Tetrahydroisoquinoline derivatives

文档序号：1855920 发布日期：2021-11-19 浏览：19次中文

阅读说明：本技术 四氢异喹啉衍生物 (Tetrahydroisoquinoline derivatives ) 是由佐藤一平上久保隆三浦理宪松岛雄司田中宏明椎名康裕山木晋斋藤智之清原宏于 2017-02-10 设计创作，主要内容包括：本发明涉及四氢异喹啉衍生物。具体地,本文公开了新的四氢异喹啉衍生化合物,其可作为活性成分用于药物组合物,特别是可用于预防或治疗对骨骼肌肌节的收缩性的调节具有响应性的疾病或病症的药物组合物。这可以例如凭借通过快骨骼肌肌球蛋白、肌动蛋白、原肌球蛋白、肌钙蛋白C、肌钙蛋白I和肌钙蛋白T及其片段和同种型中的一者或多者调节所述快骨骼肌肌节的肌钙蛋白复合体来实现。因此,所述四氢异喹啉衍生化合物可用作预防或治疗1)神经肌肉障碍,2)随意肌的障碍,3)以肌无力、萎缩和疲劳为突出症状的CNS障碍,4)源于系统性障碍的肌肉症状,以及5)盆底肌和尿道/肛门括约肌的功能障碍的药剂。(The present invention relates to tetrahydroisoquinoline derivatives. In particular, disclosed herein are novel tetrahydroisoquinoline derivative compounds useful as active ingredients in pharmaceutical compositions, particularly pharmaceutical compositions useful for the prevention or treatment of diseases or disorders responsive to the modulation of contractility of skeletal muscle sarcomere. This may be achieved, for example, by virtue of the troponin complex regulating the fast skeletal muscle sarcomere by one or more of fast skeletal muscle myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof. Accordingly, the tetrahydroisoquinoline derivative compounds are useful as agents for preventing or treating 1) neuromuscular disorders, 2) disorders of voluntary muscles, 3) CNS disorders with muscle weakness, atrophy and fatigue as prominent symptoms, 4) muscular symptoms resulting from systemic disorders, and 5) dysfunction of pelvic floor muscles and urinary/anal sphincters.)

1. (-) -6-chloro-4- (2-hydroxyethyl) -4-methyl-2H-spiro [ isoquinoline-1, 3' -oxetane]-3(4H) -one in crystalline form, when irradiated with Cu-KalphaAn X-ray powder diffraction spectrum having peaks at the following angles 2 theta (°) ± 0.2 ° when measured: 12.2, 15.5, 18.3, 21.7 and 22.7.

2. (-) -6-chloro-4- (2-hydroxyethyl) -4-methyl-2H-spiro [ isoquinoline-1, 3' -oxetane according to claim 1]-3(4H) -one in crystalline form, when irradiated with Cu-Kalpha An X-ray powder diffraction spectrum having peaks at the following angles 2 theta (°) ± 0.2 ° when measured: 6.7, 11.1, 12.2, 13.7, 15.5, 16.2, 17.0, 18.3, 21.7 and 22.7.

3.4, 4-dimethyl-3-oxo-3, 4-dihydro-2H-spiro [ isoquinoline-1, 3' -oxetane]-6-carbonitrile in crystalline form, which is irradiated with Cu-KaX-ray powder having peaks at the following angles 2 theta (°) ± 0.2 ° when measuredEnd diffraction spectrum: 12.1, 15.6, 16.6, 21.4 and 23.4.

4. 4, 4-dimethyl-3-oxo-3, 4-dihydro-2H-spiro [ isoquinoline-1, 3' -oxetane according to claim 3]-6-carbonitrile in crystalline form, which is irradiated with Cu-Ka An X-ray powder diffraction spectrum having peaks at the following angles 2 theta (°) ± 0.2 ° when measured: 8.3, 12.1, 15.6, 16.6, 17.3, 20.5, 21.4, 23.4, 24.0 and 25.7.

5. A pharmaceutical composition comprising the crystalline form according to any one of claims 1 to 4 and a pharmaceutically acceptable excipient.

6. Use of a crystalline form according to any one of claims 1 to 4, a pharmaceutical composition comprising a crystalline form according to any one of claims 1 to 4 or a pharmaceutical composition according to claim 5 in the manufacture of a medicament for the treatment of a disease selected from Stress Urinary Incontinence (SUI), Mixed Urinary Incontinence (MUI), fecal incontinence, frailty, sarcopenia, muscle weakness caused by cachexia associated with Chronic Obstructive Pulmonary Disease (COPD), cachexia syndrome and/or muscle wasting due to heart failure, cancer or chronic kidney disease/dialysis, muscle dysfunction after Spinal Cord Injury (SCI), muscle dysfunction after stroke, muscle weakness and fatigue associated with peripheral vascular disease or peripheral arterial disease, post-operative muscle weakness, use in medicine of a disease or condition of muscle weakness associated with metabolic syndrome or obesity, ventilator-induced muscle weakness and chronic fatigue syndrome.

7. Use of the crystalline form according to any one of claims 1 to 4, a pharmaceutical composition comprising the crystalline form according to any one of claims 1 to 4, or a pharmaceutical composition according to claim 5, in the manufacture of a medicament for treating a disease or disorder selected from Amyotrophic Lateral Sclerosis (ALS), Spinal Muscular Atrophy (SMA), myasthenia gravis, and muscle myopathy.

8. Use of the crystalline form according to any one of claims 1 to 4 in the manufacture of a pharmaceutical composition for the treatment of a disease or disorder selected from Stress Urinary Incontinence (SUI), Mixed Urinary Incontinence (MUI), fecal incontinence, frailty, sarcopenia, cachexia associated with Chronic Obstructive Pulmonary Disease (COPD), cachexia syndrome and/or wasting of muscle caused by heart failure, cancer or chronic kidney disease/dialysis, muscle dysfunction after Spinal Cord Injury (SCI), muscle dysfunction after stroke, muscle weakness and fatigue associated with peripheral vascular disease or peripheral arterial disease, muscle weakness after surgery, muscle weakness associated with metabolic syndrome or obesity, ventilator-induced muscle weakness and chronic fatigue syndrome.

9. Use of the crystalline form according to any one of claims 1 to 4 in the manufacture of a pharmaceutical composition for treating a disease or disorder selected from Amyotrophic Lateral Sclerosis (ALS), Spinal Muscular Atrophy (SMA), myasthenia gravis, and muscle myopathy.

10. A method for preparing fast skeletal muscle myofibrils, the method comprising:

myofibrils were prepared within 2 days of ordering from rabbit psoas major stored on ice;

The minced muscle was homogenized in 10 volumes of ice cold standard buffer (50mM Tris, pH 7.4, 0.1M KOAc, 5mM KCl, 2mM Dithiothreitol (DTT), 0.2mM phenylmethylsulfonyl fluoride (PMSF), 10. mu.M leupeptin, 5. mu.M pepstatin, and 0.5mM sodium azide) containing 5mM ethylenediaminetetraacetic acid (EDTA) and 0.5% Triton X-100 using an Omni-Macro homogenizer;

myofibrils were recovered by low speed centrifugation (3000rpm for 10 min) and washed twice in buffer containing Triton X-100 to ensure removal of cell membranes;

after Triton washing, myofibrils were washed 3 times in "standard" buffer containing 2mM magnesium acetate; and

the final wash was performed in assay buffer (12mM piperazine-1, 4-bis (2-ethanesulfonic acid) (PIPES), pH 6.8, 60mM KCl, 1mM DTT) and added to 10% sucrose for quick freezing in liquid nitrogen and storage at-80 ℃.

Technical Field

The present invention relates to tetrahydroisoquinoline derivatives or salts thereof which are useful as active ingredients in pharmaceutical compositions, in particular for the treatment of diseases or disorders responsive to the modulation of the contractility of skeletal muscle sarcomere.

Background

The cytoskeleton of skeletal muscle and cardiac muscle cells is unique compared to all other cells. It consists of a nearly crystalline array of closely packed cytoskeletal proteins called sarcomeres. The muscle segments are finely organized into an interdigitated array of thin and thick filaments. The crude myofilaments are composed of myosin, a motor protein responsible for converting the chemical energy of ATP hydrolysis into force and directed movement. The thin myofilaments are composed of actin monomers arranged in a helical array. There are four regulatory proteins that bind to actin filaments, which allow contraction to be regulated by calcium ions. The influx of intracellular calcium initiates muscle contraction; the thick and thin filaments slide past each other driven by the repetitive interaction of the myosin motor domain with the thin actin filaments.

