, J H-F =7.5 Hz, 1H), 4.12 (t, 2H), 3.21(m, 2H).

[0235] 19< F NMR (300 MHz, CDCl 3 ) δ 134.52

[0236] ES-MS: 232.60 [M+1].

[0237] HPLC: Retention Time: 7.57 min., purity 88.3 % at 254 nm.Example 7: 6-Chloro-7-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid (A-7)

[0238] Step 1: 6-Chloro-7-fluoro-4-methyl-2,4-dihydro-1,4-benzoxazin-3-one

[0239] Cs 2 CO 3 (4.429 g, 13.6 mmol, 2.0 eq.) and CH 3 I (1.27 mL, 20.39 mmol, 3.0 eq.) were added to a solution of 6-chloro-7-fluoro-2,4-dihydro-1,4-benzoxazin-3-one (1.37 g, 6.80 mmol, 1.0 eq.) in DMF (10 mL) the mixture stirred at ambient temperature for 18 h. EtOAc (25 mL) was added and the mixture was washed with sat. NaHCO 3 solution (3 x 50 mL). The organic layer was dried (Na 2 SO 4 ), evaporated, and the residual yellow oil was used in the next step without further purification.

[0240] 1< H NMR (300 MHz, CDCl 3 ); δ 7.26 (d, 1H), 7.12 (d, 1H), 4.90 (s, 2H), 3.62 (s, 3H) ppm. 19< F NMR (300 MHz, CDCl 3 ); δ 119.83 ppm.Step 2: 6-Chloro-7-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazine

[0241] A mixture of 6-chloro-7-fluoro-4-methyl-2,4-dihydro-1,4-benzoxazin-3-one (400 mg, 1.855 mmol, 1.0 eq.) and 1M BH 3 -THF solution (7.42 mL, 7.421 mmol, 4.0 eq.) was stirred at 70°C for 16 h. The reaction mixture was quenched with MeOH (20 mL), evaporated and 1N NaOH (50 mL) was added. Extraction with CH 2 Cl 2 (3 x 50 mL) followed by washing of the combined extracts with brine (50 mL) provided an organic layer which was dried (Na 2 SO 4 ). The residue on evaporation was purified by column chromatography on silica gel (0 - 5% EtOAc / hexane) to afford the title compound (320 mg, 85.5 % yield) as a brown solid

[0242] 1< H NMR (300 MHz, CDCl 3 ); δ 6.59 (d, 1H), 6.56 (d, 1H), 4.20 (m, 2H), 3.21 (m, 2H), 2.82 (s, 3H) ppm.

[0243] 19< F NMR (300 MHz, CDCl 3 ); δ 128.65 ppm.Step 3: 6-Chloro-7-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid

[0244] n-BuLi (2.5 M in hexane) (0.536 mL, 1.339 mmol, 1.5 eq.) was added to a solution of 6-chloro-7-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazine (180 mg, 0.893 mmol, 1.0 eq.) in THF (6 mL) and TMEDA (0.402 mL, 2.679 mmol, 3 eq.) at -78°C. The reaction mixture was stirred at the same temperature for 2 h. CO 2 (g) was bubbled for 10 min., and the reaction mixture was slowly brought to 0°C before being basified with 1M NaOH to pH ~11. It was washed with EtOAc (2 x 20 mL and the aqueous layer was separated and acidified with 1N HCl to pH ~1. The mixture was extracted with EtOAc (3 x 50 mL) and the combined extracts were dried (Na 2 SO 4 ) and concentrated to provide the title compound as a solid (150 mg 68).

[0245] 1< H NMR (300 MHz, CDCl 3 ); δ 6.76 (d, J H-F =6.9 Hz, 1H), 4.35 (t, 2H), 3.29 (t, 2H), 2.89 (s, 3H) ppm.

[0246] 19< F NMR (300 MHz, CDCl 3 ); δ 134.24 ppm.

[0247] ES-MS: 244.27 [M-1].

[0248] HPLC: Retention Time: 9.26 min., purity >98% at 254 nm.Example 8: 7-Chloro-6-fluoro-1,4-dimethyl-1,2,3,4-tetrahydroquinoxaline-5-carboxylic acid (A-8)

[0249] Step 1: 6-Chloro-7-fluoroquinoxaline-2,3(1H,4H)-dione

[0250] A mixture of 4-chloro-5-fluorobenzene-1,2-diamine (2.0 g, 12.45 mmol), and diethyl oxalate (8.5 mL, 62.3 mmol) was heated under microwave conditions at 180°C for 1.5h. The reaction mixture was cooled, hexane (50 mL) was added. The solid was filtered and washed with additional hexane to provide the title compound (1.5 g, 56%) as a dark solid.

[0251] 1< H NMR (300 MHz, DMSO-d 6 ) δ 12.04 (br s, 1H), 11.96 (br s, 1H), 7.20 (d, 1H), 7.06 (d, 1H).

[0252] 19< F NMR (300 MHz, DMSO-d 6 ) δ -122.97 ppm.Step 2: 6-Chloro-7-fluoro-1,4-dimethylquinoxaline-2,3(1H,4H)-dione

[0253] K 2 CO 3 (2.9 g, 21.0 mmol) and methyl iodide (2.6 g, 18.2 mmol) were added to a solution of 6-chloro-7-fluoroquinoxaline-2,3(1H,4H)-dione (1.5 g, 7.0 mmol), in DMF (12 mL). The reaction mixture was heated at 50°C for 3 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel eluting with CH 2 Cl 2 / CH 3 OH (0 -3%) to provide the title compound (0.5 g, 29%) as a brown solid.

[0254] 1< H NMR (300 MHz, CD 3 OD) δ 7.51 (d, 1H), 7.38 (d, 1H), 3.59 (s, 3H), 3.58 (s, 3H).

[0255] 19< F NMR (300 MHz, CD 3 OD) δ -121.80 ppm.Step 3: 6-Chloro-7-fluoro-1,4-dimethyl-1,2,3,4-tetrahydroquinoxaline

[0256] 6-Chloro-7-fluoro-1,4-dimethylquinoxaline-2,3(1H,4H)-dione (0.3 g, 1.24 mmol), and 1M BH 3 .THF (4.95 mL, 4.95 mmol) were heated at reflux for 16 h. The reaction mixture was cooled, carefully quenched with CH 3 OH, evaporated and the residue purified by column chromatography on silica gel eluting with hexane / EtOAc (0-50%) to obtain the title compound (0.12 g, 45%) as a light yellow solid.

[0257] 1< H NMR (300 MHz, CDCl 3 ) δ 6.37 (d, 1H), 6.25 (d, 1H), 3.34 (t, 2H), 3.32(t, 2H), 2.82 (s, 3H), 2.80 (s, 3H).

[0258] 19< F NMR (300 MHz, CDCl 3 ) δ -129.20 ppm.Step 4: 7-Chloro-6-fluoro-1,4-dimethyl-1,2,3,4-tetrahydroquinoxaline-5-carboxylic acid

[0259] n-BuLi (2.5 M in hexane) (0.25 mL, 0.615 mmol) was added to a solution of 6-chloro-7-fluoro-1,4-dimethyl-1,2,3,4-tetrahydroquinoxaline (120 mg, 0.559 mmol) in THF (10 mL) at -78°C, along with TMEDA (71.5 mg, 0.615 mmol). The reaction mixture was stirred at that temperature for 1.5 h., and CO 2 gas was bubbled for 10 min. The reaction mixture was stirred at -78°C for a further 1 h., slowly brought to ambient temperature and quenched with 1M NaOH (5 mL). The mixture was washed with EtOAc (2 x 10 mL), the aqueous layer was acidified to pH ~2.0 using 1.0 N HCl and concentrated. The residue was purified by semi-prep HPLC eluting 0 - 100% acetonitrile / 0.1% formic acid in water to obtain the title compound (5 mg, 4%) as a gum.

[0260] 1< H NMR (300 MHz, CDCl 3 ) δ 6.67 (d, J H-F =7.5 Hz, 1H), 3.31 - 3.26 (m, 2H), 3.25 - 3.19 (m, 2H), 2.90 (s, 3H), 2.89 (s, 3H).

[0261] 19< F NMR (300 MHz, CDCl 3 ) δ -133.88 ppm.

[0262] ES-MS: m / z 259.1 (M-H).

[0263] HPLC: Retention time 6.71 min., purity 96.0% at 254nm.Example 9: 6-Chloro-7-fluoro-2,2,4-trimethyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid (A-9)

[0264] Step 1: 6-Chloro-7-fluoro-2,2,4-trimethyl-1,4-benzoxazin-3-one

[0265] A mixture of KF (0.72 g, 12.4 mmol) and ethyl 2-bromo-2-methylpropanoate (1.21 g, 6.2 mmol) in DMF (5 mL) was added to a solution of 2-amino-4-chloro-5-fluorophenol (0.5 g, 3.1 mmol) and the reaction mixture was stirred at 60°C for 16 h in a sealed tube. The black solution was poured into a mixture of crushed ice and water; a solid formed, which was collected by filtration after the ice had melted. The solid was washed with water (15 mL), dried, and used for next stage without purification. It was dissolved in DMF (10 mL), Cs 2 CO 3 (4.04 g, 12.4 mmol), methyl iodide (1.32 g, 9.3 mmol) were added and the reaction mixture stirred at ambient temperature for 16 h. The solvent was removed under reduced pressure and the residue, purified by column chromatography on silica gel eluting with CH 2 Cl 2 / CH 3 OH (0-5%) to obtain the title compound (0.22 g, 29%) as an orange solid.

[0266] 1< H NMR (300 MHz, CDCl 3 ) δ 6.90 (d, 1H), 6.76 (d, 1H), 3.30 (s, 3H), 1.47 (s, 6H).

[0267] 19< F NMR (300 MHz, CD 3 OD) δ -120.64 ppm.Step 2: 6-Chloro-7-fluoro-2,2,4-trimethyl-3H-1,4-benzoxazine

[0268] A mixture of 6-chloro-7-fluoro-2,2,4-trimethyl-1,4-benzoxazin-3-one (0.22 g, 0.9 mmol), and 1M BH 3 .THF (3.6 mL, 3.6 mmol) was heated at reflux for 16 h. The reaction mixture was cooled, carefully quenched with CH 3 OH and evaporated. The residue was purified by column chromatography on silica gel eluting with hexane / EtOAc (0-20%) to obtain the title compound (0.20 g, 97%) as a colourless oil.

[0269] 1< H NMR (300 MHz, CDCl 3 ) δ 6.59 (d, 1H), 6.56 (d, 1H), 2.91 (s, 2H), 2.86 (s, 3H), 1.31 (s, 6H).

[0270] 19< F NMR (300 MHz, CD 3 OD) δ -128.82 ppm.Step 3: 6-chloro-7-fluoro-2,2,4-trimethyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid

[0271] TMEDA (0.11 g, 0.96 mmol) and n-BuLi (2.5 M in hexane) (0.384 mL, 0.96 mmol) were added to a solution of 6-chloro-7-fluoro-2,2,4-trimethyl-3H-1,4-benzoxazine (0.2 g, 0.87 mmol) in THF (10 mL) at -78°C. The reaction mixture was stirred at that temperature for 1.5 h., and CO 2 gas was bubbled for 10 min. The reaction mixture was stirred at - 78°C for 1 h., slowly brought to ambient temperature and quenched with 1M NaOH (5 mL). The reaction mixture was extracted with EtOAc (2 x 10 mL), the aqueous layer was acidified to pH ~2.0 using 1.0 N HCl and extracted with EtOAc (2 x 20 mL). The combined organic layers were dried (Na 2 SO 4 ), concentrated to provide the title compound (0.062 g, 26%) as an orange solid.

[0272] 1< H NMR (300 MHz, CDCl 3 ) δ 6.75 (d, J H-F =6.9 Hz, 1H), 3.04 (s, 2H), 2.92 (s, 3H), 1.41 (s, 6H).

[0273] 19< F NMR (300 MHz, CDCl 3 ) δ -126.67 ppm.

[0274] ES-MS: m / z 272.3 (M-H).

[0275] HPLC: Retention time 10.90 min., purity >98% at 254 nm.Example 10: 7-Chloro-6-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid (A-10)

[0276] Step 1: 7-Chloro-6-methoxy-2H-benzoxazin-3(4H)-one

[0277] Cs 2 CO 3 (11.0 g, 33.9 mmol) and 2-chloroacetyl chloride (1.54 g, 13.6 mmol) were added to a solution of 2-amino-5-chloro-4-methoxyphenol (1.97 g, 11.3 mmol) at 0°C in acetonitrile (25 mL) and the mixture was stirred at ambient temperature for 16 h. The solvent was removed under reduced pressure and the crude product filtered through celite pad using 20% CH 3 OH / CH2Cl2, concentrated to obtain the title compound (2.3 g, 95%) as a brown gum.

[0278] 1< H NMR (300 MHz, CDCl 3 ) δ 9.20 (br s, 1H) 7.02 (s, 1H), 6.42 (s, 1H), 4.57 (s, 2H), 3.84 (s, 3H).Step 2: 7-Chloro-6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazine

[0279] A mixture of 7-chloro-6-methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one (2.3 g, 10.77 mmol) and 1M BH 3 .THF (43.1 mL, 43.1 mmol) was heated at reflux for 16 h. The mixture was cooled, carefully quenched with CH 3 OH, evaporated and purified by column chromatography on silica gel eluting with CH 3 OH / CH 2 Cl 2 (0-2%) to obtain the title compound (1.2 g, 53%) as a brown solid.

[0280] 1< H NMR (300 MHz, CDCl 3 ) δ 6.79 (s, 1H), 6.21 (s, 1H), 4.18 (t, 2H), 3.78 (s, 3H), 3.40 (t, 2H).Step 3: 5-Bromo-7-chloro-6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazine

[0281] NBS (0.71 g, 4.0 mmol) was added to a solution of 7-chloro-6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazine (0.8 g, 4.0 mmol) in DMF (5 mL) at ambient temperature. The mixture was stirred at ambient temperature for 16 h. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel eluting with EtOAc / hexane (0-50%) to obtain the title compound (0.15 g, 13%) as a light brown solid.

[0282] 1< H NMR (300 MHz, CDCl 3 ) δ 6.79 (s, 1H), 4.18 (t, 2H), 3.81 (s, 3H), 3.47 (t, 2H).Step 4: 5-Bromo-7-chloro-6-methoxy-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine

[0283] NaH (60% dispersion in mineral oil) (0.77 g, 5.4 mmol) and methyl iodide (0.192 g, 1.35 mmol) were added to a solution of 5-bromo-7-chloro-6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazine (0.1 g, 0.54 mmol) in DMF (3 mL). The mixture was stirred at ambient temperature for 16 h and the solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel eluting with EtOAc / hexane (0-30%) to obtain the title compound (0.22 g, 29%) as a colourless oil.

[0284] 1< H NMR (300 MHz, CDCl 3 ) δ 6.88 (s, 1H), 4.13(t, 2H), 3.83 (s, 3H), 3.11 (t, 2H), 2.85 (s, 3H).Step 5: 7-Chloro-6-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid

[0285] n-BuLi (2.5 M in hexane) (0.15 mL, 0.38 mmol) was added to a solution of 5-bromo-7-chloro-6-methoxy-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (0.1 g, 0.342 mmol) in THF (6 mL) at -78°C. The mixture was stirred at that temperature for 0.5 h., CO 2 gas was bubbled for 10 min. and the reaction stirred at -78°C for a further 1 h. and slowly brought to ambient temperature before being quenched with 1M NaOH (5 mL). The mixture was washed with EtOAc (2 x 10 mL), the aqueous layer was acidified to pH ~2.0 using 1.0 N HCl and extracted with EtOAc (2 x 20 mL). The combined organic layers were dried (Na 2 SO 4 ), concentrated and the residue crystallised from CH 2 Cl 2 / hexane to provide the title compound (9 mg, 10%) as an off-white solid.

[0286] 1< H NMR (300 MHz, CDCl 3 ) δ 10.02- 9.80 (br s, 1H), 6.97 (s, 1H), 4.21 (t, 2H), 3.87 (s, 3H), 3.24 (t, 2H), 2.88 (s, 3H).

[0287] ES-MS: m / z 244.2 (M-H).

[0288] HPLC: Retention time 9.10 min., purity >98% at 280 nm.Example 11: 7-Chloro-6-fluoro-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid (A-11)

[0289] Step 1: 7-Chloro-6-fluoro-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid

[0290] A mixture of 5-bromo-7-chloro-6-fluoro-3,4-dihydro-2H-1,4-benzoxazine (300 mg, 1.13 mmol), Mo(CO) 6 (357 mg,1.36 mmol), (t-Bu) 3 -H BF4 (17 mg, 0.06 mmol), Pd(OAc) 2 (13 mg, 0.06 mmol) and Na 2 CO 3 (179 mg, 1.68 mmol) in DME (3.0 mL) and water (1.0 mL) was heated at 120°C under microwave conditions for 1 h. The reaction mixture was diluted with water (25 mL) and washed with EtOAc (2 x 25 mL). The aqueous layer was acidified to pH ~2.0 using 1.0 N HCl, extracted with EtOAc (2 x 25 mL) and the combined extracts were dried (Na 2 SO 4 ) and concentrated under reduced pressure to afford the title compound (65 mg, 25%).

[0291] 1< H NMR (300 MHz, CDCl 3 ) δ 7.77 (br s, 1H), 6.92 (d, J H-F = 7.2 Hz, 1H), 4.17 (t, 2H), 3.54 (t, 2H).

[0292] ES-MS: m / z 230.4 (M-H).

[0293] HPLC: Retention time 9.93 min., purity >98% at 254 nm.Example 12: 7-Chloro-8-methoxy-5-methyl-2,3,4,5-tetrahydro-1,5-benzoxazepine-9-carboxylic acid (A-12)

[0294] Step 1: 3-Chloro-2-fluoro-6-hydroxybenzoic acid

[0295] s-BuLi (1.4 M in cyclohexane) (8.25 mL, 11.55 mmol) was added to a solution of 1-chloro-2-fluoro-4-(methoxymethoxy)benzene (2.0 g, 10.5 mmol) in THF (25 mL) at - 78°C and TMEDA (1.34 g, 11.55 mmol). The reaction mixture was stirred at that temperature for 1.5 h., and CO 2 gas was bubbled for 10 min. The reaction mixture was stirred for a further hour at -78°C for 1 h., slowly brought to ambient temperature and quenched with 1M NaOH (20 mL). The reaction mixture was washed with EtOAc (2 x 10 mL), the aqueous layer was acidified to pH ~1.0 using 6.0 N HCl (20 mL) and stirred at ambient temperature for 16 h before being extracted with EtOAc (2 x 35 mL). The combined organic extracts were dried (Na 2 SO 4 ) and concentrated to obtain the title compound (1.4 g, 70%) as a white solid.

[0296] 1< H NMR (300 MHz, CD 3 OD) δ 7.56 - 7.46 (m, 1H), 6.79 (dd, 1H).

[0297] 19< F NMR (300 MHz, CD 3 OD) δ -108.56 ppm.Step 2: 3-Chloro-2-fluoro-6-hydroxy-5-nitrobenzoic acid

[0298] 70% HNO 3 (0.46 g, 5.12 mmol) was added to a solution of 3-chloro-2-fluoro-6-hydroxybenzoic acid (0.75 g, 3.94 mmol) in sulphuric acid (20 mL) at 0°C. The reaction mixture was stirred at ambient temperature for 16 h. The solution was poured into a mixture of crushed ice and water and a solid formed, which was collected by filtration after the ice had melted. The solid was washed with water (15 mL) and dried to obtain the title compound (0.70 g, 75%) as a light yellow solid.

[0299] 1< H NMR (300 MHz, CD 3 OD) δ 8.39 (d, 1H).

[0300] 19< F NMR (300 MHz, CD 3 OD) δ -100.38 ppm.Step 3: Methyl 3-chloro-6-hydroxy-2-methoxy-5-nitrobenzoate

[0301] A solution of 3-chloro-2-fluoro-6-hydroxy-5-nitrobenzoic acid (0.70 g, 2.97 mmol) in CH 3 OH (20 mL) and sulphuric acid (2 mL) was heated at reflux for 48 hours. The reaction mixture was cooled, evaporated, and purified by column chromatography on silica gel eluting with CH 3 OH / CH 2 Cl 2 (0-30%) to obtain the title compound (0.5 g, 64%) as a yellow oil.

[0302] 1< H NMR (300 MHz, CDCl 3 ) δ 10.90 (br s, 1H), 8.23 (s, 1H), 4.02 (s, 3H), 3.98 (s, 3H).Step 4: Methyl 3-amino-5-chloro-2-hydroxy-6-methoxybenzoate

[0303] 5% Pt / C catalyst (0.05 g) was added to a solution of methyl 3-chloro-6-hydroxy-2-methoxy-5-nitrobenzoate (0.50 g, 2.97 mmol) in EtOAc (20 mL). The reaction mixture was stirred under a hydrogen atmosphere at 30 psi for 4 h., filtered through a celite pad, washed with CH 3 OH (20 mL) and concentrated to obtain the title compound (0.4 g, 90%) as a dark brown solid.

[0304] 1< H NMR (300 MHz, CD 3 OD) δ 6.93 (s, 1H), 3.99 (s, 3H), 3.76 (s, 3H).Step 5: Methyl 3-amino-5-chloro-2-(3-chloropropoxy)-6-methoxybenzoate

[0305] 1-Bromo-3-chloropropane (2.37 g, 15.1 mmol), K 2 CO 3 (2.1 g, 15.1 mmol) was added to a solution of methyl 3-amino-5-chloro-2-hydroxy-6-methoxybenzoate (0.35 g, 1.51 mmol) in acetone (20 mL). The reaction mixture was heated at reflux for 16 h., cooled and extracted with EtOAc (2 x 20 mL), evaporated and the residue was purified by column chromatography on silica gel eluting with EtOAc / hexane (0-50%) to obtain the title compound (0.45 g, 97%) as a yellow oil.

[0306] 1< H NMR (300 MHz, CD 3 OD) δ 6.82 (s, 1H), 4.09 (t, 2H), 3.93 (s, 3H), 3.81 (s, 3H), 3.76 (t, 2H), 2.23 - 2.12 (m, 2H).Step 6: Methyl 7-chloro-8-methoxy-5-methyl-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-9-carboxylate

[0307] K 2 CO 3 (0.4 g, 2.92 mmol) and KI (0.485 g, 2.92 mmol) were added to a solution of methyl 3-amino-5-chloro-2-(3-chloropropoxy)-6-methoxybenzoate (0.45 g, 1.46 mmol) in DMF (6 mL) and the reaction mixture was heated at 85°C for 48 h., cooled and evaporated. The crude residue in THF (10 mL) was mixed with NaH (60% in mineral oil) (0.234 g, 5.84 mmol) at 0°C and the reaction mixture was stirred for 30 min. Methyl iodide (0.41 g, 2.92 mmol) was added at 0°C and the reaction stirred at ambient temperature for 16 h. The reaction mixture was treated with water (20 mL) and the mixture extracted with EtOAc (2 x 20 mL). The combined extracts were evaporated, and the residue purified by column chromatography on silica gel eluting with EtOAc / hexane (0-50%) to obtain the title compound (0.026 g, 6%) as a yellow oil.

[0308] 1< H NMR (300 MHz, CD 3 OD) δ 6.83 (s, 1H), 4.07 (t, 2H), 3.91 (s, 3H), 3.83 (s, 3H), 3.13 (t, 2H), 2.86 (s, 3H), 2.07 - 1.93 (m, 2H).Step 7: 7-Chloro-8-methoxy-5-methyl-2,3,4,5-tetrahydro-1,5-benzoxazepine-9-carboxylic acid

[0309] NaOH (0.018 g, 0.46 mmol) was added to a solution of methyl 7-chloro-8-methoxy-5-methyl-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-9-carboxylate (0.026 g, 0.091 mmol) in a mixture of MeOH and H 2 O (3 and 1 mL). The reaction mixture was heated at 110°C for 1 h. under microwave conditions, cooled and evaporated. The residue was purified by semi-prep HPLC eluting with 10 - 100% acetonitrile / 0.1% formic acid in water to obtain the title compound (15 mg, 61%) as a colourless liquid.

[0310] 1< H NMR (300 MHz, CD 3 OD) δ 6.92 (s, 1H), 4.07 (t, 2H), 3.84 (s, 3H), 3.13 (t, 2H), 2.87 (s, 3H), 2.08 - 1.99 (m, 2H).

[0311] ES-MS: m / z 270.2 (M-H).

[0312] HPLC: Retention time 7.99 min., purity >98% at 254 nm.Example 13: 7-Chloro-8-fluoro-5-methyl-2,3,4,5-tetrahydro-1,5-benzoxazepine-9-carboxylic acid (A-13) and 7-chloro-8-ethoxy-5-methyl-2,3,4,5-tetrahydro-1,5-benzoxazepine-9-carboxylic acid (A-16)

[0313] Step 1: Ethyl 3-amino-5-chloro-2-(3-chloropropoxy)-6-fluorobenzoate

[0314] K 2 CO 3 (2.96 g, 21.6 mmol), and 1-bromo-3-chloropropane (0.40 g, 2.57 mmol) was added to a solution of ethyl 3-amino-5-chloro-6-fluoro-2-hydroxybenzoate (0.5 g, 2.14 mmol) in acetone (30 mL). The reaction mixture was heated at reflux for 16 h, cooled, treated with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined extracts were dried (Na 2 SO 4 ), evaporated and the residue purified by column chromatography on silica gel eluting with hexane / EtOAc (0-50%) to provide the title compound (0.45 g, 68%) as a yellow oil.

[0315] 1< H NMR (300 MHz, CDCl 3 ) δ 6.81 (d, 1H), 4.41 (q, 2H), 4.10 (t, 2H), 3.76 (t, 2H), 2.25 - 2.08 (m, 2H), 1.38 (t, 3H).

[0316] 19< F NMR (300 MHz, CDCl 3 ) δ -128.62 ppm.Step 2: Ethyl 7-chloro-8-fluoro-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-9-carboxylate

[0317] K 2 CO 3 (0.393 g, 2.84 mmol), and KI (0.47 g, 2.84 mmol) were added to a solution of ethyl 3-amino-5-chloro-2-(3-chloropropoxy)-6-fluorobenzoate (0.44 g, 1.42 mmol) in DMF (6 mL). The reaction mixture was heated at 85°C for 16 h in a sealed tube, cooled and evaporated. The residue was purified by column chromatography on silica gel eluting with hexane / EtOAc (10 - 50%) to give the title compound (0.38 g, 98%) as a light-yellow gum.

[0318] 1< H NMR (300 MHz, CDCl 3 ) δ 6.80 (d, 1H), 4.40 (q, 2H), 4.10 (t, 2H), 3.20 (t, 2H), 2.07 - 1.95 (m, 2H), 1.37 (t, 3H).

[0319] 19< F NMR (300 MHz, CDCl 3 ) δ -127.45 ppm.

[0320] ES- MS: m / z 274.6 (M+H).Step 3: Ethyl 7-chloro-8-fluoro-5-methyl-2,3,4,5-tetrahydro-1,5-benzoxazepine-9-carboxylate and ethyl 7-chloro-8-ethoxy-5-methyl-2,3,4,5-tetrahydro-1,5-benzoxazepine-9-carboxylate

[0321] NaH (60% in mineral oil) (0.222 g, 5.55 mmol) was added to a solution of ethyl 7-chloro-8-fluoro-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-9-carboxylate in DMF (4 mL) at 0°C and stirred for 30 min. Methyl iodide (0.24 g, 1.67 mmol) was added at 0°C and the reaction mixture stirred at ambient temperature for 16 h., evaporated and the residue purified by column chromatography on silica gel eluting with hexane / EtOAc (0 - 30%) to afford a mixture of ethyl 7-chloro-8-fluoro-5-methyl-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-9-carboxylate and ethyl 7-chloro-8-ethoxy-5-methyl-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-9-carboxylate (0.2 g, 50%) as a yellow gum, used in the next step without separation.

[0322] 1< H NMR (300 MHz, CDCl 3 ) δ 6.80 (d, 1H), 4.46 - 4.31 (m, 2H), 4.14 - 3.98 (m, 2H), 3.17 - 3.04 (m, 2H), 2.85 (s, 3H), 2.08 - 1.94 (m, 2H), 1.44 - 1.26 (m, 6H).

[0323] 19< F NMR (300 MHz, CDCl 3 ) δ -127.45 ppm.Step 4: 7-Chloro-8-fluoro-5-methyl-2,3,4,5-tetrahydro-1,5-benzoxazepine-9-carboxylic acid and 7-chloro-8-ethoxy-5-methyl-2,3,4,5-tetrahydro-1,5-benzoxazepine-9-carboxylic acid

[0324] NaOH (0.084 g, 2.1 mmol) was added to a solution of 7-chloro-8-fluoro-5-methyl-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-9-carboxylic acid and 7-chloro-8-ethoxy-5-methyl-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-9-carboxylic acid (0.06 g, 0.21 mmol) in MeOH / H 2 O (4 / 2 mL). The reaction mixture was heated at 110°C for 1 hour under microwave conditions, cooled and evaporated. The resultant residue was separated by semi-prep HPLC eluting with acetonitrile / 0.1% formic acid in water 30 - 50% to provide 7-chloro-8-fluoro-5-methyl-2,3,4,5-tetrahydro-1,5-benzoxazepine-9-carboxylic acid (6 mg) as a gum and 7-chloro-8-ethoxy-5-methyl-2,3,4,5-tetrahydro-1,5-benzoxazepine-9-carboxylic acid (8.7 mg) as an off-white solid.7-Chloro-8-fluoro-5-methyl-2,3,4,5-tetrahydro-1,5-benzoxazepine-9-carboxylic acid (A-13)

[0325] 1< H NMR (300 MHz, CD 3 OD) δ 6.91 (d, 1H), 4.10 (t, 2H), 3.13 (t, 2H), 2.87 (s, 3H), 2.09 - 1.97 (m, 2H).

[0326] 19< F NMR (300 MHz, CD 3 OD) δ -130.57 ppm.

[0327] ES- MS: m / z 260.6 (M+H).

[0328] HPLC: Retention time 8.86 min., Purity: 98.7% @ 254 nm.7-Chloro-8-ethoxy-5-methyl-2,3,4,5-tetrahydro-1,5-benzoxazepine-9-carboxylic acid (A-16)

[0329] 1< H NMR (300 MHz, CD 3 OD) δ 6.89 (s, 1H), 4.13 - 4.02 (m, 4H), 3.12 (t, 2H), 2.87 (s, 3H), 2.08 - 1.97 (m, 2H) 1.35 (t, 3H).

[0330] ES- MS: m / z 286.6 (M+H).

[0331] HPLC: Retention time 9.21 min., Purity: 95.9% @ 254 nm.Example 14: 6-Chloro-7-methoxy-2,2,4-trimethyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid (A-37)

[0332] Step 1: 6-Chloro-7-methoxy-2,2,4-trimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one

[0333] KF (0.604 g, 10.4 mmol), and ethyl 2-bromo-2-methylpropanoate (1.0 g, 5.2 mmol) were added to a solution of 2-amino-4-chloro-5-methoxyphenol (0.45 g, 2.6 mmol) in DMF (5 mL) and the reaction mixture was stirred at 60°C for 16 h in a sealed tube. The dark solution was poured on to a mixture of crushed ice and water; a solid formed, which was collected by filtration after the ice had melted. The solid was washed with water (15 mL), dried in vacuo and utilised in the next step without purification.

[0334] Cs 2 CO 3 (3.4 g, 10.4 mmol), and methyl iodide (1.1 g, 7.8 mmol) were added to the solid product from the previous step in DMF (10 mL) and the reaction mixture was stirred at ambient temperature for 16 h. The solvent was removed and the residue was purified by column chromatography on silica gel eluting with hexane / EtOAc (0 - 30%) to obtain the title compound (0.22 g, 33%) as a gum.

[0335] 1< H NMR (300 MHz, CDCl 3 ) δ 7.00 (s, 1H), 6.67 (s, 1H), 3.90 (s, 3H), 3.37 (s, 3H), 1.55(s, 6H).Step 2: 6-Chloro-7-methoxy-2,2,4-trimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine

[0336] 6-Chloro-7-methoxy-2,2,4-trimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one (0.21 g, 0.82 mmol), and 1M BH 3 .THF (3.3 mL, 3.3 mmol) were heated at reflux for 16 h. The reaction mixture was cooled, carefully quenched with methanol (10 mL) and evaporated. The resultant residue was purified by column chromatography on silica gel eluting with hexane / EtOAc (0 - 20%) to obtain the title compound (0.20 g, 97%) as an oil.

[0337] 1< H NMR (300 MHz, CDCl 3 ) δ 6.70 (s, 1H), 6.50 (s, 1H), 3.85 (s, 3H), 2.94 (s, 2H), 2.89 (s, 3H), 1.39 (s, 6H).Step 3: 6-Chloro-7-methoxy-2,2,4-trimethyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid

[0338] s-BuLi (1.4 M in cyclohexane) (0.52 mL, 0.73 mmol) and TMEDA (0.085 g, 0.73 mmol) were added to a solution of 6-chloro-7-methoxy-2,2,4-trimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (0.16 g, 0.66 mmol) in THF (6 mL) at -78°C. The reaction mixture was stirred at that temperature for 1.5 h and CO 2 gas was bubbled for 10 min. The reaction mixture was stirred at -78°C for 1 h., slowly brought to ambient temperature and quenched with 1N NaOH (5 mL). The reaction mixture was washed with EtOAc (2 x 10 mL), the aqueous layer was acidified to pH ~2.0 using 1.0 N HCl and extracted into EtOAc (2 x 20 mL). The combined extracts were dried (Na 2 SO 4 ) and concentrated in vacuo to afford the title acid (0.04 g, 21%) as a white solid.

[0339] 1< H NMR (300 MHz, CD 3 OD) δ 6.74 (s, 1H), 3.81 (s, 3H), 3.02 (s, 2H), 2.92 (s, 3H), 1.33 (s, 6H).

[0340] ES- MS: m / z 284.2 (M-H).

[0341] HPLC: Retention time 10.39 min., Purity: >99% @ 254 nm.Example 15: 6-chloro-7-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzothiazine-8-carboxylic acid (A-19)

[0342] Step 1: Methyl (4-chloro-5-fluoro-2-nitrophenylthio)acetate

[0343] Triethylamine (4.40 mL, 31.0 mmol) was added to a solution of 1-chloro-2,4-difluoro-5-nitrobenzene (5.00 g, 25.8 mmol) and methyl thioglycolate (2.30 mL, 25.8 mmol) in CH 2 Cl 2 (40 mL) at 0°C. The reaction mixture was stirred at ambient temperature for 16 h and quenched with 1.0 N HCl (75 mL). The organic layer was dried (Na 2 SO 4 ), concentrated under reduced pressure and the residue was purified by column chromatography on silica gel eluting with CH 2 Cl 2 to obtain the title compound (5.06 g, 70%).

[0344] 1< H NMR (300 MHz, CDCl 3 ); δ 8.11 (d, 1H), 7.21 (d, 1H), 3.81 (s, 2H), 3.79 (s, 3H).Step 2: 6-Chloro-7-fluoro-2,4-dihydro-1,4-benzothiazin-3-one

[0345] Fe powder (3.99 g, 71.4 mmol) was added to a solution of methyl (4-chloro-5-fluoro-2-nitrophenylthio)acetate (4.00 g, 17.2 mmol) in AcOH (55.0 mL) at ambient temperature. The reaction mixture was heated at 95°C for 2 h and stirred at ambient temperature for 20 h. The reaction mixture was quenched with 2.0 N HCl (200 mL) and stirred for 1 h. The precipitate was collected by filtration, washed with water (20 mL) and dissolved in EtOAc (60 mL). The solution was washed with water (60 mL) and the organic layer dried (Na 2 SO 4 ), concentrated under reduced pressure and the residue was triturated with hexanes (10 mL) to provide the title compound (0.41 g, 11 %).