Of the 13 different myosin classes in human cells, class II myosins are responsible for the contraction of skeletal, cardiac and smooth muscles. This class of myosins differs significantly in amino acid composition and overall structure from myosins in the other 12 different classes. Class II myosins form a homodimer, creating two globular head domains linked together by a long alpha-helical coil-coil tail to form the core of the thick muscle filament of the sarcomere. The globular head has a catalytic domain where actin binding of myosin and ATPase function occur. Once bound to actin filaments, the release of phosphate (referred to as ADP-Pi to ADP) signals a conformational change in the structure of the catalytic domain which in turn alters the orientation of the lever arm domain of the bound light chain protruding from the globular head; this motion is referred to as a power stroke. This change in orientation of the myosin head relative to actin causes the thick myofilaments which it is part of to move relative to the thin actin myofilaments to which it binds.Detachment of the globular head from the actin filaments (Ca)²⁺Regulated) coupled with the return of the catalytic domain and light chain to their original conformation/orientation, completes the catalytic cycle responsible for intracellular movement and muscle contraction.

Tropomyosin and troponins mediate the calcium effect on actin-myosin interactions. The troponin complex comprises 3 polypeptide chains: troponin C binding to calcium ions, troponin I binding to actin, and troponin T binding to tropomyosin. The skeletal muscle troponin-tropomyosin complex regulates myosin binding sites that extend across several actin units at once.

Troponin, which is a complex of the above-mentioned 3 polypeptides, is an accessory protein closely related to actin filaments in vertebrate muscles. The troponin complex acts in conjunction with the muscle form of tropomyosin to mediate Ca for myosin ATPase activity²⁺Dependence and thereby regulation of muscle contraction. Troponin polypeptides T, I and C are named for their tropomyosin binding, inhibitory and calcium binding activities, respectively. Troponin T binds to tropomyosin and is believed to be responsible for the localization of troponin complexes to the muscle filaments. Troponin I binds to actin, and the complex formed by troponin I and T and tropomyosin inhibit the interaction of actin with myosin. Skeletal muscle troponin C is capable of binding up to 4 calcium molecules. Studies have shown that troponin C exposes a binding site for troponin I, recruiting troponin I away from actin when calcium levels in muscle are elevated. This also causes the tropomyosin molecule to move its position, thereby exposing the myosin binding site on actin and stimulating myosin ATPase activity.

Human skeletal muscle is composed of different types of contractile fibers, classified according to their myosin type and called slow or fast fibers. Table 1 summarizes the different proteins that make up these muscle types.

TABLE 1

MHC IIb is not expressed in human muscle, but is present in rodents and other mammals. TPM3 representing tropomyosin 3

In healthy humans, most skeletal muscles are composed of both fast and slow fibers, although the proportion of each varies with muscle type. Slow skeletal muscle fibers, commonly referred to as type I fibers, have more structural similarity to the heart muscle and tend to be more used for fine and postural control. They generally have a higher oxidizing power and are more resistant to fatigue on continuous use. Fast skeletal muscle fibers, commonly referred to as type II fibers, are classified as fast oxidative (IIa) and fast glycolytic (IIx/d) fibers. Although these muscle fibers have different myosin types, they share many components, including troponin and tropomyosin regulatory proteins. Fast skeletal muscle fibers tend to exert greater strength but fatigue faster than slow skeletal muscle fibers and are functionally useful for strenuous, large-scale exercises such as getting up from a chair or correcting a fall.

Muscle contraction and force production is controlled by neural stimulation, via innervating motor neurons. Each motor neuron may innervate a number (about 100 to 380) of muscle fibers, which as contractile totality are called motor units. When the muscles need to contract, the motor neurons will send stimuli as nerve impulses (action potentials) from the brainstem or spinal cord to each fiber in the motor unit. The contact area between the nerve and muscle fiber is a specialized synapse called the neuromuscular junction (NMJ). Here, membrane depolarization action potentials in nerves are converted to impulses in muscle fibers by the release of the neurotransmitter acetylcholine (ACh). ACh triggers a second action potential in the muscle, which rapidly propagates along the fibers and into the invagination in the membrane called the t-tubule. The T-tubule is physically linked to Ca within the Sarcoplasmic Reticulum (SR) of the muscle via the dihydropyridine receptor (DHPR)²⁺And (4) storing. Stimulation of DHPR activates the second Ca in SR²⁺Channel Lancini base receptor to trigger Ca²⁺From the reservoir in the SR to the muscle cytoplasm, where it can interact with the troponin complex to initiate muscle contraction. If muscle stimulation ceases, calcium passes through ATP-dependent Ca ²⁺Pump sarcoplasmic/endoplasmic reticulum Ca²⁺The ATPase (SERCA) is rapidly retrieved into the SR.

In disease, muscle function can become impaired by a number of mechanisms. Examples include frailty associated with aging (known as sarcopenia) and cachexia syndrome associated with diseases such as cancer, heart failure, Chronic Obstructive Pulmonary Disease (COPD) and chronic kidney disease/dialysis. Severe muscle dysfunction may result from neuromuscular diseases (e.g., Amyotrophic Lateral Sclerosis (ALS), Spinal Muscular Atrophy (SMA), and myasthenia gravis) or muscle myopathies (e.g., muscular dystrophy). In addition, muscle function may become impaired due to deficiencies associated with rehabilitation, such as deficiencies associated with surgical recovery (e.g., post-operative muscle weakness), long-term bed rest, or stroke rehabilitation. Other examples of diseases or conditions in which muscle function becomes impaired include peripheral vascular disease (e.g. claudication), chronic fatigue syndrome, metabolic syndrome, obesity, dysfunction of the pelvic floor muscles and urinary/anal sphincters (e.g. urinary incontinence such as Stress Urinary Incontinence (SUI) and Mixed Urinary Incontinence (MUI) and fecal incontinence), muscle dysfunction following Spinal Cord Injury (SCI) and ventilator-induced muscle weakness.

Currently, there is limited or no cure for most neuromuscular diseases. WO2008/016669 discloses a compound represented by the following general formula (a) for use in treating a patient suffering from a disease responsive to modulation of skeletal muscle troponin C or the like.

For the symbols, reference is made to this publication.

WO2011/0133888 discloses a compound represented by the following general formula (B) for use in treating a patient suffering from a disease responsive to modulation of skeletal muscle troponin C or the like.

For the symbols, reference is made to this publication.

WO2011/0133882, WO2011/133920 and US2013-0060025 disclose another compound for use in treating patients suffering from a disease responsive to modulation of skeletal muscle troponin C or the like.

WO2013/151938, WO2013/155262 and WO2015/168064 disclose methods of treatment, such as increasing diaphragm muscle function, increasing resistance to skeletal muscle fatigue, reducing decline in lung capacity, by using skeletal muscle troponin activators.

US3947451 and US3301857 and Journal of Heterocyclic Chemistry,7(3) p615-22, (1970) and Synthetic Communications,32(12) p1787-90, (2002) disclose compounds having the structure 1, 4-dihydroisoquinoline-3 (2H), but do not disclose any pharmacological activity of the compounds described therein.

Tetrahedron Letters,50(47) p6476-6479, (2009) discloses 1, 1-diallyl-3-oxo-2, 4-dihydroisoquinoline-4-carboxylate, but does not disclose any pharmacological activity of the compounds described therein.

Therefore, there is a need to develop new compounds that modulate skeletal muscle contractility. There remains a need for agents that exploit new mechanisms of action and may have better results in both short-term and long-term cases with improved therapeutic index in terms of symptom relief, safety and patient mortality.

Disclosure of Invention

It is therefore an object of the present invention to provide novel tetrahydroisoquinoline compounds and salts thereof which are useful as active ingredients in pharmaceutical compositions, in particular for the treatment of diseases or disorders responsive to the modulation of contractility of skeletal muscle sarcomere.

It is another object of the present invention to provide novel pharmaceutical compositions containing such compounds.

It is another object of the present invention to provide a novel process for preparing such compositions.

It is another object of the present invention to provide novel methods for preventing or treating diseases or conditions that are responsive to modulation of contractility of skeletal muscle sarcomere.

These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors 'discovered compounds of formulae (I) and (I') described below.

The present invention provides novel compounds which are intended as active ingredients for use in pharmaceutical compositions, in particular for the prevention or treatment of diseases or disorders responsive to the modulation of the contractility of skeletal muscle sarcomere. The modulation of the skeletal muscle sarcomere may be, for example, modulation by modulating the troponin complex of the fast skeletal muscle sarcomere by one or more of fast skeletal muscle myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof.

Provided herein are compounds of formula (I), (I') and embodiments thereof, as well as pharmaceutical compositions containing these compounds, methods of making these compounds, and methods of using these compounds in therapy. Any pharmaceutical composition, method of preparation, and method of use provided herein is intended to encompass any compound of formula (I), (I') provided herein and any embodiment thereof, including but not limited to embodiments 1-1 to 8-4 and embodiments (1) - (57).

The present invention relates to a compound of formula (I) or a salt thereof and a pharmaceutical composition comprising a compound of formula (I) or a salt thereof and an excipient.

Wherein the content of the first and second substances,

X¹：C-R¹¹or N;

X²：C-R¹²or N;

R¹¹: i) h, ii) halogen, iii) -CN, or iv)-O-C_1-6An alkyl group;

R¹²: h or halogen;

R¹：i)H，ii)C_1-6alkyl, which may be substituted by one or more substituents selected from halogen and pyrazolyl, iii) C_2-6Alkenyl, OR iv) -OR⁰；

R²：i)C_1-6Alkyl, which may be substituted with one or more substituents selected from: -OR⁰Halogen, -COOR⁰，-CONR²¹R²²Can be selected from G¹Phenyl substituted with one or more substituents of the group, and a substituent selected from pyridyl, pyrazolyl, imidazolyl, thiazolyl, thiadiazolyl, thienyl,Azolyl radical, isoHeteroaryl of azolyl and triazolyl, wherein said heteroaryl may be selected from G²Substituted by one or more substituents of the group, ii) C_2-6Alkenyl, iii) C_2-6Alkynyl, iv) -OR⁰，v)-NR²³R²⁴，vi)-COOR⁰Or vii) phenyl;

R²¹: h or C_1-6An alkyl group;

R²²：i)C_1-6alkyl, which may be substituted with one or more phenyl groups, or ii) phenyl;

R²³: i) h, or ii) C_1-6Alkyl, which may be substituted with one or more-OH;

R²⁴：i)C_1-6alkyl which may be substituted by one or more phenyl groups which may be substituted by one or more halogen, ii) C_3-8Cycloalkyl, which may be substituted by one or more C _1-6Alkyl substituted, iii) phenyl, which may be substituted with one or more halogens, or iv) tetrahydropyranyl; or

R¹、R²And by R¹And R²The carbon atom bound may beTo interact to form a 4-piperidine ring or a 4-tetrahydropyran ring, and said substituted aryl group¹And R²The carbon atom bound is a spiro atom and the 4-piperidine ring may be selected from-SO₂-(C_1-6Alkyl) and-COOR⁰Substituted with one or more substituents of (a);

R³、R⁴: identical or different from each other, i) C_1-3Alkyl, which may be substituted by one or more substituents selected from halogen and-OH, or ii) C_2-6Alkenyl which may be substituted with one or more substituents selected from-OH and heteroaryl selected from pyrazolyl and thienyl, wherein said heteroaryl may be substituted with one or more C_1-6Alkyl is substituted, or

R³、R⁴And by R³And R⁴The bound carbon atoms may interact to form a 3-oxetane ring and the compound is R³And R⁴The carbon atom bound is a spiro atom;

R⁵：i)H，ii)C_1-6alkyl, which may be substituted by one or more-O- (C)_1-6Alkyl) substituted, iii) -O-C_1-6Alkyl, iv) halogen, v) -COO- (C)_1-6Alkyl) or vi) C_3-8A cycloalkyl group;

R⁶：i)H，ii)C_1-6alkyl, which may be selected from-O- (C which may be substituted by one or more halogens)_1-6Alkyl) and halogen, iii) -OH, iv) -O- (C which may be substituted by one or more halogens _1-6Alkyl), v) halogen, vi) -CN, vii) -S- (C_1-6Alkyl), viii) C_3-8Cycloalkyl, ix) -NR⁰R⁰Or x) C_2-6An alkenyl group;

G¹group (b): i) halogen, ii) -COOR⁰，iii)-CONR⁰R⁰，iv)-OH，v)C_1-6Alkyl which may be substituted by one or more substituents selected from the group consisting of-OH and halogen, or vi) -O- (C which may be substituted by one or more substituents selected from the group consisting of-OH and halogen_1-6Alkyl groups);

G²group (b): i) halogen, ii) C_1-6Alkyl, which may be selectedSubstituted by one or more substituents selected from-OH and halogen, or iii) -CONR⁰R⁰；

R⁰: identical or different from each other, H or C_1-6An alkyl group.

In one embodiment, the invention relates to a compound of formula (I) or a salt thereof and a pharmaceutical composition comprising a compound of formula (I) or a salt thereof and an excipient.

Wherein the content of the first and second substances,

X¹：C-R¹¹or N;

X²：C-R¹²or N;

R¹¹: i) h, ii) halogen, iii) -CN, or iv) -O-C_1-6An alkyl group;

R¹²: h or halogen;

R¹：i)H，ii)C_1-6alkyl, which may be substituted by one or more substituents selected from halogen and pyrazolyl, iii) C_2-6Alkenyl, OR iv) -OR⁰；

R²：i)C_1-6Alkyl, which may be substituted with one or more substituents selected from: -OR⁰Halogen, -COOR⁰，-CONR²¹R²²Can be selected from G¹Phenyl substituted with one or more substituents of the group, and a substituent selected from pyridyl, pyrazolyl, imidazolyl, thiazolyl, thiadiazolyl, thienyl, Azolyl radical, isoHeteroaryl of azolyl and triazolyl, wherein said heteroaryl may be selected from G²Substituted by one or more substituents of the group, ii) C_2-6Alkenyl, iii) C_2-6Alkynyl, iv) -OR⁰，v)-NR²³R²⁴，vi)-COOR⁰Or vii) phenyl;

R²¹: h or C_1-6An alkyl group;

R²²：i)C_1-6alkyl, which may be substituted with one or more phenyl groups, or ii) phenyl;

R²³: i) h, or ii) C_1-6Alkyl, which may be substituted with one or more-OH;

R²⁴：i)C_1-6alkyl which may be substituted by one or more phenyl groups which may be substituted by one or more halogen, ii) C_3-8Cycloalkyl, which may be substituted by one or more C_1-6Alkyl substituted, iii) phenyl, which may be substituted with one or more halogens, or iv) tetrahydropyranyl; or

R¹、R²And by R¹And R²The bound carbon atoms may interact to form a 4-piperidine ring or a 4-tetrahydropyran ring, and the R group¹And R²The carbon atom bound is a spiro atom and the 4-piperidine ring may be selected from-SO₂-(C_1-6Alkyl) and-COOR⁰Substituted with one or more substituents of (a);

R³、R⁴And by R³And R⁴The bound carbon atoms may interact to form a 3-oxetane ring and the compound is R³And R⁴The carbon atom bound is a spiro atom;

R⁵：i)H，ii)C_1-6alkyl, which may be substituted by one or more-O- (C)_1-6Alkyl) substituted, iii) -O-C_1-6Alkyl, iv) halogen, v) -COO- (C)_1-6Alkyl) or vi) C_3-8A cycloalkyl group;

R⁶：i)H，ii)C_1-6alkyl, which may be selected from-O- (C which may be substituted by one or more halogens)_1-6Alkyl) and halogen, iii) -OH, iv) -O- (C which may be substituted by one or more halogens_1-6Alkyl), v) halogen, vi) -CN, vii) -S- (C_1-6Alkyl), viii) C_3-8Cycloalkyl, ix) -NR⁰R⁰Or x) C_2-6An alkenyl group;

G²group (b): i) halogen, ii) C_1-6Alkyl, which may be substituted by one or more substituents selected from-OH and halogen, or iii) -CONR⁰R⁰；

R⁰: identical or different from each other, H or C_1-6An alkyl group, a carboxyl group,

with the proviso that the compound is not 1, 1-diallyl-3-oxo-2, 4-dihydroisoquinoline-4-carboxylic acid methyl ester or a salt thereof.