[0346] 1< H NMR (300 MHz, CDCl 3 ); δ 8.26 (br s, 1H), 7.14 (d, 1H), 6.91 (d, 1H), 3.43 (s, 2H).Step 3: 6-Chloro-7-fluoro-4-methyl-2,4-dihydro-1,4-benzothiazin-3-one

[0347] CH 3 I (0.31 mL, 6.18 mmol) was added to a suspension of 6-chloro-7-fluoro-2,4-dihydro-1,4-benzothiazin-3-one (0.27 g, 1.24 mmol) and Cs 2 CO 3 (0.61 g, 1.87 mmol) in DMF (6.0 mL) in a sealed tube at 0°C. The reaction mixture was stirred at ambient temperature for 16 h, quenched with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined extracts were washed with 1.0 N HCl (2 x 20 mL), dried (Na 2 SO 4 ) and concentrated under reduced pressure to obtain the title compound (180 mg, 63%). 1< H NMR (300 MHz, CDCl 3 ); δ 7.17 (d, 1H), 7.09 (d, 1H), 3.42 (s, 5H).Step 4: 6-Chloro-7-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzothiazine

[0348] BH 3 -THF (1.0 M solution) (4.0 mL, 5.42 mmol) was added to 6-chloro-7-fluoro-4-methyl-2,4-dihydro-1,4-benzothiazin-3-one (180 mg, 0.78 mmol) at 0°C and the reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was cooled to 0 °C and quenched with 1.0 N NaOH (3.0 mL). EtOAc (20 mL) and water (20 mL) were added to the mixture, and layers separated. The aqueous layer was extracted with EtOAc (2 x 15 mL) and combined extracts were dried (Na 2 SO 4 ) and concentrated under reduced pressure to obtain the title compound (150 mg, 89 %).

[0349] 1< H NMR (300 MHz, CDCl 3 ); δ 6.86 (d, 1H), 6.61 (d, 1H), 3.52 - 3.48 (m, 2H), 3.09 - 3.06 (m, 2H), 2.91 (s, 3H).

[0350] Step 5: 6-Chloro-7-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzothiazine-8-carboxylic acid n-BuLi (2.5 M in hexane) (0.33 mL, 0.83 mmol) and TMEDA (0.13 mL, 0.83 mmol) were added to a solution of 6-chloro-7-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzothiazine (150 mg, 0.69 mmol) in THF at -78°C. The reaction mixture was stirred at -78°C for 1 h and CO 2 (g) was bubbled through it for 45 min. The reaction mixture was slowly brought to 0°C, quenched with water (10 mL) and washed with EtOAc (3 x 15 mL). The aqueous layer was acidified with 1.0 N HCl to ~pH 4 and the mixture was extracted with EtOAc (2 x 20 mL). The combined extracts were dried (Na 2 SO 4 ), concentrated and triturated with hexanes (2.0 mL) to afford the title compound (42 mg, 14 %).

[0351] 1< H NMR (300 MHz, CD 3 OD); δ 6.73 (d, 1H), 3.60 (t, 2H), 2.97 (t, 2H), 2.96 (s, 3H) ES-MS: m / z 262.5 (M+1)

[0352] HPLC retention time: 10.2 min., purity: 98.0% at 280 nm.Example 16: 6-Chloro-4-methyl-7-(methylsulfanyl)-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid (A-26)

[0353] Step 1: 4-Chloro-5-(methylthio)-2-nitrophenol

[0354] NaSCH 3 (2.20 g, 31.4 mmol) was added to a solution of 4-chloro-5-fluoro-2-nitrophenol (3.00 g, 15.7 mmol) in methanol (30 mL) at 0°C in a sealed tube and the reaction mixture was heated at 80°C for 3 h. The reaction was brought to room temperature and the solvent was removed under reduced pressure. The residue was treated with EtOAc (60 mL) and water (60 mL), the layers were separated, and the aqueous layer was extracted further with EtOAc (2 x 60 mL). The combined organic layers were dried (Na 2 SO 4 ), concentrated under reduced pressure and the residue was triturated with ether (2 x 5.0 mL) to obtain the title compound (2.30 g, 67 %).

[0355] 1< H NMR (300 MHz, CDCl 3 ); δ 10.7 (s, 1H), 8.01 (s, 1H), 6.82 (s, 1H), 3.53 (s, 3H).Step 2: 2-Amino-4-chloro-5-(methylthio)phenol

[0356] Tin(II) chloride dihydrate (7.08 g, 31.4 mmol) was added to a solution of 4-chloro-5-(methylthio)-2-nitrophenol (2.30 g, 10.5 mmol) in ethanol (25 mL). The reaction mixture was heated at 80°C for 1 h, solvent was removed under reduced pressure, the pH was adjusted with satd. NaHCO 3 to ~9 and the mixture was extracted with EtOAc (3 x 30 mL). The combined extracts were dried (Na 2 SO 4 ) and concentrated under reduced pressure to obtain the title compound (1.00 g, 50 %).

[0357] 1< H NMR (300 MHz, CDCl 3 ); δ 6.80 (s, 1H), 6.73 (s, 1H), 3.72 (br s, 2H), 2.39 (s, 3H).Step 3: 6-Chloro-7-(methylthio)-2,4-dihydro-1,4-benzoxazin-3-one

[0358] Chloroacetyl chloride (0.46 mL, 5.84 mmol) was added to a suspension of 2-amino-4-chloro-5-(methylthio)phenol (1.00g, 5.27 mmol) and Cs 2 CO 3 (4.29 g, 13.2 mmol) at 0°C. The reaction mixture was stirred at ambient temperature for 16 h and the solvent was removed under reduced pressure. EtOAc (30 mL) and water (30 mL) were introduced to the residue, the layers were separated and the aqueous layer was extracted with EtOAc (2 x 30 mL). The combined extracts were dried (Na 2 SO 4 ), concentrated under reduced pressure and the residue was triturated with diethyl ether (3 x 10 mL) to provide the title compound (0.98 g, 81%).

[0359] 1< H NMR (300 MHz, DMSO-d 6 ) δ 10.8 (br s, 1H), 6.93 (s, 1H), 6.90 (s, 1H), 4.60 (s, 2H), 2.45 (s, 3H).Step 4: 6-Chloro-4-methyl-7-(methylthio)-2,4-dihydro-1,4-benzoxazin-3-one

[0360] CH 3 I (1.10 mL, 21.3 mmol) was added to a mixture of 6-chloro-7-(methylthio)-2,4-dihydro-1,4-benzoxazin-3-one (0.98 g, 4.27 mmol), Cs 2 CO 3 (2.08 g, 6.38 mmol) and DMF (12.0 mL) in a sealed tube at 0°C. The reaction mixture was stirred at ambient temperature for 16 h, quenched with water (20 mL) and extracted into EtOAc (2 x 20 mL). The combined organic layers were washed with 1.0 N HCl (2 x 20 mL), dried (Na 2 SO 4 ) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with EtOAc / hexanes (10 - 20%) to afford the title compound (0.70 g, 67%).

[0361] 1< H NMR (300 MHz, CDCl 3 ); δ 6.98 (s, 1H), 6.82 (s, 1H), 4.60 (s, 2H), 3.32 (s, 3H), 2.46 (s, 3H).Step 5: 6-Chloro-4-methyl-7-(methylthio)-3,4-dihydro-2H-1,4-benzoxazine

[0362] BH 3 -THF (1.0 M solution) (6.0 mL, 6.15 mmol) was added to 6-chloro-4-methyl-7-(methylthio)-2,4-dihydro-1,4-benzoxazin-3-one (300 mg, 1.23 mmol) at 0°C and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was cooled to 0°C, quenched with 1.0 N NaOH (3.0 mL) and EtOAc (20 mL) and water (20 mL) were introduced. The layers were separated and the aqueous layer was extracted further with EtOAc (2 x 20 mL). The combined extracts were dried (Na 2 SO 4 ) and concentrated under reduced pressure to obtain the title compound (250 mg, 88 %).

[0363] 1< H NMR (300 MHz, CDCl 3 ); δ 6.74 (s, 1H), 6.67 (s, 1H), 4.28 - 4.25 (m, 2H), 3.27 - 3.24 (m, 2H), 2.86 (s, 3H), 2.40 (s, 3H).Step 6: 6-Chloro-4-methyl-7-(methylsulfanyl)-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid

[0364] n-BuLi (2.5 M in hexane) (1.00 mL, 2.50 mmol) was added to a solution of 6-chloro-4-methyl-7-(methylthio)-3,4-dihydro-2H-1,4-benzoxazine (290 mg, 1.26 mmol) and TMEDA (0.38 mL, 2.52 mmol) in THF at -78°C. The reaction mixture was stirred at that temperature for 1 h and CO 2 was bubbled for 45 min. The reaction mixture was slowly brought to 0°C, quenched with water (15 mL) and washed with EtOAc (3 x 20 mL). The aqueous layer was acidified with 1.0 N HCl to pH ~4 and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried (Na 2 SO 4 ) and concentrated under reduced pressure to afford the title compound (3.3 mg, 1%).

[0365] 1< H NMR (300 MHz, CDCl 3 ); δ 6.74 (s, 1H), 4.31 (t, 2H), 3.34 (t, 2H), 2.92 (s, 3H), 2.35 (s, 3H).

[0366] m / z 272.6 (M-1)

[0367] HPLC retention time: 9.55 min., purity: 97.2% at 280 nm.Example 17: 6-Fluoro-7-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid (A-30)

[0368] Step 1: 1-Fluoro-2,4-dimethoxy-5-nitrobenzene

[0369] NaOMe (25% in MeOH, 27.0 mL, 124 mmol) was added to a solution of 1,2,4-trifluoro-5-nitrobenzene (10.0 g, 56.4 mmol) in methanol (80 mL) at 0°C. The reaction mixture was allowed to reach ambient temperature and stirred for 16 h. The solvent was removed under reduced pressure, the residue was diluted with EtOAc (200 mL) and washed with 1.0 N HCl (200 mL). The organic layer was dried (Na 2 SO 4 ) and concentrated under reduced pressure. The resultant residue was triturated with hexanes (3 x 75 mL) to give the title compound (10.2 g, 89%) as a white solid.

[0370] 1< H NMR (300 MHz, CDCl 3 ); δ 7.83 (d, 1H), 6.60 (s, 1H), 4.00 (s, 3H), 3.98 (s, 3H).Step 2: 4-Fluoro-5-methoxy-2-nitrophenol

[0371] AlCl 3 (10.1 g, 75.7 mmol) was added to a solution of 1-fluoro-2,4-dimethoxy-5-nitrobenzene (10.2 g, 50.7 mmol) in CHCl 3 (100 mL) at 0°C, the mixture was heated at 70°C for 1 h and was poured into ice water (400 mL) and the mixture was acidified with 1.0 N HCl to pH 2.0. The mixture was extracted with EtOAc (2 x 250 mL), the combined extracts were dried (Na 2 SO 4 ) and evaporated. The residue was triturated with hexanes (2 x 75 mL) to obtain the title compound (9.00 g, 95%) as a yellow solid.

[0372] 1< H NMR (300 MHz, CDCl 3 ); δ 10.0 (s, 1H), 7.82 (d, 1H), 6.62 (s, 1H), 3.97 (s, 3H).Step 3: 2-Amino-4-fluoro-5-methoxyphenol

[0373] 5% Pt / C catalyst (20% w / w, 600 mg) was added to a solution of 4-fluoro-5-methoxy-2-nitrophenol (3.00 g, 16.0 mmol) in EtOAc (60 mL). The mixture was stirred for 16 h under a hydrogen atmosphere at 20 psi pressure, filtered through a celite pad and concentrated in vacuo to provide the title compound as a brown solid, which was utilised directly in the next step.

[0374] 1< H NMR (300 MHz, CDCl 3 ); δ 6.61 (d, 1H), 6.50 (d, 1H), 3.80 (s, 3H).Step 4: 6-Fluoro-7-methoxy-2,4-dihydro-1,4-benzoxazin-3-one

[0375] Chloroacetyl chloride (2.00 mL, 24.1 mmol) was added to a suspension of 2-amino-4-fluoro-5-methoxyphenol (2.52 g, 16.0 mmol) and Cs 2 CO 3 (13.0 g, 39.9 mmol) in acetonitrile (40 mL) at 0°C. The reaction mixture was stirred at ambient temperature for 16 h and the solvent was removed under reduced pressure. EtOAc (60 mL) and water (60 mL) were added to the residue, the layers were separated and the aqueous layer was extracted further with EtOAc (2 x 60 mL). The combined extracts were dried (Na 2 SO 4 ), concentrated under reduced pressure and the residue was triturated with diethyl ether (3 x 15 mL) to give the title compound (2.00 g, 63 %) as a brown solid.

[0376] 1< H NMR (300 MHz, DMSO-d 6 ) δ 10.5 (br s, 1H), 6.85 (d, 1H), 6.74 (d, 1H), 4.53 (s, 2H), 3.77 (s, 3H).Step 5: 6-Fluoro-7-methoxy-4-methyl-2,4-dihydro-1,4-benzoxazin-3-one

[0377] CH 3 I (1.80 mL, 35.5 mmol) was added to a suspension of 6-fluoro-7-methoxy-2,4-dihydro-1,4-benzoxazin-3-one (1.40 g, 7.10 mmol) and Cs 2 CO 3 (3.47 g, 10.7 mmol) in DMF (20.0 mL) in a sealed tube at 0°C. The reaction mixture was stirred at ambient temperature for 16 h, quenched with water (50 mL) and extracted into EtOAc (2 x 50 mL). The combined extracts were washed with 1.0 N HCl (2 x 50 mL), dried (Na 2 SO 4 ) and concentrated. The residue was purified by column chromatography on silica gel eluting with EtOAc / hexanes (10 - 20%) to afford the title compound (0.54 g, 36 %).

[0378] 1< H NMR (300 MHz, CDCl 3 ); δ 6.76 (d, 1H), 6.65 (d, 1H), 4.58 (s, 2H), 3.85 (s, 3H), 3.31 (s, 3H).Step 6: 6-Fluoro-7-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazine

[0379] BH 3 -THF (1.0 M solution) (6.0 mL, 5.98 mmol) was added to 6-fluoro-7-methoxy-4-methyl-2,4-dihydro-1,4-benzoxazin-3-one (0.25 g, 1.18 mmol) at 0°C and the mixture was stirred at ambient temperature for 2 h. The reaction mixture was again cooled to 0°C, quenched with 1.0 N NaOH (3.0 mL) then EtOAc (20 mL) and water (20 mL) were introduced to the mixture. The layers were separated and the aqueous layer was extracted with EtOAc (2 x 20 mL). The combined extracts were dried (Na 2 SO 4 ) and concentrated in vacuo to give the title compound (220 mg, 94 %).

[0380] 1< H NMR (300 MHz, CDCl 3 ); δ 6.51 - 6.46 (m, 2H), 1.43 (t, 2H), 3.79 (s, 3H), 3.19 (s, 2H), 2.81 (s, 3H).Step 7: 6-Fluoro-7-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid

[0381] s-BuLi (1.4 M in hexane) (2.6 mL, 3.65 mmol) was added to a solution of 6-fluoro-7-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazine (0.24 g, 1.22mmol) and TMEDA (0.55 mL, 3.65 mmol) in THF (6.0 mL) at -78 °C. The reaction mixture was stirred at that temperature for 1 h and CO2 was bubbled through it for 45 min. The mixture was slowly brought to 0°C, quenched with water (15 mL) and washed with EtOAc (3 x 20 mL). The aqueous layer was acidified with 1.0 N HCl to pH ~4 and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried (Na 2 SO 4 ) and concentrated to afford the title compound (20 mg, 7 %).

[0382] 1< H NMR (300 MHz, CDCl 3 ); δ 6.50 (d, 1H), 4.34 (t, 2H), 3.90 (s, 3H), 3.34 - 3.22 (m, 2H), 2.86 (s, 3H).

[0383] ES-MS: 240.7 [M-1]

[0384] HPLC retention time: 7.92 min, purity: 97.5% at 280 nm.Example 18: 6-Chloro-4-methyl-7-(propan-2-yloxy)-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid (A-24)

[0385] Step 1: 4-Chloro-5-isopropoxy-2-nitrophenol

[0386] Nitric acid (70%) (0.24 mL, 5.36 mmol) was added to a solution of 4-chloro-3-isopropoxyphenol (1.0 g, 5.36 mmol) in CH 2 Cl 2 (10 mL) at 0°C. The reaction mixture was stirred at ambient temperature for 2 h. The mixture was poured onto crushed ice and extracted with EtOAc (2 x 50 mL). The combined extracts were dried (Na 2 SO 4 ) and concentrated to afford the title compound (0.78 g, quantitative) which was used directly in the next step.

[0387] 1< H NMR (300 MHz, CDCl 3 ) δ 10.87 (s, 1H), 8.07 (s, 1H), 6.53 (s, 1H), 4.72-4.58 (m, 1H), 1.42 (d, 6H).Step 2: 2-Amino-4-chloro-5-isopropoxyphenol

[0388] Platinum on carbon (5 wt. %, 10% w / w, 78 mg) was added to a solution of 4-chloro-5-isopropoxy-2-nitrophenol (0.78 g, 3.36 mmol) in EtOAc (25 mL). The reaction mixture was hydrogenated at 20 psi at ambient temperature for 16 h. The reaction mixture was filtered through a pad of celite and concentrated to afford the title compound (0.63 g) which was reacted directly in the next step.

[0389] 1< H NMR (300 MHz, CD 3 OD) δ 6.64 (s, 1H), 6.39 (s, 1H), 4.25-4.12 (m, 1H), 1.16 (d, 6H).Step 3: 6-Chloro-7-isopropoxy-2,4-dihydro-1,4-benzoxazin-3-one

[0390] Cs 2 CO 3 (3.05 g, 9.37 mmol) and 2-chloroacetyl chloride (0.53 g, 4.68 mmol) were added to a solution of 2-amino-4-chloro-5-isopropoxyphenol (0.63 g, 3.12 mmol) in acetonitrile (25 mL) at 0°C and the reaction mixture was stirred at ambient temperature for 16 h. The solvent was removed under reduced pressure, the crude product was treated with 20% methanol / CH 2 Cl 2 , filtered through a celite pad and the filtrate concentrated in vacuo to provide the title compound (0.63 g) utilised dire°C ctly in the next step.