Unless otherwise explicitly described, when a symbol in one formula is also used in other formulae in this specification, the same symbol means the same meaning. When the same symbol is used more than once in a given formula, it is understood that each occurrence of the symbol in the formula represents an independently selected chemical moiety, and the symbol does not necessarily represent a uniform chemical moiety on all occasions in the formula.

Furthermore, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or a salt thereof and a pharmaceutically acceptable excipient. Furthermore, the present invention relates to a pharmaceutical composition for preventing or treating a disease or disorder responsive to modulation of contractility of skeletal muscle sarcomere, for example modulation of troponin complexes of fast skeletal muscle sarcomere by one or more of fast skeletal muscle myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof, comprising a compound of formula (I) or a salt thereof. Furthermore, the present invention relates to an agent for preventing or treating a disease or disorder responsive to modulation of contractility of skeletal muscle sarcomere, for example modulation of troponin complexes of fast skeletal muscle sarcomere by one or more of fast skeletal muscle myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof, comprising a compound of formula (I) or a salt thereof.

Furthermore, the present invention relates to the use of a compound of formula (I) or a salt thereof for the manufacture of a pharmaceutical composition for the prevention or treatment of a disease or disorder responsive to the modulation of contractility of skeletal muscle sarcomere, for example modulation of troponin complexes of fast skeletal muscle sarcomere by one or more of fast skeletal muscle myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof; also relates to the use of a compound of formula (I) or a salt thereof in the prevention or treatment of a disease or disorder responsive to modulation of contractility of skeletal muscle sarcomere, for example modulation of troponin complexes of fast skeletal muscle sarcomere by one or more of fast skeletal muscle myosin, actin, tropomyosin, troponin C, troponin I and troponin T, and fragments and isoforms thereof; also relates to a compound of formula (I) or a salt thereof for use in the prevention or treatment of a disease or disorder responsive to modulation of contractility of skeletal muscle sarcomere, for example modulation of troponin complexes of fast skeletal muscle sarcomere by one or more of fast skeletal muscle myosin, actin, tropomyosin, troponin C, troponin I and troponin T, and fragments and isoforms thereof; and to a method for preventing or treating a disease or condition which is responsive to modulation of contractility of skeletal muscle sarcomere, for example modulation of troponin complexes of fast skeletal muscle sarcomere by one or more of fast skeletal muscle myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof, comprising administering to a subject an effective amount of a compound of formula (I) or a salt thereof. Furthermore, the "subject" is a human or non-human animal in need of such prevention or treatment, and in one embodiment, a human in need of such prevention or treatment.

In one instance, a compound of formula (I) or a salt thereof modulates the contractility of skeletal muscle sarcomere. In particular, the compounds modulate the troponin complex of the fast skeletal muscle sarcomere by one or more of fast skeletal muscle myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof. When used in this context, "modulate" means to increase or decrease activity. In certain instances, a compound described and/or disclosed herein enhances (i.e., increases activity of) one or more of fast skeletal muscle myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof. In other instances, the compounds described and/or disclosed herein inhibit (i.e., decrease activity of) one or more of fast skeletal muscle myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof. As used in this context, "activation of fast skeletal muscle fibers such as myofibrils" means amplification of the stimulus/Ca of fast skeletal muscle fibers (e.g., myofibrils) ²⁺In response to (2).

In another instance, the compounds and pharmaceutical compositions described and/or disclosed herein are capable of modulating contractility of fast skeletal muscle sarcomere in vivo, and may have applications in both human and animal diseases. Modulation is desirable in a variety of conditions or diseases, including but not limited to: 1) neuromuscular disorders such as Amyotrophic Lateral Sclerosis (ALS), Spinal Muscular Atrophy (SMA), peripheral neuropathy, and myasthenia gravis; 2) voluntary muscle disorders including muscular dystrophy, myopathies, and conditions of muscle wasting such as sarcopenia and cachexia syndromes (e.g., cachexia syndrome caused by diseases such as cancer, heart failure, Chronic Obstructive Pulmonary Disease (COPD), and chronic kidney disease/dialysis), defects associated with rehabilitation such as defects associated with surgical recovery (e.g., post-operative muscle weakness), long-term bed rest or stroke rehabilitation, and ventilator-induced muscle weakness; 3) central Nervous System (CNS) disorders that are characterized by muscle weakness, atrophy and fatigue, such as multiple sclerosis, parkinson's disease, stroke and spinal cord injury; 4) muscular symptoms resulting from systemic disorders including Peripheral Vascular Disease (PVD) or Peripheral Arterial Disease (PAD) (e.g., claudication), metabolic syndrome, chronic fatigue syndrome, obesity, and weakness due to aging; and 5) dysfunction of the pelvic floor muscles and urethral/anal sphincters, such as stress incontinence, mixed urinary incontinence, and fecal incontinence.

In another aspect, the present invention relates to a pharmaceutical composition for preventing or treating a disease or disorder selected from Stress Urinary Incontinence (SUI), Mixed Urinary Incontinence (MUI), and fecal incontinence, comprising a compound of formula (I) or a salt thereof. In another aspect, the present invention relates to a pharmaceutical composition for preventing or treating a disease or condition selected from frailty and sarcopenia, the pharmaceutical composition comprising a compound of formula (I) or a salt thereof. In another aspect, the present invention relates to a pharmaceutical composition for preventing or treating Chronic Obstructive Pulmonary Disease (COPD), comprising a compound of formula (I) or a salt thereof. In another aspect, the present invention relates to a pharmaceutical composition for preventing or treating cachexia syndrome and/or muscle wasting due to heart failure, cancer or chronic kidney disease/dialysis, comprising a compound of formula (I) or a salt thereof. In another aspect, the present invention relates to a pharmaceutical composition for preventing or treating a disease or disorder selected from Amyotrophic Lateral Sclerosis (ALS), Spinal Muscular Atrophy (SMA), myasthenia gravis, and muscle myopathy, the pharmaceutical composition comprising a compound of formula (I) or a salt thereof. In another aspect, the present invention relates to a pharmaceutical composition for preventing or treating a disease or disorder selected from the group consisting of muscle dysfunction after Spinal Cord Injury (SCI) and muscle dysfunction after stroke, comprising a compound of formula (I) or a salt thereof. In another aspect, the present invention relates to a pharmaceutical composition for preventing or treating a disease or disorder selected from the group consisting of peripheral vascular disease, peripheral arterial disease, defects associated with rehabilitation, metabolic syndrome, obesity, ventilator-induced muscle weakness, and chronic fatigue syndrome, the pharmaceutical composition comprising a compound of formula (I) or a salt thereof.

In another aspect, the present invention relates to the use of a compound of formula (I) or a salt thereof in the manufacture of a pharmaceutical composition for the prevention or treatment of a disease or disorder selected from Stress Urinary Incontinence (SUI), Mixed Urinary Incontinence (MUI) and fecal incontinence. In another aspect, the invention relates to the use of a compound of formula (I) or a salt thereof in the manufacture of a pharmaceutical composition for the prevention or treatment of a disease or condition selected from frailty and sarcopenia. In another aspect, the present invention relates to the use of a compound of formula (I) or a salt thereof in the manufacture of a pharmaceutical composition for the prevention or treatment of Chronic Obstructive Pulmonary Disease (COPD). In another aspect, the present invention relates to the use of a compound of formula (I) or a salt thereof in the manufacture of a pharmaceutical composition for the prevention or treatment of cachexia syndrome and/or muscle wasting due to heart failure, cancer or chronic kidney disease/dialysis. In another aspect, the invention relates to the use of a compound of formula (I) or a salt thereof in the manufacture of a pharmaceutical composition for the prevention or treatment of a disease or disorder selected from Amyotrophic Lateral Sclerosis (ALS), Spinal Muscular Atrophy (SMA), and myasthenia gravis, a muscle myopathy. In another aspect, the invention relates to the use of a compound of formula (I) or a salt thereof in the manufacture of a pharmaceutical composition for the prevention or treatment of a disease or condition selected from the group consisting of muscle dysfunction after Spinal Cord Injury (SCI) and muscle dysfunction after stroke. In another aspect, the invention relates to the use of a compound of formula (I) or a salt thereof for the manufacture of a pharmaceutical composition for the prevention or treatment of a disease or condition selected from the group consisting of peripheral vascular disease, peripheral arterial disease, a defect associated with rehabilitation, metabolic syndrome, obesity, ventilator-induced muscle weakness, and chronic fatigue syndrome.