[0391] 1< H NMR (300 MHz, CD 3 OD) δ 6.79 (s, 1H), 6.61 (s, 1H), 4.45 (s, 2H), 4.38 (m, 1H), 1.20 (d, 6H).

[0392] ES-MS: 242.7 [M+1].Step 4: 6-Chloro-7-isopropoxy-4-methyl-2,4-dihydro-1,4-benzoxazin-3-one

[0393] Cs 2 CO 3 (2.55 g, 7.83 mmol) and CH 3 I (0.56 g, 3.91 mmol) were added to a solution of 6-chloro-7-isopropoxy-2,4-dihydro-1,4-benzoxazin-3-one (0.63 g, 2.61 mmol) in DMF (25 mL). The reaction mixture was stirred at ambient temperature for 16 h, diluted with EtOAc (100 mL). The solution was washed with brine (3 x 50 mL), dried (Na 2 SO 4 ), concentrated under reduced pressure and the residue purified by column chromatography on silica gel eluting with EtOAc / hexane (0 - 40%) to obtain the title compound (0.17 g, 25%).

[0394] 1< H NMR (300 MHz, CDCl 3 ) δ 6.94 (s, 1H), 6.61 (s, 1H), 4.57(s, 2H), 4.43 (p, 1H), 3.29 (s, 3H), 1.36 (d, 6H).

[0395] ES-MS: 256.8 [M+1].Step 5: 6-Chloro-7-isopropoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazine

[0396] 6-chloro-7-isopropoxy-4-methyl-2,4-dihydro-1,4-benzoxazin-3-one (0.16 g, 0.63 mmol) was added to BH 3 .THF (1M in THF) (2.5 mL, 2.5 mmol) and the reaction was stirred at ambient temperature for 16 h. The reaction mixture was quenched with methanol (10 mL), evaporated and purified by column chromatography on silica gel eluting with EtOAc / hexane (5 - 50%) to give the title compound (0.13 g, 87%).

[0397] 1< H NMR (300 MHz, CDCl 3 ) δ 6.63 (s, 1H), 6.47 (s, 1H), 4.38-4.23 (m, 3H), 3.17 (t, 2H), 2.80 (s, 3H), 1.31 (d, 6H).

[0398] ES-MS: 242.8 [M+1].Step 6: 6-chloro-4-methyl-7-(propan-2-yloxy)-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid

[0399] s-BuLi (1.4 M in hexane) (0.222 mL, 0.31 mmol) was added to a solution of 6-chloro-7-isopropoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazine (50 mg, 0.21 mmol) and TMEDA (36 mg, 0.31 mmol) in THF (4 mL) at -78°C. The reaction mixture was stirred at that temperature for 2 h and CO 2 (g) was bubbled for 10 min and slowly brought to 0°C. Quenching with water (20 mL) and washing with CH 2 Cl 2 (2 x 20 mL) provided an aqueous layer which was acidified with 1N HCl to pH ~4. Extraction with EtOAc (3 x 25 mL), drying the combined extracts (Na 2 SO 4 ) and concentration under reduced pressure afforded the title compound (27 mg, 46%).

[0400] 1< H NMR (300 MHz, CDCl 3 ) δ 6.67 (s, 1H), 4.48 (p, 1H), 4.35 (t, 2H), 3.26 (t, 2H), 2.86 (s, 3H), 1.30 (d, 6H).

[0401] ES-MS: 284.6 [M-1].

[0402] HPLC: Retention Time: 10.03 min., purity: 95.6% @ 254 nm.Example 19: 6-Chloro-7-methoxy-2-(methoxymethyl)-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid (A-35)

[0403] Step 1: 6-Chloro-7-fluoro-2,2,4-trimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one

[0404] KF (0.54 g, 9.22 mmol), and methyl 2-bromo-3-methoxypropionate (0.91 g, 4.61 mmol) were added to a solution of 2-amino-4-chloro-5-methoxyphenol (0.40 g, 2.30 mmol) in DMF (5 mL) and the reaction was stirred at 60°C for 16 h in a sealed tube. The solution was poured into a mixture of crushed ice and water and a solid formed, which was collected by filtration. The solid was washed with water (15 mL) and dried to provide the title compound (0.57 g) which was utilised directly in the next step.

[0405] 1< H NMR (300 MHz, CDCl 3 ) δ 6.90 (s, 1H), 6.73 (s, 1H), 4.85-4.79 (m, 1H), 4.0-3.72 (m, 5H), 3.48 (s, 3H).

[0406] ES-MS: 258.7 [M+1].Step 2: 6-Chloro-7-methoxy-2-(methoxymethyl)-4-methyl-2,4-dihydro-1,4-benzoxazin-3-one

[0407] Cs 2 CO 3 (2.09 g, 6.40 mmol) and CH 3 I (0.45 g, 3.20 mmol) were added to a solution of 6-chloro-7-fluoro-2,2,4-trimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one (0.55 g, 2.13 mmol) in DMF (15 mL). The reaction mixture was stirred at ambient temperature for 16 h, diluted with EtOAc (100 mL), washed with brine solution (3 x 50 mL), dried (Na 2 SO 4 ) and the solution concentrated under reduced pressure and purified by column chromatography on silica gel eluting with EtOAc / hexane (0-40%) to obtain the title compound (0.21 g, 36%).

[0408] 1< H NMR (300 MHz, CDCl 3 ) δ 6.97 (s, 1H), 6.72 (s, 1H), 4.76 (t, 1H), 3.94-3.90 (m, 2H), 3.87 (s, 3H), 3.44 (s, 3H). 3.33 (s, 3H).

[0409] ES-MS: 272.9 [M+1].Step 3: 6-Chloro-7-methoxy-2-(methoxymethyl)-4-methyl-3,4-dihydro-2H-1,4-benzoxazine

[0410] BH 3 .THF (1M in THF) (2.94 mL, 2.94 mmol) was added to 6-chloro-7-methoxy-2-(methoxymethyl)-4-methyl-2,4-dihydro-1,4-benzoxazin-3-one (0.20 g, 0.74 mmol), and reaction was stirred at ambient temperature for 16 h. The reaction mixture was cooled, and carefully quenched with methanol, evaporated and purified by column chromatography on silica gel eluting with EtOAc / hexane (5-50%) to obtain the title compound (0.134 g, 71%).

[0411] 1< H NMR (300 MHz, CDCl 3 ) δ 6.72 (s, 1H), 6.58 (s, 1H), 4.50-4.39 (m, 1H), 3.83 (s, 3H), 3.71-3.53 (m, 2H), 3.47 (s, 3H), 3.21 (dd, 1H), 3.06 (dd, 1H). 2.84 (s, 3H).

[0412] ES-MS: 258.7 [M+1].Step 4: 6-Chloro-7-methoxy-2-(methoxymethyl)-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid

[0413] s-BuLi (1.4 M in hexane) (0.40 mL, 0.56 mmol) was added to a solution of 6-chloro-7-methoxy-2-(methoxymethyl)-4-methyl-3,4-dihydro-2H-1,4-benzoxazine (130 mg, 0.50 mmol) and TMEDA (83.2 mg, 0.56 mmol) in THF (7 mL) at -78°C. The reaction mixture was stirred at that temperature for 1 h and CO 2 (g) was bubbled through for 10 min and slowly brought to 0°C. Quenching with water (20 mL) and washing with CH 2 Cl 2 (2 x 20 mL) provided an aqueous layer which was acidified with 1N HCl to pH 4 - 5. The mixture was extracted with EtOAc (3 x 25 mL) then the combined extracts were dried (Na 2 SO 4 ) and concentrated under reduced pressure. The residue product was purified by semi preparative HPLC using 10-100 % CH 3 CN / 0.1% formic acid in water to provide the title compound (18 mg, 12%).

[0414] 1< H NMR (300 MHz, CDCl 3 ) δ 7.91-6.80 (br, 1H), 6.73 (s, 1H), 4.58-4.45 (m, 1H), 3.92 (s, 3H), 3.75-3.57 (m, 2H), 3.48 (s, 3H), 3.35 (dd, 1H), 3.19 (dd, 1H), 2.92 (s, 3H) ES-MS: 300.7 [M-1].

[0415] HPLC: Retention Time: 9.14 min., purity: >99 % @ 254 nm.Example 20: 6-Chloro-7-methoxy-4-methyl-3,4-dihydrospiro[1,4-benzoxazine-2,1'-cyclobutane]-8-carboxylic acid (A-39)

[0416] Step 1: 6-Chloro-7-methoxy-4H-spiro[1,4-benzoxazine-2,1'-cyclobutan]-3-one

[0417] KF (0.60 g, 10.36 mmol), and methyl 1-bromocyclobutanecarboxylate (1.0 g, 5.18 mmol) were added to a solution of 2-amino-4-chloro-5-methoxyphenol (0.45 g, 2.59 mmol) in DMF (5 mL), and reaction was stirred at 60°C for 16 h in a sealed tube. The solution was poured into a mixture of crushed ice and water and the resultant solid was collected by filtration. It was washed with water (15 mL), dried to provide the title compound (0.61 g) which was utilised directly in the next step.

[0418] 1< H NMR (300 MHz, CDCl 3 ) δ 6.94 (s, 1H), 6.56 (s, 1H), 3.87 (s, 3H), 2.77-2.60 (m, 2H), 2.43-2.22 (m, 2H), 2.10-1.86 (m, 2H).

[0419] ES-MS: 254.6 [M+1].Step 2: 6-Chloro-7-methoxy-4-methyl-4H-spiro[1,4-benzoxazine-2,1'-cyclobutan]-3-one

[0420] Cs 2 CO 3 (2.31 g, 7.09 mmol) and CH 3 I (0.50 g, 3.55 mmol) were added to a solution of 6-chloro-7-methoxy-4H-spiro[1,4-benzoxazine-2,1'-cyclobutan]-3-one (0.60 g, 2.36 mmol) in DMF (20 mL). The reaction mixture was stirred at ambient temperature for 16 h, diluted with EtOAc (100 mL), washed with brine (3 x 50 mL) and the solution was dried (Na 2 SO 4 ). The residue on evaporation was purified by column chromatography on silica gel eluting with EtOAc / hexane (0 - 40%) to give the title compound (49 mg, 8%).

[0421] 1< H NMR (300 MHz, CDCl 3 ) δ 6.99 (s, 1H), 6.72 (s, 1H), 3.92 (s, 3H), 3.37 (s, 3H). 2.73-2.60 (m, 2H), 2.40-2.25 (m, 2H), 2.11-1.92 (m, 2H).

[0422] ES-MS: 268.7 [M+1].Step 3: 6-Chloro-7-methoxy-4-methyl-3,4-dihydrospiro[1,4-benzoxazine-2,1'-cyclobutane

[0423] BH 3 .THF (1M in THF) (0.67 mL, 0.67 mmol) was added to 6-chloro-7-methoxy-4-methyl-4H-spiro[1,4-benzoxazine-2,1'-cyclobutan]-3-one (45 mg, 0.17 mmol), and reaction was stirred at ambient temperature for 16 h. The reaction mixture was quenched with methanol, evaporated and purified by column chromatography on silica gel eluting with EtOAc / hexane (5 - 50%) to obtain the title compound (38 mg, 89%). 1< H NMR (300 MHz, CDCl 3 ) δ 6.70 (s, 1H), 6.53 (s, 1H), 3.85 (s, 3H), 3.11 (s, 2H), 2.91 (s, 3H), 2.39-2.24 (m, 2H), 2.21-2.08 (m, 2H), 2.05-1.68 (m, 2H).

[0424] ES-MS: 254.7 [M+1].Step 4: 6-Chloro-7-methoxy-4-methyl-3,4-dihydrospiro[1,4-benzoxazine-2,1'-cyclobutane]-8-carboxylic acid

[0425] s-BuLi (1.4 M in hexane) (0.11 mL, 0.14 mmol) was added to a solution of 6-chloro-7-methoxy-4-methyl-3,4-dihydrospiro[1,4-benzoxazine-2,1'-cyclobutane] (35 mg, 0.15 mmol) and TMEDA (17.6 mg, 0.15 mmol) in THF (4 mL) at -78°C. The reaction mixture was stirred at that temperature for 1 h and CO 2 (g) was bubbled for 10 min and slowly brought to 0°C. Quenching with water (20 mL) and washing with CH 2 Cl 2 (2 x 20 mL) provided an aqueous layer which was acidified with 1N HCl to pH ~4. The mixture was extracted with EtOAc (3 x 25 mL), the combined extracts were dried (Na 2 SO 4 ) and concentrated in vacuo to provide the title compound (12 mg 29%).

[0426] 1< H NMR (300 MHz, CD 3 OD) δ 6.70 (s, 1H), 3.81 (s, 3H), 3.20 (s, 2H), 2.93 (s, 3H), 2.35-2.20 (m, 2H), 2.18-2.05 (m, 2H), 2.01-1.70 (m, 2H).

[0427] ES-MS: 296.6 [M-1].

[0428] HPLC: Retention Time: 10.790 min., purity: 98.5 % @ 254 nm.Example 21: 6-chloro-4,7-dimethyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid (A-48)

[0429] Step 1: 2-Bromo-6-chloro-4-nitro-3-cresol:

[0430] NBS (1.89 g, 10.66 mmol) was added to a solution of 6-chloro-4-nitro-3-cresol (2.0 g, 10.66 mmol) in acetonitrile (25 mL) and the reaction mixture was stirred at ambient temperature for 16 h. The reaction was quenched with water (100 mL), extracted with EtOAc (2 x 150 mL), dried (Na 2 SO 4 ) and concentrated. The resultant residue was purified by column chromatography on silica gel eluting with hexane / EtOAc (0-20%) to give the title compound (1.12 g, 39.0 %).

[0431] 1< H NMR (300 MHz, CDCl 3 ) δ 11.37 (s, 1H), 8.34 (s, 1H), 2.83 (s, 3H).Step 2: 4-Amino-2-bromo-6-chloro-3-cresol

[0432] Platinum on carbon (5 wt. %, 10% w / w, 50 mg) was added to a solution of 2-bromo-6-chloro-4-nitro-3-cresol (0.50 g, 1.88 mmol) in EtOAc (15 mL). The reaction mixture was hydrogenated at 15 psi at ambient temperature for 16 h and filtered through a pad of celite. The filtrate was concentrated to afford 4-amino-2-bromo-6-chloro-3-cresol (0.44 g) which was utilised directly in the next step.

[0433] 1< H NMR (300 MHz, CDCl 3 ) δ 6.72 (s, 1H), 4.78-3.60 (br s, 2H), 2.38 (s, 3H).

[0434] ES-MS: 236.5 [M+1].Step 3: 8-Bromo-6-chloro-7-methyl-2,4-dihydro-1,4-benzoxazin-3-one

[0435] Cs 2 CO 3 (1.82 g, 5.58 mmol) and 2-chloroacetyl chloride (0.23 g, 2.04 mmol) were added to a solution of 4-amino-2-bromo-6-chloro-3-cresol (0.44 g, 1.86 mmol) in acetonitrile (15 mL) at 0°C and the reaction mixture was stirred at ambient temperature for 16 h. The solvent was removed under reduced pressure and the crude product taken up in 20% methanol / CH 2 Cl 2 (25 mL), filtered through a celite pad and concentrated to obtain the title compound (0.50 g) which was utilised directly in the next step.

[0436] 1< H NMR (300 MHz, CDCl 3 ) δ 6.80 (s, 1H), 4.81 (s, 2H), 2.46 (s, 3H).

[0437] ES-MS: 277.5 [M+1].Step 4: 8-Bromo-6-chloro-4-methyl-7-methyl-2,4-dihydro-1,4-benzoxazin-3-one

[0438] Cs 2 CO 3 (1.77 g, 5.43 mmol) and CH 3 I (0.39 g, 2.71 mmol) were added to a solution of 8-bromo-6-chloro-7-methyl-2,4-dihydro-1,4-benzoxazin-3-one (0.50 g, 1.81 mmol) in DMF (20 mL). The reaction mixture was stirred at ambient temperature for 16 h, diluted with EtOAc (100 mL) and washed with brine (3 x 50 mL). The organic layer was dried (Na 2 SO 4 ), the solution concentrated in vacuo and the residue purified by column chromatography on silica gel eluting with EtOAc / hexane (0 - 40%) to provide the title compound (0.21 g, 41%).

[0439] 1< H NMR (300 MHz, CDCl 3 ) δ 7.25 (s, 1H), 4.99 (s, 2H), 3.62 (s, 3H), 2.77 (s, 3H). ES-MS: 291.5 [M+1].Step 5: 8-Bromo-6-chloro-4-methyl-7-methyl-3,4-dihydro-2H-1,4-benzoxazine

[0440] BH 3 .THF (1M in THF) (2.89 mL, 2.89 mmol) was added to 8-bromo-6-chloro-4-methyl-7-methyl-2,4-dihydro-1,4-benzoxazin-3-one (0.21 g, 0.72 mmol) and the reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was cooled, quenched with methanol (20 mL), evaporated and the residue purified by column chromatography on silica gel eluting with EtOAc / hexane (5-50%) to give the title compound (57 mg, 29%).

[0441] 1< H NMR (300 MHz, CDCl 3 ) δ 6.62 (s, 1H), 4.36 (t, 2H), 3.26 (t, 2H), 2.86 (s, 3H), 2.40 (s, 3H).

[0442] ES-MS: 278.6 [M+1].Step 6: 6-Chloro-4,7-dimethyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid

[0443] n-BuLi (2.5 M in hexane) (0.088 mL, 0.22 mmol) was added to a solution of 8-bromo-6-chloro-4-methyl-7-methyl-3,4-dihydro-2H-1,4-benzoxazine (55 mg, 0.20 mmol) in THF (5 mL) at -78°C. The reaction mixture was stirred at that temperature for 1 h, CO 2 (g) was bubbled through it for 10 min and slowly brought to 0°C. Quenching with water (20 mL) and washing with CH 2 Cl 2 (2 x 20 mL) provided an aqueous layer which was acidified with 1N HCl to pH ~4. The mixture was extracted with EtOAc (3 x 25 mL), the combined extracts were dried (Na 2 SO 4 ) and concentrated under reduced pressure to provide the title compound (28.3 mg, 59%).

[0444] 1< H NMR (300 MHz, CDCl 3 ) δ 6.70 (s, 1H), 4.33 (t, 2H), 3.28 (t, 2H), 2.86 (s, 3H), 2.30 (s, 3H).

[0445] ES-MS: 240.7 [M-1].

[0446] HPLC: Retention Time: 9.42 min., purity: 98.8% @ 254 nm.Example 22: 6-Chloro-7-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzothiazine-8-carboxylic acid (A-29)

[0447] Step 1: 1-Chloro-4-fluoro-2-methoxy-5-nitrobenzene

[0448] A mixture of HNO 3 (4.8 mL, 74.73 mol) and H 2 SO 4 (3.98 mL, 74.73 mmol) was added to a solution of 1-chloro-4-fluoro-2-methoxybenzene (10 g, 62.3 mmol) in CH 2 Cl 2 (30 mL) at 0°C and the reaction mixture was stirred at room temperature for 16 h. The mixture was poured into ice cold water (50 mL) and diluted with EtOAc (50 mL). The organic layer was extracted, washed with water (2 x 50 mL), dried (Na 2 SO 4 ) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with hexanes / EtOAc (5 - 10%) to give the title compound as a yellow solid (4.18 g, 33%).

[0449] 1< H NMR (300 MHz, CDCl 3 ) δ 8.04 (d, 1H), 6.79 (d, 1H), 3.97 (s, 3H).Step 2: Methyl 2-(4-chloro-5-methoxy-2-nitrophenylthio) acetate

[0450] Triethylamine (3.4 mL, 24.41 mmol) and methyl thioglycolate (1.99 mL, 22.4 mmol) were added to a solution of 1-chloro-4-fluoro-2-methoxy-5-nitrobenzene (4.18 gm, 20.34 mmol) in CH 2 Cl 2 (32 mL) at 0°C and the reaction mixture was stirred at ambient temperature for 16 h. The mixture was cooled to 0°C, 1N HCl solution was slowly added and the mixture was stirred for 30 min. The organic layer was separated, dried (Na 2 SO 4 ) and concentrated under reduced pressure. The residue was triturated with hexanes to obtain the title compound as a yellow solid (5.0 g, 84%).

[0451] 1< H NMR (300 MHz, CDCl 3 ); δ 8.42 (s, 1H), 7.26 (s, 1H), 4.13 (s, 3H), 3.87 (s, 3H), 3.82 (s, 2H).Step 3: 6-Chloro-7-methoxy-2H-benzo[b][1,4]thiazin-3(4H)-one

[0452] Iron (3.83 g, 68.56 mmol) was added to a mixture of methyl 2-(4-chloro-5-methoxy-2-nitrophenylthio) acetate (5 g, 17.14 mmol) in acetic acid (55 mL). The reaction mixture was heated at 90°C for 2 h, and then stirred at room temperature for 16 h. The mixture was cooled to 0°C followed by slow addition of 1N HCl (90 mL) and stirred for 1 h at 0°C. The precipitate was filtered and dissolved in EtOAc (100 mL). The solution was washed with water (2 x 50 mL) and the organic layer was dried (Na 2 SO 4 ) and concentrated under reduced pressure. The resultant residue was triturated with hexane to obtain the title compound as a white solid (5.0 g, 84%).

[0453] 1< H NMR (300 MHz, CDCl 3 ) δ 8.78 (br, 1H), 6.94 (s, 1H), 6.87 (s, 1H), 3.87 (s, 3H), 3.43 (s, 2H).Step 4: 6-Chloro-7-methoxy-4-methyl-2H-benzo[b][1,4]thiazin-3(4H)one

[0454] Cs 2 CO 3 (3.19 g, 9.79 mmol) and CH 3 I (3.29 mL, 65.31 mmol) were added to a solution of 6-chloro-7-methoxy-2H-benzo[b][1,4]thiazin-3(4H)-one (1.5 g, 6.53 mmol) in DMF (15 mL) and the mixture stirred at ambient temperature for 16 h. The mixture was diluted with EtOAc (50 mL), washed with water (2 x 50 mL), dried (Na 2 SO 4 ), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with hexane / EtOAc (5 - 10%) to provide the title compound as a white solid (1.34 gm, 84 %).

[0455] 1< H NMR (300 MHz, CDCl 3 ) δ 7.26 (s, 1H), 7.07 (s, 1H), 4.04 (s, 3H), 3.57-3.56 (m, 5H).Step 5: 6-Chloro-7-methoxy-4-methyl-3,4-dihydro-2H-benzo[b]1[1,4]thiazinine

[0456] BH 3 .THF (28 mL, 27.45 mmol) was added to a solution of 6-chloro-7-methoxy-4-methyl-2H-benzo[b][1,4]thiazin-3(4H)-one (1.34 g, 5.49 mmol) in THF (5 mL) at 0°C and the mixture was stirred at ambient temperature for 3 h, cooled to 0°C before 1N NaOH was added slowly. The mixture was extracted with EtOAc (2 x 50 mL), dried (Na 2 SO 4 ) and concentrated under reduced pressure. The residue was triturated with hexanes to obtain the title compound as a white solid (1.2 gm, 96 %).

[0457] 1< H NMR (300 MHz, CDCl 3 ) δ 6.67-6.66 (m, 2H), 3.78 (s, 3H), 3.43-3.40 (m, 2H), 3.08-3.04 (m, 2H), 2.86 (s, 3H).Step 6: 6-Chloro-7-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzothiazine-8-carboxylic acid

[0458] TMEDA (2.5 mL, 16.88 mmol) and s-BuLi (12.0 mL, 16.88 mmol) were added to a solution of 6-chloro-7-methoxy-4-methyl-3,4-dihydro-2H-benzo[b][1,4]thiazinine (970 mg, 4.22 mmol) in THF (20.0 mL) at -78°C. The reaction mixture was stirred at that temperature for 1 h, CO 2 was bubbled for 45 mins at -78°C. The mixture was slowly brought to room temperature, quenched with water (25 mL) and washed with EtOAc (30 mL). The aqueous layer was acidified to pH ~2.0 using 1.0 N HCl and the product was extracted using EtOAc (2 x 30 mL). The combined organic layers were dried (Na 2 SO 4 ) and concentrated to afford the title compound as a brown oil (577 mg, 49%) which was utilised directly in the next step.

[0459] 1< H NMR (300 MHz, CDCl 3 ) δ 11.41-11.14 (br s, 1H), 6.68 (s, 1H), 3.84 (s, 3H), 3.57-3.53 (m, 2H), 2.96-2.92 (m, 5H).

[0460] ES-MS: 272.6 [M-1]Step 7: Sodium 6-chloro-7-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzothiazine-8-carboxylate

[0461] NaHCO 3 (141.64 mg, 1.69 mmol) was added to a solution of 6-chloro-7-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzothiazine-8-carboxylic acid (577 mg, 2.11 mmol) in acetonitrile (10 mL) and water (10 mL). The mixture was stirred for 1 h at ambient temperature, the solvents were removed under vacuum and the residue was washed with EtOAc (30 mL). The aqueous layer was concentrated under reduced pressure and the residue was triturated with chloroform to afford the title compound as a brown solid (300 mg, 48%).

[0462] 1< H NMR (300 MHz, CD 3 OD) δ 6.59 (s, 1H), 3.83 (s, 3H), 3.54-3.51 (m, 2H), 3.02-2.98 (m, 2H), 2.92 (s, 3H).

[0463] ES-MS: 272.6 [M-1]

[0464] HPLC: Retention time 11.51 min., Purity: 96.5% @ 254 nm.Example 23: Methyl 6-chloro-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate

[0465] Step 1: Methyl 2-hydroxy-6-methoxy-3-nitrobenzoate

[0466] Nitric acid (70%) (4.91 mL, 82.34 mmol) was added to a solution of methyl 2-hydroxy-6-anisate (15.0 g, 82.34 mmol) in DCM (100 mL) at 0°C. The reaction mixture was stirred at ambient temperature for 16 hours. The mixture was poured into ice cold water and extracted with EtOAc (2 x 50 mL), the combined extracts were dried (Na 2 SO 4 ) and concentrated. The yellow residue was purified by column chromatography on silica gel eluting with hexane / EtOAc (0 - 15%) to provide the title compound as a yellow solid (5.70 g, 31% yield).

[0467] 1< H NMR (300 MHz, CDCl 3 ); δ 11.12 (s, 1H), 8.18 (d, 1H), 6.61 (d, 1H), 3.95 (s, 6H) ppm.Step 2: Methyl 5-chloro-2-hydroxy-6-methoxy-3-nitrobenzoate

[0468] NCS (3.858 g, 28.89 mmol) was added to a solution of methyl 2-hydroxy-6-methoxy-3-nitrobenzoate (5.47 g, 24.08 mmol) in CH 3 CN (25 mL) and stirred at ambient temperature for 48 h. The reaction mixture was quenched with 1N HCl solution, extracted with EtOAc (3 x 50 mL), then the combined extracts were washed with brine (50 mL), dried (Na 2 SO 4 ) and evaporated. The residue was purified by column chromatography on silica gel eluting with hexane / EtOAc (0 - 10%) to give the title compound (5.52 g, 87% yield) as a solid.

[0469] 1< H NMR (300 MHz, CDCl 3 ); δ 10.96 (s, 1H), 8.23 (s, 1H), 4.02 (s, 3H), 3.98 (s, 3H) ppm.Step 3: Methyl 3-amino-5-chloro-2-hydroxy-6-anisate

[0470] Pt / C catalyst 5 wt % (10% w / w, 0.550 g) was added to a solution of methyl 5-chloro-2-hydroxy-6-methoxy-3-nitrobenzoate (5.5 g, 21.02 mmol) in MeOH (100 mL). The reaction mixture was hydrogenated at 20 psi at ambient temperature for 2 h. The reaction mixture was filtered through a pad of celite and concentrated in vacuo to afford the title compound (5.20 g), used directly in the next step.

[0471] 1< H NMR (300 MHz, CDCl 3 ); δ 6.90 (s, 1H), 4.04 (s, 2H), 4.00 (s, 3H), 3.78 (s, 3H) ppm.Step 4: Methyl 3-amino-5-chloro-2-(2-chloroethoxy)-6-anisate

[0472] K 2 CO 3 (18.617 g, 134.70 mmol) and 1-bromo-2-chloroethane (2.43 mL, 29.187 mmol) were added to a solution of methyl 3-amino-5-chloro-2-hydroxy-6-anisate (5.2 g, 22.45 mmol) in acetone (100 mL). The reaction mixture was heated at reflux for 16 h, cooled, evaporated and the residue extracted with EtOAc (2 x 50 mL). The combined extracts were dried (Na 2 SO 4 ), evaporated and the residue was purified by column chromatography on silica gel eluting with hexane / EtOAc (0-50%) to provide the title ester (2.4 g, 68%) as a yellow liquid.

[0473] 1< H NMR (300 MHz, CDCl 3 ); δ 6.80 (s, 1H), 4.23 (m, 2H), 3.93 (s, 3H), 3.81 (s, 3H), 3.87 (m, 2H) ppm.Step 5: Methyl 6-chloro-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate

[0474] K 2 CO 3 (4.699 g, 34.0 mmol), and KI (5.644 g, 34.0 mmol) was added to a solution of methyl 3-amino-5-chloro-2-(2-chloroethoxy)-6-anisate (5.0 g, 17.0 mmol) in DMF (30 mL). The reaction mixture was heated at 85°C for 16 h in a sealed tube, cooled and evaporated. The residue was purified by column chromatography on silica gel eluting with hexane / EtOAc (0 - 50%) to give the title ester (1.5 g, 34%) as a light-yellow solid. 1< H NMR (300 MHz, CDCl 3 ); δ 6.60 (s, 1H), 4.22 (m, 2H), 3.91 (s, 3H), 3.80 (s, 3H), 3.77 (m, 2H) ppm.

[0475] ES- MS: m / z 258.7 (M+H).Example 24: Ethyl 6-chloro-7-fluoro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate

[0476] Step 1: Ethyl 3-chloro-2-fluoro-6-methoxybenzoate

[0477] n-BuLi (2.5 M in hexane) (13.2 mL, 33.0 mmol) was added to a solution of 1-chloro-2-fluoro-4-methoxybenzene (5.0 g, 31.1 mmol) in THF (50 mL) at -78°C. The reaction mixture was stirred at same temperature for 1 h. After 1 h, ethyl chloroformate (3.6g, 33.0 mmol) was added dropwise and stirred for 1h at same temperature. The mixture was slowly brought to 0°C, quenched with saturated NH 4 Cl solution (10 mL) and washed with CH 2 Cl 2 (2 x 20 mL). The aqueous layer was acidified with 1N HCl to pH ~4 and extracted with EtOAc (2 x 75 mL). The combined extracts were dried (Na 2 SO 4 ) and concentrated in vacuo. The resultant residue was purified by column chromatography on silica gel eluting with hexane / EtOAc (0 - 10%) to give ethyl 3-chloro-2-fluoro-6-methoxybenzoate as a light-yellow oil (4.2 g, 58 % yield).

[0478] 1< H NMR (300 MHz, CDCl 3 ) δ 7.25 (t, 1H), 6.56 (d, 1H), 4.29 (q, 2H), 3.73 (s, 3H), 1.26 (t, 3H).

[0479] 19< F NMR (300 MHz, CDCl 3 ) δ -114.99 ppm.Step 2: Ethyl 3-chloro-2-fluoro-6-hydroxybenzoate

[0480] Aluminium chloride (7.7 mL, 58.0 mmol) was added to a solution of ethyl 3-chloro-2-fluoro-6-methoxybenzoate (4.2 g, 18.0 mmol) in CH 2 Cl 2 (50 mL). The reaction mixture was stirred at ambient temperature for 16 h before the mixture was poured into 1N HCl (50 mL) and stirred for 30 min. The aqueous mixture was extracted with CH 2 Cl 2 (2 x 75 mL), the combined extracts dried (Na 2 SO 4 ) and concentrated under reduced pressure. The resultant residue was purified by column chromatography on silica gel eluting with hexane / EtOAc (0 - 10%) to afford the title compound as a yellow oil (3.6 g, 92 % yield). 1< H NMR (300 MHz, CDCl 3 ) δ 11.11 (s, 1H), 7.26 (t, 1H), 6.59 (dd, 1H), 4.30 (q, 2H), 3.37 (s, 3H), 1.27 (t, 3H).

[0481] 19< F NMR (300 MHz, CDCl 3 ) δ -105.25 ppm.Step 3: Ethyl 3-chloro-2-fluoro-6-hydroxy-5-nitrobenzoate

[0482] A premixed solution of sulphuric acid (1.6 mL, 29.6 mmol) and nitric acid (70%) (1.9 mL, 29.6 mmol) was added to a solution of ethyl 3-chloro-2-fluoro-6-hydroxybenzoate (3.6 g, 16.5 mmol) in CH 2 Cl 2 (6 mL) at 0°C. The reaction mixture was stirred at ambient temperature for 5 h, poured into crushed ice. After melting the mixture was extracted with EtOAc (2 x 50 mL), dried (Na 2 SO 4 ), and concentrated under reduced pressure to afford the title compound as a light yellow oil (4.2 g, 97 % yield).

[0483] 1< H NMR (300 MHz, CD 3 OD) δ 8.42 (d, 1H), 4.48 (q, 2H), 1.42 (t, 3H).

[0484] 19< F NMR (300 MHz, CD 3 OD) δ -103.50 ppm.Step 4: Ethyl 3-amino-5-chloro-6-fluoro-2-hydroxybenzoate

[0485] Platinum on carbon (5 wt %) as catalyst (10% w / w), 420 mg) was added to a solution of ethyl 3-chloro-2-fluoro-6-hydroxybenzoate (4.2 mL, 15.9 mmol) in EtOAc (60 mL). The reaction mixture was subjected to 20 psi hydrogen at ambient temperature for 16 h. The reaction mixture was filtered through a pad of celite and concentrated to provide the title amine (3.7 g) as a brown solid, which was utilised directly in the next step.

[0486] 1< H NMR (300 MHz, CDCl 3 ) δ 11.68 - 11.18 (br s, 1H), 6.86 (d, 1H), 4.45 (q, 2H), 4.13 - 4.16 (br s, 1H), 1.43 (t, 3H).

[0487] 19< F NMR (300 MHz, CDCl 3 ) δ -120.44 ppm.Step 5: Ethyl 3-amino-5-chloro-2-(2-chloroethoxy)-6-fluorobenzoate

[0488] K 2 CO 3 (16.6 g, 120 mmol), and 1-bromo-2-chloroethane (2.1 g, 14.4 mmol) was added to a solution of ethyl 3-amino-5-chloro-6-fluoro-2-hydroxybenzoate (2.8 g, 12.0 mmol) in acetone (50 mL). The reaction mixture was heated at refluxed 16 h., cooled and water added (50 mL). The mixture was extracted with EtOAc (2 x 50 mL) and the combined extracts dried (Na 2 SO 4 ), evaporated and purified by column chromatography on silica gel eluting with hexane / EtOAc (0 -50%) to provide the title compound (2.4 g, 68%) as a yellow liquid.

[0489] 1< H NMR (300 MHz, CDCl 3 ) δ 6.82 (d, 1H), 4.40 (q, 2H), 4.23 (t, 2H), 3.80 (t, 2H), 1.38 (t, 3H).

[0490] 19< F NMR (300 MHz, CDCl 3 ) δ -128.82 ppm.Step 6: Ethyl 6-chloro-7-fluoro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate

[0491] K 2 CO 3 (2.35 g, 17.0 mmol), and KI (2.83 g, 17.0 mmol) were added to a solution of ethyl 3-amino-5-chloro-2-(2-chloroethoxy)-6-fluorobenzoate (2.4 g, 8.5 mmol) in DMF (12 mL). The reaction mixture was heated at 85°C in a sealed tube for 16 h, cooled and evaporated. The residue was purified by column chromatography on silica gel eluting with hexane / EtOAc (0-50%) to obtain the title ester (1.7 g, 81%) as a light yellow gum. 1< H NMR (300 MHz, CDCl 3 ) δ 6.65 (d, 1H), 4.39 (q, 2H), 4.27 (t, 2H), 3.41 (t, 2H), 1.37 (t, 3H).