In another aspect, the present invention relates to the use of a compound of formula (I) or a salt thereof in the prevention or treatment of a disease or disorder selected from Stress Urinary Incontinence (SUI), Mixed Urinary Incontinence (MUI) and fecal incontinence. In another aspect, the invention relates to the use of a compound of formula (I) or a salt thereof in the prevention or treatment of a disease or condition selected from frailty and sarcopenia. In another aspect, the invention relates to the use of a compound of formula (I) or a salt thereof in the prevention or treatment of Chronic Obstructive Pulmonary Disease (COPD). In another aspect, the present invention relates to the use of a compound of formula (I) or a salt thereof for the prevention or treatment of cachexia syndrome and/or muscle wasting due to heart failure, cancer or chronic kidney disease/dialysis. In another aspect, the invention relates to the use of a compound of formula (I) or a salt thereof, for the prevention or treatment of a disease or condition selected from Amyotrophic Lateral Sclerosis (ALS), Spinal Muscular Atrophy (SMA), myasthenia gravis, and muscle myopathy. In another aspect, the invention relates to the use of a compound of formula (I) or a salt thereof for the prevention or treatment of a disease or condition selected from the group consisting of muscle dysfunction after Spinal Cord Injury (SCI) and muscle dysfunction after stroke. In another aspect, the present invention relates to the use of a compound of formula (I) or a salt thereof for the prevention or treatment of a disease or condition selected from the group consisting of peripheral vascular disease, peripheral arterial disease, a defect associated with rehabilitation, metabolic syndrome, obesity, ventilator-induced muscle weakness, and chronic fatigue syndrome.

In another aspect, the present invention relates to a method for preventing or treating a disease or disorder selected from Stress Urinary Incontinence (SUI), Mixed Urinary Incontinence (MUI), and fecal incontinence, the method comprising administering to a subject an effective amount of a compound of formula (I) or a salt thereof. In another aspect, the present invention relates to a method for preventing or treating a disease or condition selected from frailty and sarcopenia, the method comprising administering to a subject an effective amount of a compound of formula (I) or a salt thereof. In another aspect, the present invention relates to a method for preventing or treating Chronic Obstructive Pulmonary Disease (COPD), which comprises administering to a subject an effective amount of a compound of formula (I) or a salt thereof. In another aspect, the present invention relates to a method for preventing or treating cachexia syndrome and/or muscle wasting due to heart failure, cancer or chronic kidney disease/dialysis, the method comprising administering to a subject an effective amount of a compound of formula (I) or a salt thereof. In another aspect, the present invention relates to a method for preventing or treating a disease or disorder selected from Amyotrophic Lateral Sclerosis (ALS), Spinal Muscular Atrophy (SMA), myasthenia gravis, and muscle myopathy, the method comprising administering to a subject an effective amount of a compound of formula (I) or a salt thereof. In another aspect, the present invention relates to a method for preventing or treating a disease or condition selected from the group consisting of muscle dysfunction after Spinal Cord Injury (SCI) and muscle dysfunction after stroke, comprising administering to a subject an effective amount of a compound of formula (I) or a salt thereof. In another aspect, the present invention relates to a method for preventing or treating a disease or condition selected from the group consisting of peripheral vascular disease, peripheral arterial disease, defects associated with rehabilitation, metabolic syndrome, obesity, ventilator-induced muscle weakness, and chronic fatigue syndrome, the method comprising administering to a subject an effective amount of a compound of formula (I) or a salt thereof. In any of the variations described herein, the subject is a human or non-human animal in need of such prevention or treatment, and in one embodiment, a human in need of such prevention or treatment.

In another aspect, the present invention relates to a compound of formula (I) or a salt thereof for use in the prevention or treatment of a disease or disorder selected from Stress Urinary Incontinence (SUI), Mixed Urinary Incontinence (MUI) and fecal incontinence. In another aspect, the invention relates to a compound of formula (I) or a salt thereof for use in the prevention or treatment of a disease or condition selected from frailty and sarcopenia. In another aspect, the present invention relates to a compound of formula (I) or a salt thereof for use in the prevention or treatment of Chronic Obstructive Pulmonary Disease (COPD). In another aspect, the present invention relates to a compound of formula (I) or a salt thereof for use in the prevention or treatment of cachexia syndrome and/or muscle wasting due to heart failure, cancer or chronic kidney disease/dialysis. In another aspect, the invention relates to a compound of formula (I) or a salt thereof for use in the prevention or treatment of a disease or disorder selected from Amyotrophic Lateral Sclerosis (ALS), Spinal Muscular Atrophy (SMA), myasthenia gravis, and muscle myopathy. In another aspect, the present invention relates to a compound of formula (I) or a salt thereof for use in the prevention or treatment of a disease or condition selected from the group consisting of muscle dysfunction after Spinal Cord Injury (SCI) and muscle dysfunction after stroke. In another aspect, the present invention relates to a compound of formula (I) or a salt thereof for use in the prevention or treatment of a disease or condition selected from the group consisting of peripheral vascular disease, peripheral arterial disease, a defect associated with rehabilitation, metabolic syndrome, obesity, ventilator-induced muscle weakness, and chronic fatigue syndrome.

Drawings

A more complete appreciation of the invention and many of the attendant advantages thereof will be readily obtained as the same becomes better understood by reference to the following detailed description when considered in connection with the accompanying drawings, wherein:

fig. 1 is a graph showing the results obtained by the measurement of running performance of a rat treadmill. Significance was defined as p <0.05 compared to media treatment. In fig. 1, example 20 means example compound 20 and example 22b means example compound 22 b.

Fig. 2 is a graph showing the results obtained by measurement of concentration caused by Electric Field Stimulation (EFS) of the isolated External Anal Sphincter (EAS). In fig. 2, example 20 means example compound 20.

FIG. 3 is a graph showing results obtained by EFS-induced focused assay of detached EAS. In fig. 3, example 22b means example compound 22 b.

Fig. 4 is a graph showing the results obtained by the measurement of anal canal pressure caused by electrical stimulation of the pudendal nerve. In fig. 4, example 20 means example compound 20, and example 22b means example compound 22 b.

Fig. 5 is a graph showing the results obtained by the measurement of the urine Leak Point Pressure (LPP) under the abdominal pressure. In fig. 5, example 20 means example compound 20.

Fig. 6 is a graph showing the results obtained by the measurement of urine LPP under abdominal pressure. In fig. 6, example 22b means example compound 22 b.

Fig. 7 is a graph of a study timeline showing the determination of Basso, Beattie, and bresnahan (bbb) scores after Spinal Cord Injury (SCI). In fig. 7, example 52 means example compound 52.

Fig. 8 is a graph showing the results obtained by measurement of BBB score after SCI. In fig. 8, example 52 means example compound 52.

Fig. 9 is a graph showing results obtained by determination of the force-calcium relationship in Chronic Obstructive Pulmonary Disease (COPD) diaphragm muscle biopsy samples. In fig. 9, example 20 means example compound 20.

Fig. 10 is a graph showing results obtained by determination of the force-calcium relationship in Chronic Obstructive Pulmonary Disease (COPD) latissimus dorsi biopsy samples. In fig. 10, example 20 means example compound 20.

Detailed Description

Hereinafter, the present invention will be described in detail.

The term "alkyl" refers to straight or branched chain alkyl groups. Thus, "C_1-6Alkyl "is a straight or branched chain alkyl group having 1 to 6 carbon atoms, and specific examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl; in one embodiment, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; in one embodiment, is a group selected from methyl, ethyl, and isopropyl; and in one embodiment is a group selected from methyl and ethyl. It is to be understood that the straight or branched chain alkyl group refers to a straight or branched chain saturated hydrocarbon.

The term "alkenyl" refers to an unsaturated, straight or branched alkyl group having the indicated number of carbon atoms (e.g., 2 to 8 or 2 to 6 carbon atoms) and at least one carbon-carbon double bond created by the removal of one hydrogen molecule from the adjacent carbon atom of the corresponding alkyl group. The group may adopt cis or trans configuration (Z or E configuration) around the double bond. Alkenyl groups include, but are not limited to, ethenyl, propenyl (e.g., prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl)), and butenyl (e.g., but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-2-yl, but-1, 3-dien-1-yl, but-1, 3-dien-2-yl). The alkenyl group may be prepared by any method known in the art.