[0492] 19< F NMR (300 MHz, CDCl 3 ) δ -128.82 ppm.

[0493] ES- MS: m / z 261.2 (M+H).Example 25: Methyl 7-chloro-6-fluoro-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylate

[0494] Step 1: Methyl 2,6-difluoro-3-hydroxybenzoate

[0495] Sulphuric acid (1.0 mL) was added to a solution of 2,6-difluoro-3-hydoxybenzoic acid (4.00 g, 23.0 mmol) in methanol (50 mL) at ambient temperature. The reaction mixture was heated at 73 °C for 16 h, cooled and the solvent removed under reduced pressure. The residue was treated with EtOAc (100 mL) and the mixture washed with satd. NaHCO 3 solution (2 x 75 mL). The organic layer was dried (Na 2 SO 4 ) concentrated in vacuo to provide the title compound (3.70 g, 86 %).

[0496] 1< H NMR (300 MHz, CDCl 3 ); δ 7.12 - 7.05 (m, 1H), 6.89 - 6.83 (m, 1H), 5.12 (d, 1H), 3.96 (s, 3H).Step 2: Methyl 2,6-difluoro-3-[2-(tert-butoxycarbonylamino)ethoxy]benzoate

[0497] 60% NaH (0.82 g, 20.4 mmol) was added to a solution of methyl 2,6-difluoro-3-hydroxybenzoate (3.50 g, 18.6 mmol) in DMF (35 mL) at 0°C. The reaction mixture was stirred at ambient temperature for 15 min, cooled to 0°C, then 2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester (4.57 g, 20.5 mmol) was added and the mixture was stirred at ambient temperature for 2 h. It was cooled to 0°C, quenched with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with water (3 x 100mL), dried (Na 2 SO 4 ) and concentrated under reduced pressure. The residue was triturated with hexanes (3 x 20 mL) to afford the title compound (5.20 g, 84%).

[0498] 1< H NMR (300 MHz, CDCl 3 ); δ 7.07 - 7.00 (m, 1H), 6.90 - 6.83 (m, 1H), 5.00 (br s, 1H), 4.06 (t, 2H), 3.96 (s, 3H), 3.53 (q, 2H), 1.45 (s, 9H).Step 3: Methyl 3-(2-aminoethoxy)-2,6-difluorobenzoate

[0499] TFA (15.0 mL) was added to a solution of methyl 2,6-difluoro-3-[2-(tert-butoxycarbonylamino)ethoxy]benzoate (2.50 g, 7.55 mmol) in CH 2 Cl 2 (15.0 mL) at ambient temperature and stirred for 1 h. The solvent was removed under reduced pressure and the residue basified with satd. NaHCO 3 solution before extracted with CH 2 Cl 2 (2 x 50 mL). The combined organic layers were dried (Na 2 SO 4 ) and concentrated under reduced pressure to obtain the title compound, which was utilised directly in the next step.Step 4: Methyl 6-fluoro-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylate

[0500] Et 3 N (3.0 mL, 21.4 mmol) was added to a solution of methyl 3-(2-aminoethoxy)-2,6-difluorobenzoate (1.24 g, 5.36 mmol) in DMSO (12 mL) at 0°C. The reaction mixture was heated at 55°C for 3 h and cooled to room temperature. It was quenched with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with 1.0 N HCl (3 x 75 mL) and water (2 x 75 mL). The organic layer was dried (Na 2 SO 4 ) and evaporated in vacuo to afford the title compound (0.62 g, 55%).

[0501] 1< H NMR (300 MHz, CDCl 3 ); δ 7.47 (br s, 1H), 6.79 (dd, 1H), 6.21 (dd, 1H), 4.15 (t, 2H), 3.89 (s, 3H), 3.51 (t, 2H).Step 5: Methyl 7-chloro-6-fluoro-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylate

[0502] NCS (0.56 g, 4.93 mmol) was added to a solution of methyl 6-fluoro-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylate (0.98 g, 4.64 mmol) in CH 3 CN (20 mL) at ambient temperature and stirred for 16 h. The solvent was removed under reduced pressure and the residue was treated with EtOAc (50 mL) and washed with water (2 x 50 mL). The organic layer was dried (Na 2 SO 4 ) and concentrated under reduced pressure. The residue was triturated with hexanes (15 mL) to afford the title compound (0.77g, 68%). 1< H NMR (300 MHz, CDCl 3 ); δ 7.46 (br s, 1H), 6.88 (s, 1H), 4.15 (t, 2H), 3.90 (s, 3H), 3.51 (t, 2H).Example 26: Methyl 6-chloro-7-fluoro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate

[0503] Step 1: 1-Chloro-2-fluoro-4-(methoxymethoxy)benzene

[0504] DIPEA (5.3 mL, 40.96 mmol) and chloromethyl methyl ether (2.42 g, 30.03 mmol) were added to a solution of 4-chloro-3-fluorophenol (4.0 g, 27.3 mmol) in CH 2 Cl 2 (50 mL) at 0°C. The reaction mixture was stirred at ambient temperature for 16 h, extracted with CH 2 Cl 2 (2 x 75 mL), washed with 1M HCl (30 mL), dried (Na 2 SO 4 ), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with CH 2 Cl 2 to provide the title compound as a colourless oil (4.2 g, 81 % yield).

[0505] 1< H NMR (300 MHz, CDCl 3 ) δ 7.26 (t, 1H), 6.87 (dd, 1H), 6.80 - 6.74 (m, 1H), 5.14 (s, 2H), 3.17 (s, 3H).

[0506] 19< F NMR (300 MHz, CDCl 3 ) δ -113.05 ppm.Step 2: 3-Chloro-2-fluoro-6-hydroxybenzoic acid

[0507] Sec-BuLi (1.4 M in cyclohexane) (8.25 mL, 11.55 mmol) and TMEDA (1.34 g, 11.55 mmol) were added to a solution of 1-chloro-2-fluoro-4-(methoxymethoxy)benzene (2.0 g, 10.5 mmol) in THF (24 mL) at -78°C. The reaction mixture was stirred at that temperature for 1.5 h, and CO 2 was bubbled through it for 20 min. and the mixture was stirred for 1h at the same temperature before being brought slowly to 0°C and quenched with 1N NaOH solution (10 mL). The basic solution was washed with CH 2 Cl 2 (2 x 20 mL) and the aqueous layer was separated and acidified with 6N HCl (30 mL). The mixture was extracted with EtOAc (2 x 75 mL), dried (Na 2 SO 4 ) and concentrated under reduced pressure to provide the title acid (1.4 g, 70% yield).

[0508] 1< H NMR (300 MHz, CD 3 OD) δ 7.52 (t, 1H), 6.79 (dd, 1H).

[0509] 19< F NMR (300 MHz, CD 3 OD) δ -108.56 ppm.Step 3: Methyl 3-chloro-2-fluoro-6-hydroxybenzoate

[0510] Sulphuric acid (2mL)) was added to a solution of 3-chloro-2-fluoro-6-hydroxybenzoic acid (1.4 g mg, 7.35 mmol) in methanol (20 mL) at ambient temperature and stirred for 72 h. The reaction mixture was extracted with EtOAc (2 x 60 mL) and the combined extracts were washed with saturated NaHCO 3 dried (Na 2 SO 4 ), and evaporated in vacuo to obtain the title ester (1.0 g, 67 % yield).

[0511] 1< H NMR (300 MHz, CDCl 3 ) δ 11.19 (s, 1H), 7.42 (t, 1H), 6.76 (d, 1H), 3.98 (s, 3H).

[0512] 19< F NMR (300 MHz, CDCl 3 ) δ -105.45 ppm.Step 4: Methyl 3-amino-5-chloro-6-fluoro-2-hydroxybenzoate

[0513] Premixed sulphuric acid (0.605 g, 6.16 mmol) and nitric acid (70%) (0.554 g, 6.16 mmol) was added to a solution of methyl 3-chloro-2-fluoro-6-hydroxybenzoate (0.840 g, 4.11 mmol) in CH 2 Cl 2 (3 mL) at 0°C. The reaction mixture was stirred at ambient temperature for 6 h and poured onto crushed ice. After melting the mixture was extracted with EtOAc (2 x 50 mL), dried (Na 2 SO 4 ), and concentrated under reduced pressure. Platinum on carbon (5 wt %, 10% w / w, 84 mg) was added to a solution of the crude product in EtOAc (30 mL). The reaction mixture was hydrogenated at 20 psi at ambient temperature for 16 h. The reaction mixture was filtered through a pad of celite and concentrated to afford the title ester (0.65 g, 72%, crude yield for two steps) which was utilised directly in the next step.

[0514] 1< H NMR (300 MHz, CDCl 3 ) δ 11.37 (s, 1H), 6.84 (d, 1H), 3.99(s, 3H), 3.89 - 3.73 (br s, 2H).

[0515] 19< F NMR (300 MHz, CDCl 3 ) δ -121.42 ppm.Step 5: Methyl 3-amino-5-chloro-2-(2-chloroethoxy)-6-fluorobenzoate

[0516] K 2 CO 3 (4.09 g, 29.6 mmol), and 1-bromo-2-chloroethane (0.51 g, 3.55 mmol) was added to a solution of methyl 3-amino-5-chloro-6-fluoro-2-hydroxybenzoate (0.65 g, 2.96 mmol) in acetone (30 mL). The reaction mixture was heated at reflux for 16 h., cooled, treated with water (20 mL) and extracted with EtOAc (2 x 30 mL). and dried (Na 2 SO 4 ). The residue on evaporation was purified by column chromatography on silica gel eluting with hexane / EtOAc (0 - 50%) to afford the title compound (0.6 g, 72%) as a yellow oil.

[0517] 1< H NMR (300 MHz, CDCl 3 ) δ 6.84 (d, 1H), 4.23 (t, 2H), 4.17 - 3.98 (br s, 2H), 3.93 (s, 3H), 3.80 (t, 2H).

[0518] 19< F NMR (300 MHz, CDCl 3 ) δ -128.04 ppm.Step 6: Methyl 6-chloro-7-fluoro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate

[0519] K 2 CO 3 (0.59 g, 4.26 mmol), and KI (0.71 g, 4.26 mmol) was added to a solution of methyl 3-amino-5-chloro-2-(2-chloroethoxy)-6-fluorobenzoate (0.6 g, 2.13 mmol) in DMF (6 mL). The reaction mixture was heated at 85°C for 16 h in a sealed tube, cooled and evaporated. The crude product was purified by column chromatography on silica gel eluting with hexane / EtOAc (0 - 50%) to provide the title ester (0.3 g, 57%) as a cream solid.

[0520] 1< H NMR (300 MHz, CDCl 3 ) δ 6.66 (d, 1H), 4.28 (t, 2H), 3.92 (s, 3H), 3.41 (t, 2H).

[0521] 19< F NMR (300 MHz, CDCl 3 ) δ -128.82 ppm.

[0522] ES- MS: m / z 246.2 (M+H).Example 27: 6-Chloro-4-[2-(3,5-difluorophenyl)ethyl]-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid (A-53)

[0523] Step 1: (3,5-Difluorophenyl)acetaldehyde

[0524] Dess-Martin periodinane (1.74 g, 4.10 mmol) was added in several portions to a solution of 2-(3,5-difluorophenyl)ethanol (0.54 g, 3.41 mmol) in CH 2 Cl 2 (12.0 mL) at 0°C and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with CH 2 Cl 2 (20 mL), washed with saturated Na 2 S 2 O 3 (2 x 30 mL) and saturated NaHCO 3 (2 x 30 mL). The organic layer was dried (Na 2 SO 4 ) and concentrated in vacuo. The residue was treated with hexanes (3 x 7.0 mL) and the washes were concentrated in vacuo to afford the title compound (0.32 g, 60 %).

[0525] 1< H NMR (300 MHz, CDCl 3 ); δ 9.76 (s, 1H), 6.79 - 6.74 (m, 3H), 3.70 (s, 2H).Step 2: Methyl 6-chloro-4-[(1E)-2-(3,5-difluorophenyl)ethenyl]-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate

[0526] (3,5-Difluorophenyl)acetaldehyde (115 mg, 0.74 mmol) was added to a solution of methyl 6-chloro-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate (63 mg, 0.24 mmol) in 1,2-dichloroethane (3.0 mL) and the reaction mixture was stirred for 30 min. To this mixture, NaBH(OAc) 3 (155 mg, 0.73 mmol) was added and the reaction mixture was stirred at ambient temperature for 16 h. The reaction was diluted with CH 2 Cl 2 (15 mL) and washed with saturated NaHCO 3 solution (2 x 15 mL). The organic layer was dried (Na 2 SO 4 ), concentrated in vacuo and the product was utilised directly in the next step.Step 3: 6-Chloro-4-[(1E)-2-(3,5-difluorophenyl)ethenyl]-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid

[0527] NaOH (59 mg, 1.48 mmol) was added to a solution of methyl 6-chloro-4-[(1E)-2-(3,5-difluorophenyl)ethenyl]-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate (98 mg, 0.25 mmol) in a mixture of CH 3 OH (2.0 mL) and water (1.0 mL) and the reaction mixture was heated at 150°C under microwave conditions for 1 h. The solvent was removed under reduced pressure, the residue was acidified with 1.0 N HCl to pH ~4 and extracted with EtOAc (2 x 15 mL). The combined organic layers were dried (Na 2 SO 4 ) and concentrated in vacuo. The resultant residue was triturated with hexanes (2 x 3.0 mL) to obtain the title compound (60 mg, 63 %).

[0528] 1< H NMR (300 MHz, CD 3 OD); δ 7.63 (d, 1H), 7.19 (s, 1H), 7.01 - 6.98 (m, 2H), 6.61 - 6.56 (m, 1H), 5.80 (d, 1H), 4.29 (t, 2H), 3.88 (s, 3H), 3.69 (t, 2H).Step 4: 6-chloro-4-[2-(3,5-difluorophenyl)ethyl]-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid

[0529] 10% Pd / C catalyst (50% w / w, 30 mg) was added to a solution of 6-chloro-4-[(1E)-2-(3,5-difluorophenyl)ethenyl]-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid (60 mg, 0.16 mmol) in ethanol (4.0 mL). The mixture was stirred for 2 h under a hydrogen atmosphere at balloon pressure, filtered through a pad of celite and concentrated in vacuo to provide the title compound (20 mg, 33 %).

[0530] 1< H NMR (300 MHz, CD 3 OD); 7.19 (s, 1H), 6.83 - 6.76 (m, 1H), 6.69 - 6.65 (m, 1H), 6.54 - 6.52 (m, 1H), 4.20 (t, 2H), 3.76 (s, 3H), 3.50 (t, 2H), 3.69 (t, 2H), 2.89 (t, 2H).

[0531] m / z 384.7 (M+1)

[0532] HPLC retention time: 13.5 min., purity: 95.1 % at 280 nm.Example 28: 6-chloro-7-methoxy-4-[(thiophen-2-yl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid (A-42)

[0533] Step 1: Methyl 6-chloro-7-methoxy-4-thenyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate

[0534] Sodium triacetoxyborohydride (197 mg, 0.93 mmol) was added to a solution of methyl 6-chloro-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate (80 mg, 0.31 mmol) and 2-thiophenecarboxaldehyde (104 mg, 0.93 mmol) in 1,2-dichloroethane (4 mL). The reaction was stirred at ambient temperature for 16 h, diluted with CH2Cl2 (100 mL), washed with brine (3 x 50 mL), dried (Na 2 SO 4 ) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with hexane / EtOAc (0-40%) to give the title compound (107 mg, 97%).

[0535] 1< H NMR (300 MHz, CDCl 3 ) δ 7.57 (d, 1H), 7.56 (d, 1H), 7.52 (dd, 1H), 7.11 (s, 1H), 4.83 (s, 2H), 4.54 (t, 2H), 4.21 (s, 3H), 4.11 (s, 3H), 3.61 (t, 2H).

[0536] ES-MS: 354.8 [M+1].Step 2: 6-Chloro-7-methoxy-4-[(thiophen-2-yl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid

[0537] NaOH (35.6 mg, 0.89 mmol) was added to a solution of methyl 6-chloro-7-methoxy-4-thenyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate (105 mg, 0.29 mmol) in methanol (2.0 mL) and water (1.0 mL), and the reaction mixture was heated at 130°C under microwave conditions for 1 h. The solvent was removed under reduced pressure and the residue was diluted with water (15 mL) which was washed with CH 2 Cl 2 (2 x 20 mL). The aqueous layer which was acidified with 1N HCl to pH ~4. The mixture was extracted with EtOAc (3 x 25 mL) and the combined extracts were dried (Na 2 SO 4 ) and concentrated in vacuo to provide the title compound (63 mg, 62%).

[0538] 1< H NMR (300 MHz, CDCl 3 ) δ 7.17 (d, 1H), 6.90 (d, 1H), 6.85 (dd, 1H), 6.77 (s, 1H), 4.50 (s, 2H), 4.12 (t, 2H), 3.67 (s, 3H), 3.23 (t, 2H).

[0539] ES-MS: 340.6 [M+1].

[0540] HPLC: Retention Time: 10.81 min., purity: 98.0% @ 254 nm.Example 29: 6-chloro-7-fluoro-4-(3-methylbutyl)-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid (A-17)

[0541] Step 1: Methyl 6-chloro-7-fluoro-4-isopentyl-2,3-dihydro-1,4-benzoxazine-8-carboxylate

[0542] A solution of methyl 6-chloro-7-fluoro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate (20 mg, 0.081 mmol), 3-methylbutanal (18 µL, 0.16 mmol) and acetic acid (23 µL, 0.40 mmol) in 1,2-dichloroethane (1 mL) was stirred at ambient temperature for 10 minutes prior to the addition of sodium triacetoxyborohydride (86 mg, 0.41 mmol). The resulting suspension was stirred at ambient temperature for 18 h. The reaction was quenched with NaHCO 3 solution (2 mL) and the biphasic mixture was washed with CH 2 Cl 2 (5 mL). The organics eluted were concentrated to dryness to afford the title compound (22 mg, 84%) as a colourless oil.