The term "alkynyl" refers to an unsaturated, straight or branched alkyl group having the indicated number of carbon atoms (e.g., 2 to 8 or 2 to 6 carbon atoms) and at least one carbon-carbon triple bond created by the removal of two hydrogen molecules from adjacent carbon atoms of the corresponding alkyl group. Alkynyl groups include, but are not limited to, ethynyl, propynyl (e.g., prop-1-yn-1-yl or prop-2-yn-1-yl), and butynyl (e.g., but-1-yn-1-yl, but-1-yn-3-yl, or but-3-yn-1-yl). Alkynyl groups can be prepared by any method known in the art.

The term "cycloalkyl" refers to a non-aromatic, fully saturated carbocyclic ring having the indicated number of carbon atoms, e.g., 3 to 10 or 3 to 8 or 3 to 6 ring carbon atoms. Cycloalkyl groups may be monocyclic or polycyclic (e.g., bicyclic or tricyclic). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, as well as bridged or caged ring groups (e.g. norbornane or bicyclo [2.2.2] octane).

The term "heteroaryl" refers to a monocyclic aromatic heterocycle or a bicyclic aromatic heterocycle. The "monocyclic aromatic heterocycle" includes monocyclic aromatic heterocyclic groups having 5 to 7 ring members, which have 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as ring-constituting atoms, and specific examples thereof include pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furyl, thienyl, and the like,Azolyl radical, isoAzolyl group,Diazolyl, thiazolyl, thiaOxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl; in one embodiment, pyrazolyl, imidazolyl, triazolyl, thienyl, triazolyl, and the like are included,Azolyl radical, isoOxazolyl, thiazolyl, thiadiazolyl or pyridyl.

The term "bicyclic aromatic heterocycle" means a bicyclic aromatic heterocyclic group in which a monocyclic aromatic heterocycle is fused with a benzene ring or a monocyclic aromatic heterocycle, and includes partially hydrogenated ring groups thereof, and specific examples thereof include indolyl, isoindolyl, indazolyl, benzotriazolyl, benzofuranyl, benzothienyl, and benzofuranyl Azolyl, benzothiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pyridopyridyl (propylpyridyl), thienopyridyl, indolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, dihydropyridinopyridyl, or dihydrothienopyridyl; and in one embodiment, is benzothienyl.

The term "saturated heterocyclic ring" includes a 3-to 8-membered saturated cyclic group having 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as atoms constituting the ring, and C may be used_1-6An alkylene bridge in which a sulfur atom as an atom constituting a ring may be oxidized. Specific examples thereof include azepanyl, diazepanyl, oxazepanyl, thiazepanyl, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrazolidinyl, piperazinyl, azocinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, piperazinyl, azacycloheptyl, thiazepanyl, and the like,Oxazolinyl, morpholinyl, thiomorpholinyl, tetrahydrothiopyranyl, oxathiocyclopropane, oxacyclopropane, oxetanyl, dioxacyclopropane, tetrahydrofuranyl, tetrahydropyranyl or 1, 4-dioxanyl.

The term "halogen" means fluorine, chlorine, bromine or iodine; in a particular embodiment, fluorine, chlorine or bromine; in another particular embodiment, is fluorine; in another particular embodiment, is chlorine; and in another particular embodiment, is bromine.

The term "R³、R⁴And by R³And R⁴The bound carbon atoms interact to form a 3-oxetane ring and the compound is R³And R⁴The carbon atom bound is a spiro atom ", meaning, as is clear from the description, R³And R⁴Together with the carbon to which they are attached form a 3-oxetane ring as follows:

the term "R¹、R²And by R¹And R²The bound carbon atoms interact to form a 4-piperidine ring or a 4-tetrahydropyran ring, and the substituted aryl is¹And R²The carbon atom bound is a spiro atom ", meaning, as is clear from the description, R¹And R²Together with the carbon to which they are attached form a 4-piperidine ring or a 4-tetrahydropyran ring as described below:

in the present specification, the expression "which may be substituted" means "which is not substituted" or "which is substituted by about 1 to about 5 substituents". Further, if it has a plurality of substituents, the substituents may be the same as or different from each other.

In the powder X-ray diffraction pattern described in the present specification, the pitch of the crystal lattice and the overall pattern are important in identifying the crystal according to the nature of the powder X-ray diffraction data, and the diffraction angle and diffraction intensity should not be strictly interpreted because they may include some errors according to the crystal growth direction, the particle diameter, and the measurement conditions. As an embodiment, the diffraction angle (2 θ (°)) of the powder X-ray diffraction pattern in the present specification may include a measurement error of ± 0.2 ° in consideration of a generally accepted error margin in the measurement method. Further, for example, in the case of performing powder X-ray measurement in a state of forming a mixture with a pharmaceutical excipient, a peak in the vicinity of a peak derived from the pharmaceutical excipient and on a tilted baseline of the peak may visually migrate ± 0.3 °.

In both preclinical and clinical settings, it has been shown that activators of The Fast Skeletal Muscle Troponin complex amplify The response of Fast Skeletal Muscle to neural stimulation, leading to an increase in Muscle strength at sub-maximal Muscle activation (see, e.g., Russell et al, "Fast Skeletal Muscle Troponin Activator CK-2017357 Increases Skeletal Muscle strength in vitro and in situ" (The Fast Skeletal Troponin Activator, CK-2017357, incorporated Skeletal Muscle Force in vitro and in situ), 2009Experimental Biology Conference, New oreans, LA, April 2009). It has been shown that the activators of the fast skeletal muscle troponin complex increase the sensitivity of the cutaneous skeletal muscle fibers to calcium and to the frequency of stimulation in living muscles, each of which results in an increase in the onset of muscle strength at sub-maximal muscle activation. These activators have also been shown to reduce Muscle Fatigue and/or increase The overall time to Fatigue under normal and low oxygen-containing conditions (see, e.g., Russell et al, "Fast Skeletal Muscle Troponin Activator CK-2017357 improves Skeletal Muscle strength and Reduces Muscle Fatigue in vitro and in situ" (The Fast Skeletal Muscle Force Activator, CK-2017357, incorporated Skeletal Muscle Force and reduction Muscle Force in vitro and in situ), 5th Cachexia Conference, Barcell, spread, Decumber 2009; Hinken et al, "Fast Skeletal Muscle Troponin Activator-2017357 Reduces Muscle Fatigue in an in situ Model of CK dysfunction" (The Fast Skeletal Muscle Activator, CK-2017357, reduction Muscle Fatigue in a Model of Vascular Insufficiency), vacuum Muscle, tissue, Across et al, variety's 2010, simple Muscle, stress. In Healthy human volunteers, it has also been demonstrated to increase Muscle strength in response to neural input (see, e.g., Hansen et al, "New Fast Skeletal Muscle Activator CK-2017357 Increases Isometric contractility Evoked by Electrical Stimulation of the Tibialis Anterior in Healthy Male Subjects" (CK-2017357, a Novel Activator of Fast Skeletal Muscle, incorporated isomer Force observed by electric Stimulation of the inorganic biology Muscle in health Male Subjects), Society for neural conference 40th annular Meetween neural conference 2010, November 2010). Work in other preclinical models of muscle function suggests that the activator of the fast skeletal muscle troponin complex also causes an increase in muscle power and/or endurance. These pharmacological properties suggest that this mechanism of action may be useful in conditions such as impaired neuromuscular function.

There is provided a method for increasing fast skeletal muscle efficiency in a patient in need thereof, the method comprising administering to the subject an effective amount of a compound or composition of a troponin complex selectively binding fast skeletal muscle fibers or sarcomere as described and/or disclosed herein. In certain embodiments, the compounds disclosed and/or described herein activate fast skeletal muscle fibers or sarcomere. In certain embodiments, administration of a compound disclosed and/or described herein results in an increase in fast skeletal muscle power output. In certain embodiments, administration of a compound disclosed and/or described herein results in an increase in sensitivity to calcium ions of fast skeletal muscle fibers or sarcomere as compared to fast skeletal muscle fibers or sarcomere not treated with the compound. In certain embodiments, administration of a compound disclosed and/or described herein results in a decrease in calcium ion concentration, resulting in binding of fast skeletal muscle myosin to actin. In certain embodiments, administration of a compound disclosed and/or described herein causes the fast skeletal muscle fibers to produce force to a greater extent at sub-maximal levels of muscle activation.