[0543] 1< H NMR (400 MHz, CDCl 3 ) δ 6.60 (d, J = 7.1 Hz, 1H), 4.29 - 4.22 (m, 2H), 3.92 (s, 3H), 3.33 - 3.26 (m, 2H), 3.25 - 3.14 (m, 2H), 1.61 (dp, J = 13.2, 6.6 Hz, 1H), 1.50 - 1.39 (m, 2H), 0.96 (d, J = 6.6 Hz, 6H).Step 2: 6-Chloro-7-fluoro-4-(3-methylbutyl)-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid

[0544] To a solution of methyl 6-chloro-7-fluoro-4-isopentyl-2,3-dihydro-1,4-benzoxazine-8-carboxylate (22 mg, 0.070 mmol) in CH 3 OH (0.2 mL) was added a solution of NaOH (7.0 mg, 0.17 mmol) in water (0.6 mL). The reaction mixture was stirred at 80 °C overnight. The reaction mixture was concentrated in vacuo and diluted with CH 2 Cl 2 (10 mL) and water (10 mL). 1 N HCl was added until the pH of the mixture reached 2. The aqueous layer was then extracted with EtOAc (2 x 10 mL). The organic layer was washed with brine (20 mL), dried over Na 2 SO 4 , filtered then concentrated in vacuo. The crude product was suspended in Et 2 O, sonicated, and the liquors were removed with a pipette. This process was repeated twice and the solids were dried under reduced pressure to afford the title compound (13 mg, 61%) as a pink solid.

[0545] 1< H NMR (400 MHz, CDCl 3 ) δ 6.69 (d, J = 7.0 Hz, 1H), 4.38 - 4.32 (m, 2H), 3.38 - 3.32 (m, 2H), 3.27 - 3.18 (m, 2H), 1.63 (dp, J = 13.2, 6.6 Hz, 1H), 1.51 - 1.41 (m, 2H), 0.97 (d, J = 6.6 Hz, 6H).

[0546] UPLC-MS analysis (4 min, basic): rt = 1.30 min, m / z = 302.0 [M+H] +< , 99% purity.Example 30: 4-Benzyl-7-chloro-6-fluoro-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid (A-45)

[0547] Step 1: Methyl 4-benzyl-7-chloro-6-fluoro-2,3-dihydro-1,4-benzoxazine-5-carboxylate

[0548] To a solution of methyl 7-chloro-6-fluoro-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylate (35 mg, 0.142 mmol) and NaH, 60% in mineral oil (14 mg, 0.35 mmol) in NMP (1.43 mL) stirred at room temperature for 5 mins, was added benzyl bromide (0.025 mL, 0.21 mmol) and the resulting mixture was stirred at room temperature overnight. The reaction was quenched with 1M HCl (10 mL) and extracted with EtOAc (2 x 15 mL). The organic layers were dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The crude material was purified by column chromatography over silica (4 g cartridge) eluting with a gradient of EtOAc (0% to 50%; v / v) in iso-hexane to afford the title compound (30 mg, 63%).

[0549] 1< H NMR (400 MHz, CDCl 3 ) δ 7.39 - 7.28 (m, 5H), 6.95 (dd, J = 7.3, 0.6 Hz, 1H), 4.22 (s, 2H), 4.08 - 4.04 (m, 2H), 3.72 (s, 3H), 3.06 (dd, J = 4.9, 3.9 Hz, 2H).Step 2: 4-Benzyl-7-chloro-6-fluoro-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid

[0550] To a stirred solution of methyl 4-benzyl-7-chloro-6-fluoro-2,3-dihydro-1,4-benzoxazine-5-carboxylate (35 mg, 0.10 mmol) in THF (0.89 mL) was added potassium trimethylsilanolate (0.10 mL, 0.21 mmol, 2M in THF) and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was then stirred at 60 °C overnight. 1M HCl (5 mL) was added, and the mixture was extracted with EtOAc (2 x 10 mL). The organics were dried over Na 2 SO 4 and concentrated to dryness to afford the title compound (31 mg, 88%) as a brown solid.

[0551] 1< H NMR (400 MHz, CDCl 3 ) δ 7.45 - 7.33 (m, 6H), 7.13 (dd, J= 6.8, 1.0 Hz, 1H), 4.29 - 4.22 (m, 2H), 4.16 (d, J = 1.6 Hz, 2H), 3.11 (dd, J = 5.3, 4.4 Hz, 2H).

[0552] UPLC-MS analysis (4 min, basic): rt = 1.08 min, m / z = 322.0 [M+H] +< , 95% purity.Example 31: 7-Chloro-6-fluoro-4-propyl-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid (A-56)

[0553] Step 1: methyl 7-chloro-6-fluoro-4-propyl-2,3-dihydro-1,4-benzoxazine-5-carboxylate

[0554] A solution of methyl 7-chloro-6-fluoro-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylate (35 mg, 0.142 mmol) and sodium hydride, 60% in mineral oil (14 mg, 0.356 mmol) in NMP (1.42 mL) was stirred at room temperature for 5 mins, then 1-iodopropane (0.021 mL, 0.214 mmol) was added and the resulting mixture was stirred at room temperature for 18 h.

[0555] The reaction mixture was diluted with 1M HCl (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organics were washed with brine (3 × 10 mL), dried over Na 2 SO 4 and concentrated to dryness. The crude material was purified by column chromatography over silica (12 g cartridge) eluting with a gradient of EtOAc (0% to 50%; v / v) in isohexane to afford the title compound (30 mg, 70%) as a yellow oil.

[0556] 1< H NMR (400 MHz, CHLOROFORM-D) δ 6.87 (dd, J = 7.4, 0.6 Hz, 1H), 4.12 - 4.05 (m, 2H), 3.93 (d, J = 0.6 Hz, 3H), 3.24 - 3.17 (m, 2H), 2.97 - 2.90 (m, 2H), 1.62 - 1.53 (m, 2H), 0.87 (t, J = 7.4 Hz, 3H).Step 2: 7-Chloro-6-fluoro-4-propyl-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid

[0557] To a stirring solution of methyl 7-chloro-6-fluoro-4-propyl-2,3-dihydro-1,4-benzoxazine-5-carboxylate (30 mg, 0.104 mmol) in THF (1.04 mL) was added potassium trimethylsilanolate (0.10 mL, 0.209 mmol) and the reaction mixture was stirred at room temperature for 2 hours.

[0558] The reaction mixture was then stirred at 60 °C overnight.

[0559] 1M HCl (5 mL) was added, and the mixture was extracted with EtOAc (2 x 10 mL). The organics were dried over Na 2 SO 4 and concentrated to dryness to give the product as a brown solid.

[0560] The crude product was purified by prep HPLC to give the title compound (1.3 mg, 5%) as a colourless solid.

[0561] UPLC-MS analysis (4 min, basic): rt = 1.52 min, m / z = 274.1 [M+H] +< , 99% purity.

[0562] 1< H NMR (400 MHz, DMSO-D6) δ 6.96 (d, J = 7.4 Hz, 1H), 4.10 - 4.01 (m, 2H), 3.17 - 3.10 (m, 2H), 3.03 - 2.94 (m, 2H), 1.72 - 1.46 (m, 2H), 0.77 (t, J = 7.4 Hz, 3H).Example 32: 7-Chloro-6-fluoro-4-[(p-methoxyphenyl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid (A-58)

[0563] Step 1: methyl 7-chloro-6-fluoro-4-[(4-methoxyphenyl)methyl]-2,3-dihydro-1,4-benzoxazine-5-carboxylate

[0564] To a -10 °C solution of methyl 7-chloro-6-fluoro-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylate (50 mg, 0.199 mmol) in DMF (1.5 mL) was added sodium hydride, 60% in mineral oil (10 mg, 0.259 mmol) and the reaction mixture was stirred at -10 °C for 15 min. A solution of 4-methoxybenzyl bromide (64 mg, 0.319 mmol) in DMF (0.5 mL) was added to a stirred reaction mixture at -10 °C and kept stirring at this temperature for 2 h.

[0565] The reaction mixture was quenched with H 2 O (10 mL) and extracted with DCM (2 x 20 mL). The organics were washed sequentially with water (2 × 20 mL) and saturated brine solution (20 mL). The organic fraction was dried (Na 2 SO 4 ) and concentrated to dryness. The crude material was purified by column chromatography over silica (12 g cartridge) eluting with a gradient of EtOAc (0% to 100% v / v) in i-Hexane to afford the title compound (55 mg, 64%) as a colourless gum.

[0566] 1< H NMR (400 MHz, CHLOROFORM-D) δ 7.26 - 7.21 (m, 2H), 6.94 (d, J = 7.3 Hz, 1H), 6.92 - 6.86 (m, 2H), 4.14 (s, 2H), 4.06 - 4.01 (m, 2H), 3.81 (s, 3H), 3.78 (s, 3H), 3.12 - 2.94 (m, 2H).Step 2: 7-Chloro-6-fluoro-4-[(p-methoxyphenyl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid

[0567] To a solution of methyl 7-chloro-6-fluoro-4-[(4-methoxyphenyl)methyl]-2,3-dihydro-1,4-benzoxazine-5-carboxylate (50 mg, 0.116 mmol) in Et 2 O (4 mL) was added potassium tert-butoxide (117 mg, 1.05 mmol) at room temperature. To this slurry water (5 µL) was added and stirred at room temperature for 2 h.

[0568] The reaction mixture was diluted with water (20 mL), the aqueous phase was washed with EtOAc (20 mL) and acidified by 1 M HCl to pH ~ 5 and extracted with EtOAc (20 mL). The organic phase was washed with saturated brine solution (20 mL), dried (Na 2 SO 4 ) and concentrated to dryness. The crude material was purified by column chromatography over silica (12 g cartridge) eluting with a gradient of MeOH (0% to 50%; v / v) in EtOAc to afford the impure product.

[0569] This crude product was purified by prep-HPLC to afford the title compound (5.5 mg, 13%) as a white solid.

[0570] UPLC-MS analysis (4 min, basic): rt = 1.14 min, m / z = 350.0 [M-H] -< , 100% purity.

[0571] 1< H NMR (400 MHz, DMSO-D6) δ 7.42 - 7.27 (m, 2H), 7.17 - 7.05 (m, 1H), 6.87 - 6.76 (m, 2H), 4.22 (s, 2H), 4.02 - 3.88 (m, 2H), 3.70 (s, 3H), 2.85 - 2.72 (m, 2H).Example 33: 7-Chloro-6-fluoro-4-[(p-tolyl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid (A-60)

[0572] Step 1: methyl 7-chloro-6-fluoro-4-(p-tolylmethyl)-2,3-dihydro-1,4-benzoxazine-5-carboxylate

[0573] To a -15 °C solution of methyl 7-chloro-6-fluoro-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylate (50 mg, 0.199 mmol) in DMF (2 mL) was added sodium hydride, 60% in mineral oil (12 mg, 0.299 mmol) and the resulting suspension was stirred at -13 °C for 15 min. A solution of 4-methylbenzyl bromide (59 mg, 0.319 mmol) in DMF (1 mL) was added to a stirred reaction mixture at -13 °C and kept stirring at this temperature for 2 h.

[0574] The reaction mixture was quenched with H 2 O (30 mL) and extracted with EtOAc (3 x 20 mL). The organic phase was washed sequentially with water (2 × 20 mL) and saturated brine solution (20 mL). The organic fraction was dried (Na 2 SO 4 ) and concentrated to dryness. The crude product was purified by column chromatography over silica (12 g cartridge) eluting with a gradient of EtOAc (0% to 100% v / v) in i-Hexane to afford the title compound (70 mg, 95%) as a beige solid.

[0575] 1< H NMR (400 MHz, CHLOROFORM-D) δ 7.23 - 7.12 (m, 4H), 6.94 (d, J = 7.3 Hz, 1H), 4.17 (s, 2H), 4.08 - 3.98 (m, 2H), 3.75 (s, 3H), 3.10 - 3.00 (m, 2H), 2.35 (s, 3H).Step 2: 7-Chloro-6-fluoro-4-[(p-tolyl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid

[0576] To a solution of methyl 7-chloro-6-fluoro-4-(p-tolylmethyl)-2,3-dihydro-1,4-benzoxazine-5-carboxylate (65 mg, 0.177 mmol) in Et 2 O (5 mL) was added potassium tert-butoxide (113 mg, 1.01 mmol) at 0°C for 2 h then at room temperature for 2 h. The reaction mixture was diluted with ether (10 mL) and potassium tert-butoxide (90 mg, 0.802 mmol) was recharged. The reaction mixture was stirred for additional 3 h at room temperature. Water (30 µL) was added and reaction mixture was stirred overnight at room temperature.

[0577] The reaction mixture was diluted with water and adjusted pH to ~3 with 1M HCl solution. The product was extracted into EtOAc. The organic phase was washed with saturated brine solution (20 mL), dried (Na 2 SO 4 ) and concentrated to dryness to give the crude oily product which was purified by prep-HPLC to the title compound (24 mg, 39%) as a white solid.

[0578] UPLC-MS analysis (4 min, basic): rt = 1.23 min, m / z = 336.1 [M+H] +< , 97% purity.

[0579] 1< H NMR (400 MHz, DMSO-D6) δ 7.45 - 7.23 (m, 2H), 7.16 - 7.02 (m, 2H), 6.75 (d, J = 7.3 Hz, 1H), 4.32 (s, 2H), 3.99 - 3.91 (m, 2H), 2.84 - 2.76 (m, 2H), 2.28 (s, 3H).Example 34: 7-Chloro-6-fluoro-4-[(1-naphthyl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid (A-61)

[0580] Step 1: methyl 7-chloro-6-fluoro-4-(2-naphthylmethyl)-2,3-dihydro-1,4-benzoxazine-5-carboxylate

[0581] To a -15 °C solution of methyl 7-chloro-6-fluoro-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylate (51 mg, 0.203 mmol) in DMF (2 mL) was added sodium hydride, 60% in mineral oil (12 mg, 0.305 mmol) and the resulting suspension was stirred at -13 °C for 15 min. A solution of 2-(bromomethyl)naphthalene (58 mg, 0.265 mmol) in DMF (1 mL) was added and the solution was kept stirring at this temperature for 3 h. The reaction mixture was quenched with sodium hydroxide 3 M water solution (0.50 mL, 1.50 mmol) and stirred at r...

Claims

1. A compound of Formula (I): wherein: - M is CR5R6, NR7, O or S; - Q is CR5R6, NR8, O or S; - T is CR5R6, NR8, O or S; - X is absent, CR5R6, NR8, O or S; - Z is CR5R6, NR9, O or S; - two or more of M, Q, T, X and Z are NR7, NR8, NR9, O or S; - R1 is selected from the group consisting of F; Cl; Br; C1-3 alkyl optionally substituted with one or more, identical or different, substituents R10; C2-3 alkenyl optionally substituted with one or more, identical or different, substituents R10; -OC1-3 alkyl optionally substituted with one or more, identical or different, substituents R10; -OC3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R10; - SC1-3 alkyl optionally substituted with one or more, identical or different, substituents R10 and -SC3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R10; - R2 is selected from the group consisting of H; F; Cl; Br; and C1-3 alkyl optionally substituted with one or more, identical or different, substituents R10; - R3 is selected from the group consisting of H, F and Cl; - R4 is selected from the group consisting of H; C1-5 alkyl optionally substituted with one or more, identical or different, substituents R10; C2-5 alkenyl optionally substituted with one or more, identical or different, substituents R10; C2-5 alkynyl optionally substituted with one or more, identical or different, substituents R10; C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R10; phenyl optionally substituted with one or more, identical or different, substituents R11; and benzyl optionally substituted with one or more, identical or different, substituents R11; - R5 is independently selected from the group consisting of H, deuterium, F and C1-5 alkyl optionally substituted with one or more, identical or different, substituents R10; - R6 is independently selected from the group consisting of H, deuterium, F and C1-5 alkyl optionally substituted with one or more, identical or different, substituents R10; - R7 is independently selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R10; C1-3 alkyl substituted with C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R10; C1-3 alkyl substituted with phenyl optionally substituted with one or more, identical or different, substituents R11; C1-3 alkyl substituted with C5 heteroaryl optionally substituted with one or more, identical or different, substituents R11; and C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R10; - R8 is independently selected from benzyl optionally substituted with one or more, identical or different, substituents R11; - R9 is independently selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R10; C1-3 alkyl substituted with C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R10; C1-3 alkyl substituted with phenyl optionally substituted with one or more, identical or different, substituents R11; C1-3 alkyl substituted with naphthyl optionally substituted with one or more, identical or different, substituents R11; C1-3 alkyl substituted with a 5- to 10-membered heteroaryl optionally substituted with one or more, identical or different, substituents R11; and C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R10; - R10 is independently selected from the group consisting of H, deuterium, F, Cl and -OC1-3 alkyl; and - R11 is independently selected from the group consisting of deuterium, methoxy, -OCF3, Me, CF3, CF2Cl, CF2H, CFH2, CD3, cyclopropyl, NH2, -NHAc, -C(=O)-NH2, nitro, cyano, CI, Br, I, and F; when R5 and R6 are individually C1-5 alkyl optionally substituted with one or more, identical or different, substituents R10, then R5 and R6 are optionally joined together to form a ring; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof provided that: - only one of M, Q, T, X and Z is O; and - when M is O, Q and T are CH2, X is absent, Z is NH, R1 is Cl, R2 is H and R3 is H then R4 is not H.