Also provided is a method of sensitizing fast skeletal muscle fibers to production of a force in response to a lower concentration of calcium ions, the method comprising contacting the fast skeletal muscle fibers with a compound or composition described and/or disclosed herein that selectively binds to a troponin complex in a fast skeletal muscle sarcomere. In certain embodiments, contacting the fast skeletal muscle fibers with the compound causes the fast skeletal muscle fibers to activate at a lower calcium ion concentration than in untreated fast skeletal muscle fibers. In certain embodiments, contacting the fast skeletal muscle fibers with the compound results in greater force generation at lower calcium ion concentrations than untreated fast skeletal muscle fibers.

Also provided is a method of increasing the time to fast skeletal muscle fatigue in a patient in need thereof, the method comprising contacting fast skeletal muscle fibers with a compound or composition described and/or disclosed herein that selectively binds to the troponin complex of the fast skeletal muscle fibers. In certain embodiments, the compounds bind to form ligand-troponin-calcium ion complexes that activate fast skeletal muscle fibers. In certain embodiments, the formation of the complex and/or activation of fast skeletal muscle fibers results in increased strength and/or increased time to fatigue compared to untreated fast skeletal muscle fibers exposed to the same calcium ion concentration.

Some embodiments of the invention are described below.

Embodiment mode 1 to 1

A compound of formula (I) or a salt thereof, wherein

X¹Is C-R¹¹Or N;

X²is C-R¹²Or N;

R¹¹is i) H, ii) halogen, iii) -CN, or iv) -O-C_1-6An alkyl group; and is

R¹²Is H or halogen.

Embodiment modes 1 to 2

A compound of formula (I) or a salt thereof, wherein

X¹Is C-R¹¹Or N;

X²is C-R¹²Or N;

R¹¹is i) H, ii) halogen, iii) -CN, or iv) -O-C_1-6An alkyl group; and is

R¹²Is H.

Embodiments 1 to 3

A compound of formula (I) or a salt thereof, wherein

X¹Is C-R¹¹；

X²Is C-R¹²；

R¹¹Is i) H, ii) halogen, iii) -CN, or iv) -O-C _1-6An alkyl group; and is

R¹²Is H.

Embodiments 1 to 4

A compound of formula (I) or a salt thereof, wherein

X¹Is C-R¹¹；

X²Is N; and is

R¹¹Is i) H, ii) halogen, iii) -CN, or iv) -O-C_1-6An alkyl group.

Embodiments 1 to 5

A compound of formula (I) or a salt thereof, wherein

X¹Is N; and is

X²Is N.

Embodiment mode 2-1

A compound of formula (I) or a salt thereof, wherein

R¹Is i) H, ii) C_1-6Alkyl, which may be substituted by one or more substituents selected from halogen and pyrazolyl, iii) C_2-6Alkenyl, OR iv) -OR⁰；

R²Is i) C_1-6Alkyl, which may be substituted with one or more substituents selected from: -OR⁰Halogen, -COOR⁰，-CONR²¹R²²Can be selected from G¹Phenyl substituted with one or more substituents of the group, and a substituent selected from pyridyl, pyrazolyl, imidazolyl, thiazolyl, thiadiazolyl, thienyl,Azolyl radical, isoHeteroaryl of azolyl and triazolyl, wherein said heteroaryl may be selected from G²Substituted by one or more substituents of the group, ii) C_2-6Alkenyl, iii) C_2-6Alkynyl, iv) -OR⁰，v)-NR²³R²⁴，vi)-COOR⁰Or vii) phenyl;

R²¹is H or C_1-6An alkyl group;

R²²is i) C_1-6Alkyl, which may be substituted with one or more phenyl groups, or ii) phenyl;

R²³is i) H, or ii) C_1-6Alkyl, which may be substituted with one or more-OH; and is

R²⁴Is i) C_1-6Alkyl which may be substituted by one or more phenyl groups which may be substituted by one or more halogen, ii) C _3-8Cycloalkyl, which may be substituted by one or more C_1-6Alkyl substituted, iii) phenyl, which may be substituted with one or more halogens, or iv) tetrahydropyranyl; or

R¹、R²And by R¹And R²The bound carbon atoms may interact to form a 4-piperidine ring or a 4-tetrahydropyran ring, and the R group¹And R²The carbon atom bound is a spiro atom and the 4-piperidine ring may be selected from-SO₂-C_1-6Alkyl and-COOR⁰Substituted with one or more substituents of (a);

G¹the radicals being selected from i) halogen, ii) -COOR⁰，iii)-CONR⁰R⁰，iv)-OH，v)C_1-6Alkyl which may be substituted by one or more substituents selected from-OH and halogen, and vi) O-C which may be substituted by one or more substituents selected from-OH and halogen_1-6An alkyl group;

G²the radicals being selected from i) halogen, ii) C_1-6Alkyl which may be substituted by one or more substituents selected from-OH and halogen, and iii) -CONR⁰R⁰(ii) a And is

R⁰Are identical or different from each other and are H or C_1-6An alkyl group.

Embodiment mode 2 to 2

A compound of formula (I) or a salt thereof, wherein

R¹Is i) H, or ii) C_1-6An alkyl group;

R²is i) C_1-6Alkyl, which may be substituted with one or more substituents selected from: -OR⁰Halogen, -CONR²¹R²²May be selected from halogen and-COOR⁰And a heteroaryl group selected from pyrazolyl and triazolyl, ii) C _2-6Alkenyl, iii) C_2-6Alkynyl, iv) -NR²³R²⁴Or v) -COOR⁰；

R²¹Is C_1-6An alkyl group;

R²²is C_1-6An alkyl group;

R²³is C_1-6An alkyl group; and is

R²⁴Is i) C_3-8Cycloalkyl, or ii) phenyl; or

R¹、R²And by R¹And R²The bound carbon atoms may interact to form a 4-tetrahydropyran ring, and the R¹And R²The carbon atom bound is a spiro atom; and is

R⁰Are identical or different from each other and are H or C_1-6An alkyl group.

Embodiments 2 to 3

A compound of formula (I) or a salt thereof, wherein

R¹Is C_1-6An alkyl group;

R²is C_1-6Alkyl, which may be-OR⁰Substitution; and is

R⁰Are identical or different from each other and are H or C_1-6An alkyl group.

Embodiments 2 to 4

A compound of formula (I) or a salt thereof, wherein

R¹Is i) H, ii) C_1-6Alkyl, which may be substituted by one or more substituents selected from halogen and pyrazolyl, iii) C_2-6Alkenyl, OR iv) -OR⁰；

R²Is i) C_1-6Alkyl, which may be substituted with one or more substituents selected from: -OR⁰Halogen, -COOR⁰，-CONR²¹R²²Can be selected from G¹Phenyl substituted with one or more substituents of the group, and a substituent selected from pyridyl, pyrazolyl, imidazolyl, thiazolyl, thiadiazolyl, thienyl,Azolyl radical, isoHeteroaryl of azolyl and triazolyl, wherein said heteroaryl may be selected from G²Substituted by one or more substituents of the group, ii) C _2-6Alkenyl, iii) C_2-6Alkynyl, iv) -OR⁰，v)-NR²³R²⁴Or vi) phenyl;

R²¹is H or C_1-6An alkyl group;

R²²is i) C_1-6Alkyl, which may be substituted with one or more phenyl substituents, or ii) phenyl;

R²³is i) H, or ii) C_1-6Alkyl, which may be substituted with one or more-OH substituents;

R²⁴is i) C_1-6Alkyl which may be substituted by one or more phenyl substituents which may be substituted by one or more halogen substituents, ii) C_3-8Cycloalkyl, which may be substituted by one or more C_1-6Alkyl substituents, iii) phenyl, which may be substituted with one or more halogen substituents, or iv) tetrahydropyranyl;

G¹the radicals being i) halogen, ii) -COOR⁰，iii)-CONR⁰R⁰，iv)-OH，v)C_1-6Alkyl, which may be selected from-OH and halogenOr vi) -O- (C which may be substituted by one or more substituents selected from-OH and halogen_1-6Alkyl groups);

G²the radicals being i) halogen, ii) C_1-6Alkyl, which may be substituted by one or more substituents selected from-OH and halogen, or iii) -CONR⁰R⁰(ii) a And is

Each R⁰Independently is H or C_1-6An alkyl group.

Embodiment mode 3-1

A compound of formula (I) or a salt thereof, wherein

R³And R⁴Are identical to or different from each other, are i) C_1-3Alkyl, which may be substituted by one or more substituents selected from halogen and-OH, or ii) C _2-6Alkenyl which may be substituted with one or more substituents selected from-OH and heteroaryl selected from pyrazolyl and thienyl, wherein said heteroaryl may be substituted with one or more C_1-6Alkyl is substituted, or

R³、R⁴And by R³And R⁴The bound carbon atoms may interact to form a 3-oxetane ring and the compound is R³And R⁴The carbon atom bound is a spiro atom.

Embodiment mode 3-2

A compound of formula (I) or a salt thereof, wherein

R³And R⁴Are identical to or different from each other, are i) C_1-3Alkyl, which may be substituted by one or more substituents selected from halogen and-OH, or ii) C_2-6Alkenyl which may be substituted by one or more substituents selected from-OH and pyrazolyl which may be substituted by one or more C_1-6Alkyl is substituted, or

R³、R⁴And by R³And R⁴The bound carbon atoms may interact to form a 3-oxetane ring and the compound is R³And R⁴The carbon atom bound is a spiro atom.

Embodiment modes 3 to 3

A compound of formula (I) or a salt thereof, wherein

R³And R⁴Are identical or different from each other and are C_1-3An alkyl group.

Embodiments 3 to 4

A compound of formula (I) or a salt thereof, wherein

R³、R⁴And by R³And R⁴The bound carbon atoms may interact to form a 3-oxetane ring and the compound is R ³And R⁴The carbon atom bonded is a spiro atom, as represented by the following formula (II):

embodiments 3 to 5

A compound of formula (I) or a salt thereof, wherein

R³And R⁴Independently is i) C_1-3Alkyl, which may be substituted with one or more substituents selected from halogen and-OH; or

R³And R⁴Together with the carbon to which they are attached form a 3-oxetane ring.

Embodiment mode 4-1

A compound of formula (I) or a salt thereof, wherein

R⁵Is i) H, ii) C_1-6Alkyl, which may be substituted by one or more-O-C_1-6Alkyl substitution, iii) -O-C_1-6Alkyl, iv) halogen, v) -COO-C_1-6Alkyl, or vi) C_3-8A cycloalkyl group;

R⁶is i) H, ii) C_1-6Alkyl, which may be selected from-O- (C which may be substituted by one or more halogens)_1-6Alkyl) and halogen, iii) -OH, iv) -O- (C which may be substituted by one or more halogens_1-6Alkyl), v) halogen, vi) -CN, vii) -S-C_1-6Alkyl group, viii) C_3-8Cycloalkyl, ix) -NR⁰R⁰Or x) C_2-6An alkenyl group; and is

R⁰Are identical or different from each other and are H or C_1-6An alkyl group.

Embodiment mode 4-2

A compound of formula (I) or a salt thereof, wherein

R⁵Is i) H, ii) C_1-6Alkyl, iii) -O-C_1-6Alkyl, iv) halogen, or v) C_3-8A cycloalkyl group;

R⁶is i) H, ii) C_1-6Alkyl, which may be selected from-O- (C)_1-6Alkyl) and halogen, iii) -OH, iv) -O- (C which may be substituted by one or more halogens _1-6Alkyl), v) halogen, vi) -CN, vii) -S-C_1-6Alkyl, viii) -NR⁰R⁰Ix) C_2-6An alkenyl group; and is

R⁰Are identical or different from each other and are H or C_1-6An alkyl group.

Embodiment modes 4 to 3

A compound of formula (I) or a salt thereof, wherein

R⁵Is H; and is

R⁶Is i) C_1-6Alkyl, ii) -O- (C substituted by 1 to 3 halogens_1-6Alkyl), iii) halogen, or iv) -CN.

The present invention includes compounds that are combinations of two or more embodiments described in 1-1 to 4-3 above that are not inconsistent with each other. Specific examples include the following embodiments.

Embodiment 5-1

A compound of formula (I) or a salt thereof, wherein

X¹Is C-R¹¹Or N;

X²is C-R¹²Or N;

R¹¹is i) H, ii) halogen, iii) -CN, or iv) -O-C_1-6An alkyl group;

R¹²is H;

R¹is i) H, or ii) C_1-6An alkyl group;

R²is i) C_1-6Alkyl, which may be substituted with one or more substituents selected from: -OR⁰Halogen, -CONR²¹R²²May be selected from halogen and-COOR⁰And a heteroaryl group selected from pyrazolyl and triazolyl, ii) C_2-6Alkenyl, iii) C_2-6Alkynyl, iv) -NR²³R²⁴Or v) -COOR⁰；

R²¹Is C_1-6An alkyl group;

R²²is C_1-6An alkyl group;

R²³is C_1-6An alkyl group;

R²⁴is i) C_3-8Cycloalkyl, or ii) phenyl; or

R¹、R²And by R¹And R²The bound carbon atoms may interact to form a 4-tetrahydropyran ring, and the R ¹And R²The carbon atom bound is a spiro atom;

R³and R⁴Are identical to or different from each other, are i) C_1-3Alkyl, which may be substituted by one or more substituents selected from halogen and-OH, or ii) C_2-6Alkenyl which may be substituted by one or more substituents selected from-OH and pyrazolyl which may be substituted by one or more C_1-6Alkyl is substituted, or

R³、R⁴And by R³And R⁴The bound carbon atoms may interact to form a 3-oxetane ring and the compound is R³And R⁴The carbon atom bound is a spiro atom;

R⁵is i) H, ii) C_1-6Alkyl, iii) -O-C_1-6Alkyl, iv) halogen, or v) C_3-8A cycloalkyl group;

R⁶is i) H, ii) C_1-6Alkyl, which may be selected from-O-C_1-6Alkyl and halogen, iii) -OH, iv) -O-C_1-6Alkyl which may be substituted by one or more halogen, v) halogen, vi) -CN, vii) -S-C_1-6Alkyl, viii) -NR⁰R⁰Ix) C_2-6An alkenyl group;

R⁰are the same or different from each otherIs H or C_1-6An alkyl group.

Embodiment mode 5-2

A compound described in the above embodiment 5-1 or a salt thereof, wherein

R¹Is C_1-6An alkyl group;

R²is C_1-6Alkyl, which may be-OR⁰Substitution;

R³、R⁴and by R³And R⁴The bound carbon atoms interact to form a 3-oxetane ring and the compound is R ³And R⁴The carbon atom bonded is a spiro atom, as represented by the following formula (II):

R⁵is H; and is

R⁶Is i) C_1-6Alkyl, ii) -O-C_1-6Alkyl substituted with 1 to 3 halogens, iii) halogen, or iv) -CN.

Embodiment modes 5 to 3

A compound described in the above embodiment 5-2, wherein X¹And X²As described in embodiments 1 to 3.

Embodiment 6-1

A compound of formula (I) or a salt thereof, wherein R¹And R²As described in embodiment mode 2-1, and

X¹：C-R¹¹or N;

X²：C-R¹²or N;

R¹¹: i) h, ii) halogen, iii) -CN, or iv) -O-C_1-6An alkyl group;

R¹²: h or halogen;

R³、R⁴: identical or different from each other, i) C_1-3Alkyl, which may be substituted by one or more substituents selected from halogen and-OH, or ii) C_2-6Alkenyl which may be selected from-OH and from pyrazolyl and thiaSubstituted by one or more substituents of the heteroaryl radical of the thienyl radical, where the heteroaryl radical may be substituted by one or more C_1-6Alkyl is substituted, or

R³、R⁴And by R³And R⁴The bound carbon atoms may interact to form a 3-oxetane ring and the compound is R³And R⁴The carbon atom bound is a spiro atom;

R⁵：i)H，ii)C_1-6alkyl, which may be substituted by one or more-O- (C)_1-6Alkyl) substituted, iii) -O- (C)_1-6Alkyl), iv) halogen, v) -COO- (C)_1-6Alkyl) or vi) C _3-8A cycloalkyl group;

R⁶：i)H，ii)C_1-6alkyl, which may be selected from-O- (C which may be substituted by one or more halogens)_1-6Alkyl) and halogen, iii) -OH, iv) -O- (C which may be substituted by one or more halogens_1-6Alkyl), v) halogen, vi) -CN, vii) -S- (C_1-6Alkyl), viii) C_3-8Cycloalkyl, ix) -NR⁰R⁰Or x) C_2-6An alkenyl group;

G²group (b): i) halogen, ii) C_1-6Alkyl, which may be substituted by one or more substituents selected from-OH and halogen, or iii) -CONR⁰R⁰