2. The compound according to claim 1, wherein compound is of formula (II): - M is NR7, O or S; - Q is CR5R6; - T is CR5R6; - Z is NR9, O or S; - R1 is selected from the group consisting of F; Cl; Br; C1-3 alkyl optionally substituted with one or more, identical or different, substituents R10; C2-3 alkenyl optionally substituted with one or more, identical or different, substituents R10; -OC1-3 alkyl optionally substituted with one or more, identical or different, substituents R10; -OC3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R10; - SC1-3 alkyl optionally substituted with one or more, identical or different, substituents R10 and -SC3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R10; - R2 is selected from the group consisting of H; F; Cl; Br; and C1-3 alkyl optionally substituted with one or more, identical or different, substituents R10; - R3 is selected from the group consisting of H, F and Cl; - R4 is selected from the group consisting of H; C1-5 alkyl optionally substituted with one or more, identical or different, substituents R10; C2-5 alkenyl optionally substituted with one or more, identical or different, substituents R10; C2-5 alkynyl optionally substituted with one or more, identical or different, substituents R10; C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R10; phenyl optionally substituted with one or more, identical or different, substituents R11; and benzyl optionally substituted with one or more, identical or different, substituents R11; - R5 is independently selected from the group consisting of H, deuterium, F and C1-5 alkyl optionally substituted with one or more, identical or different, substituents R10; - R6 is independently selected from the group consisting of H, deuterium, F and C1-5 alkyl optionally substituted with one or more, identical or different, substituents R10; - R7 is independently selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R10; C1-3 alkyl substituted with C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R10; C1-3 alkyl substituted with phenyl optionally substituted with one or more, identical or different, substituents R11; C1-3 alkyl substituted with C5 heteroaryl optionally substituted with one or more, identical or different, substituents R11; and C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R10; - R8 is independently selected from benzyl optionally substituted with one or more, identical or different, substituents R11; - R9 is independently selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R10; C1-3 alkyl substituted with C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R10; C1-3 alkyl substituted with phenyl optionally substituted with one or more, identical or different, substituents R11; C1-3 alkyl substituted with naphthyl optionally substituted with one or more, identical or different, substituents R11; C1-3 alkyl substituted with a 5- to 10-membered heteroaryl optionally substituted with one or more, identical or different, substituents R11; and C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R10; - R10 is independently selected from the group consisting of H, deuterium, F, Cl and -OC1-3 alkyl; and - R11 is independently selected from the group consisting of deuterium, methoxy, -OCF3, Me, CF3, CF2Cl, CF2H, CFH2, CD3, cyclopropyl, NH2, -NHAc, -C(=O)-NH2, nitro, cyano, CI, Br, I, and F; when R5 and R6 are individually C1-5 alkyl optionally substituted with one or more, identical or different, substituents R10, then R5 and R6 are optionally joined together to form a ring; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof provided that: - only one of M and Z is O; and - when M is O, Q and T are CH2, Z is NH, R' is Cl, R2 is H and R3 is H then R4 is not H.

3. The compound according to claim 1, wherein the compound is selected from the group consisting of Formula (III), Formula (IV), Formula (V), Formula (VI), and Formula (VII): wherein: - R' is selected from the group consisting of F; Cl; Br; C1-3 alkyl optionally substituted with one or more, identical or different, substituents R10; C2-3 alkenyl optionally substituted with one or more, identical or different, substituents R10; -OC1-3 alkyl optionally substituted with one or more, identical or different, substituents R10; -OC3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R10; - SC1-3 alkyl optionally substituted with one or more, identical or different, substituents R10 and -SC3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R10; - R2 is selected from the group consisting of H; F; Cl; Br; and C1-3 alkyl optionally substituted with one or more, identical or different, substituents R10; - R3 is selected from the group consisting of H, F and Cl; - R4 is selected from the group consisting of H; C1-5 alkyl optionally substituted with one or more, identical or different, substituents R10; C2-5 alkenyl optionally substituted with one or more, identical or different, substituents R10; C2-5 alkynyl optionally substituted with one or more, identical or different, substituents R10; C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R10; phenyl optionally substituted with one or more, identical or different, substituents R11; and benzyl optionally substituted with one or more, identical or different, substituents R11; - R5Q, R5T and R5X are independently selected from the group consisting of H, deuterium, F and C1-5 alkyl optionally substituted with one or more, identical or different, substituents R10; - R6Q, R6T and R6X are independently selected from the group consisting of H, deuterium, F and C1-5 alkyl optionally substituted with one or more, identical or different, substituents R10; - R7 is independently selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R10; C1-3 alkyl substituted with C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R10; C1-3 alkyl substituted with phenyl optionally substituted with one or more, identical or different, substituents R11; C1-3 alkyl substituted with C5 heteroaryl optionally substituted with one or more, identical or different, substituents R11; and C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R10; - R9 is independently selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R10; C1-3 alkyl substituted with C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R10; C1-3 alkyl substituted with phenyl optionally substituted with one or more, identical or different, substituents R11; C1-3 alkyl substituted with naphthyl optionally substituted with one or more, identical or different, substituents R11; C1-3 alkyl substituted with a 5- to 10-membered heteroaryl optionally substituted with one or more, identical or different, substituents R11; and C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R10; - R10 is independently selected from the group consisting of H, deuterium, F, Cl and -OC1-3 alkyl; and - R11 is independently selected from the group consisting of deuterium, methoxy, -OCF3, Me, CF3, CF2Cl, CF2H, CFH2, CD3, cyclopropyl, NH2, -NHAc, -C(=O)-NH2, nitro, cyano, CI, Br, I, and F; when R5Q and R6Q are individually C1-5 alkyl optionally substituted with one or more, identical or different, substituents R10, then R5Q and R6Q are optionally joined together to form a ring; or when R5T and R6T are individually C1-5 alkyl optionally substituted with one or more, identical or different, substituents R10, then R5T and R6T are optionally joined together to form a ring; or when R5X and R6X are individually C1-5 alkyl optionally substituted with one or more, identical or different, substituents R10, then R5X and R6X are optionally joined together to form a ring; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

4. The compound according to any of claims 1 to 3, wherein R1 is selected from the group consisting of F, Cl, Me, OMe, OEt, OCHMe2 and SMe.

5. The compound according to any of claims 1 to 4, wherein R2 is selected from the group consisting of H, F, Cl and Me.

6. The compound according to any of claims 1 to 5, wherein R4 is H.

7. The compound according to any of claims 1 to 6, wherein R1 is OMe and R2 is F or Cl.

8. The compound according to any one of claims 1 to 7, wherein the compound is selected from the group consisting of: 6-chloro-7-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 7-chloro-6-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid; 7-chloro-6-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 5-chloro-7-fluoro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-fluoro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 7-chloro-6-fluoro-1,4-dimethyl-1,2,3,4-tetrahydroquinoxaline-5-carboxylic acid; 6-chloro-7-fluoro-2,2,4-trimethyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 7-chloro-6-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid; 7-chloro-6-fluoro-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid; 7-chloro-8-methoxy-5-methyl-2,3,4,5-tetrahydro-1,5-benzoxazepine-9-carboxylic acid; 7-chloro-8-fluoro-5-methyl-2,3,4,5-tetrahydro-1,5-benzoxazepine-9-carboxylic acid; 6-chloro-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 7-chloro-8-fluoro-2,3,4,5-tetrahydro-1,5-benzoxazepine-9-carboxylic acid; 7-chloro-8-ethoxy-5-methyl-2,3,4,5-tetrahydro-1,5-benzoxazepine-9-carboxylic acid; 6-chloro-7-fluoro-4-(3-methylbutyl)-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-4-ethyl-7-fluoro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzothiazine-8-carboxylic acid; 6-chloro-4-(cyclopropylmethyl)-7-fluoro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-fluoro-4-propyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 4-benzyl-6-chloro-7-fluoro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-fluoro-4-[3-(4-fluorophenyl)propyl]-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-4-methyl-7-(propan-2-yloxy)-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-fluoro-4-[2-(4-fluorophenyl)ethyl]-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-4-methyl-7-(methylsulfanyl)-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-fluoro-4-(3-methoxypropyl)-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-4-ethyl-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzothiazine-8-carboxylic acid; 6-fluoro-7-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 7-methoxy-4,6-dimethyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-4-(propan-2-yl)-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-4-(2-phenylethyl)-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-4-[2-(4-methoxyphenyl)ethyl]-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-2-(methoxymethyl)-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-4-[(thiophen-3-yl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-2,2,4-trimethyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-fluoro-4-(2-methoxyethyl)-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-4-methyl-3,4-dihydrospiro[1,4-benzoxazine-2,1'-cyclobutane]-8-carboxylic acid; 6-chloro-4-[3-(furan-2-yl)propyl]-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-4-[(thiophen-2-yl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-4-[(1,3-thiazol-2-yl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-5-fluoro-7-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 4-benzyl-7-chloro-6-fluoro-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid; 6-chloro-4-(cyclobutylmethyl)-7-fluoro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-4-[3-(1,3-thiazol-2-yl)propyl]-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-4,7-dimethyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-4-[(4-methoxyphenyl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-4-[(1,3-oxazol-2-yl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 7-chloro-6-fluoro-4-(3-methylbutyl)-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid; 4-benzyl-6-chloro-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-4-[2-(3,5-difluorophenyl)ethyl]-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 7-chloro-6-fluoro-4-[(thiophen-3-yl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid; 4-benzyl-6-fluoro-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; methyl 6-chloro-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate; ethyl 6-chloro-7-fluoro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate; methyl 7-chloro-6-fluoro-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylate; methyl 6-chloro-7-fluoro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate; 7-chloro-6-fluoro-4-propyl-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid; 7-chloro-6-fluoro-4-methyl-1,2,3,4-tetrahydro-5-quinoxalinecarboxylic acid; 7-chloro-6-fluoro-4-[(p-methoxyphenyl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid; 1-benzyl-7-chloro-6-fluoro-4-methyl-1,2,3,4-tetrahydro-5-quinoxalinecarboxylic acid; 7-chloro-6-fluoro-4-[(p-tolyl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid; 7-chloro-6-fluoro-4-[(1-naphthyl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid; 7-chloro-6-fluoro-4-[(o-tolyl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid; and 4-benzyl-6,7-dichloro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid.

9. A composition comprising the compound according to any one of claims 1 to 8 and a pharmaceutically acceptable carrier.

10. The compound according to any one of claims 1 to 8 or composition according to claim 9 for use as a medicament.

11. The compound according to any one of claims 1 to 8 or composition according to claim 9 for use in the treatment of an indication selected from the group consisting of myasthenia gravis, autoimmune myasthenia gravis, congenital myasthenic syndrome, seronegative myasthenia gravis, muscle specific kinase myasthenia gravis (MuSK-MG), Lambert-Eaton Syndrome, critical illness myopathy, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), critical illness myopathy (CIM), Charcot-Marie Tooth disease, diabetic polyneuropathy, periodic paralysis, hypokalemic periodic paralysis, hyperkalemic periodic paralysis, myotubular myopathy, Duchenne muscular dystrophy, Guillain-Barré syndrome, poliomyelitis, post-polio syndrome, chronic fatigue syndrome, critical illness polyneuropathy, metabolic myopathy, Kennedy's disorder, multiple sclerosis and multifocal motor neuropathy.

12. The compound according to any one of claims 1 to 8 or composition according to claim 9 for use in the symptomatic treatment of sarcopenia.

13. The compound according to any one of claims 1 to 8 or composition according to claim 9 for use in reversing and / or ameliorating a neuromuscular blockade.

14. A compound of Formula (I): wherein: - M is CR5R6, NR7, O or S; - Q is CR5R6, NR8, O or S; - T is CR5R6, NR8, O or S; - X is absent, CR5R6, NR8, O or S; - Z is CR5R6, NR9, O or S; - two or more of M, Q, T, X and Z are NR7, NR8, NR9, O or S; - R' is selected from the group consisting of H; F; Cl; Br; C1-3 alkyl optionally substituted with one or more, identical or different, substituents R10; C2-3 alkenyl optionally substituted with one or more, identical or different, substituents R10; -OC1-3 alkyl optionally substituted with one or more, identical or different, substituents R10; -OC3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R10; - SC1-3 alkyl optionally substituted with one or more, identical or different, substituents R10 and -SC3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R10; - R2 is selected from the group consisting of H; F; Cl; Br; C1-3 alkyl optionally substituted with one or more, identical or different, substituents R10 and OC1-3 alkyl optionally substituted with one or more, identical or different, substituents R10; - R3 is selected from the group consisting of H, F and Cl; - R4 is selected from the group consisting of H; C1-5 alkyl optionally substituted with one or more, identical or different, substituents R10; C2-5 alkenyl optionally substituted with one or more, identical or different, substituents R10; C2-5 alkynyl optionally substituted with one or more, identical or different, substituents R10; C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R10; phenyl optionally substituted with one or more, identical or different, substituents R11; and benzyl optionally substituted with one or more, identical or different, substituents R11; - R5 is independently selected from the group consisting of H, deuterium, F and C1-5 alkyl optionally substituted with one or more, identical or different, substituents R10; - R6 is independently selected from the group consisting of H, deuterium, F and C1-5 alkyl optionally substituted with one or more, identical or different, substituents R10; - R7 is independently selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R10; C1-3 alkyl substituted with C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R10; C1-3 alkyl substituted with phenyl optionally substituted with one or more, identical or different, substituents R11; C1-3 alkyl substituted with C5 heteroaryl optionally substituted with one or more, identical or different, substituents R11; and C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R10; - R8 is independently selected from benzyl optionally substituted with one or more, identical or different, substituents R11; - R9 is independently selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R10; C1-3 alkyl substituted with C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R10; C1-3 alkyl substituted with phenyl optionally substituted with one or more, identical or different, substituents R11; C1-3 alkyl substituted with naphthyl optionally substituted with one or more, identical or different, substituents R11; C1-3 alkyl substituted with a 5- to 10-membered heteroaryl optionally substituted with one or more, identical or different, substituents R11; and C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R10; - R10 is independently selected from the group consisting of H, deuterium, F, Cl and -OC1-3 alkyl; and - R11 is independently selected from the group consisting of deuterium, methoxy, -OCF3, Me, CF3, CF2Cl, CF2H, CFH2, CD3, cyclopropyl, NH2, -NHAc, -C(=O)-NH2, nitro, cyano, CI, Br, I, and F; when R5 and R6 are individually C1-5 alkyl optionally substituted with one or more, identical or different, substituents R10, then R5 and R6 are optionally joined together to form a ring; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof for use in treating, ameliorating and / or preventing a neuromuscular disorder, and / or for use in reversing and / or ameliorating a neuromuscular blockade.

15. The compound for use according to claim 14, wherein the compound is selected from the group consisting of: 7-chloro-2,3-dihydro-1,4-benzodioxine-5-carboxylic acid; 7-chloro-6-methoxy-2,3-dihydro-1,4-benzodioxine-5-carboxylic acid; 7-chloro-6-methyl-2,3-dihydro-1,4-benzodioxine-5-carboxylic acid; 7,8-dichloro-6-methyl-2,3-dihydro-1,4-benzodioxine-5-carboxylic acid; 6-chloro-7-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 7-chloro-6-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid; 7-chloro-6-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 5-chloro-7-fluoro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-fluoro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 7-chloro-6-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 7-chloro-6-fluoro-1,4-dimethyl-1,2,3,4-tetrahydroquinoxaline-5-carboxylic acid; 6-chloro-7-fluoro-2,2,4-trimethyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 7-chloro-6-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid; 7-chloro-6-fluoro-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid; 7-chloro-8-methoxy-5-methyl-2,3,4,5-tetrahydro-1,5-benzoxazepine-9-carboxylic acid; 7-chloro-8-fluoro-5-methyl-2,3,4,5-tetrahydro-1,5-benzoxazepine-9-carboxylic acid; 6-chloro-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 7-chloro-8-fluoro-2,3,4,5-tetrahydro-1,5-benzoxazepine-9-carboxylic acid; 7-chloro-8-ethoxy-5-methyl-2,3,4,5-tetrahydro-1,5-benzoxazepine-9-carboxylic acid; 6-chloro-7-fluoro-4-(3-methylbutyl)-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-4-ethyl-7-fluoro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzothiazine-8-carboxylic acid; 6-chloro-4-(cyclopropylmethyl)-7-fluoro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-fluoro-4-propyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 4-benzyl-6-chloro-7-fluoro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 7-fluoro-6-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-fluoro-4-[3-(4-fluorophenyl)propyl]-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-4-methyl-7-(propan-2-yloxy)-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-fluoro-4-[2-(4-fluorophenyl)ethyl]-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-4-methyl-7-(methylsulfanyl)-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-fluoro-4-(3-methoxypropyl)-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-4-ethyl-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzothiazine-8-carboxylic acid; 6-fluoro-7-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 7-methoxy-4,6-dimethyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-4-(propan-2-yl)-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-4-(2-phenylethyl)-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-4-[2-(4-methoxyphenyl)ethyl]-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-2-(methoxymethyl)-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-4-[(thiophen-3-yl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-2,2,4-trimethyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-2-(methoxymethyl)-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid; 6-chloro-7-fluoro-4-(2-methoxyethyl)-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-4-methyl-3,4-dihydrospiro[1,4-benzoxazine-2,1'-cyclobutane]-8-carboxylic acid; 6-chloro-4-[3-(furan-2-yl)propyl]-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-4-[(thiophen-2-yl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-4-[(thiophen-2-yl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-4-[(1,3-thiazol-2-yl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-5-fluoro-7-methoxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 4-benzyl-7-chloro-6-fluoro-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid; 6-chloro-4-(cyclobutylmethyl)-7-fluoro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-4-[3-(1,3-thiazol-2-yl)propyl]-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-4,7-dimethyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-4-[(4-methoxyphenyl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-7-methoxy-4-[(1,3-oxazol-2-yl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 7-chloro-6-fluoro-4-(3-methylbutyl)-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid; 4-benzyl-6-chloro-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 6-chloro-4-[2-(3,5-difluorophenyl)ethyl]-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; 7-chloro-6-fluoro-4-[(thiophen-3-yl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid; 4-benzyl-6-fluoro-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid; methyl 6-chloro-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate; ethyl 6-chloro-7-fluoro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate; methyl 7-chloro-6-fluoro-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylate; methyl 6-chloro-7-fluoro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate; 7-chloro-6-fluoro-4-propyl-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid; 7-chloro-6-fluoro-4-methyl-1,2,3,4-tetrahydro-5-quinoxalinecarboxylic acid; 7-chloro-6-fluoro-4-[(p-methoxyphenyl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid; 1-benzyl-7-chloro-6-fluoro-4-methyl-1,2,3,4-tetrahydro-5-quinoxalinecarboxylic acid; 7-chloro-6-fluoro-4-[(p-tolyl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid; 7-chloro-6-fluoro-4-[(1-naphthyl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid; 7-chloro-6-fluoro-4-[(o-tolyl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid; and 4-benzyl-6,7-dichloro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid.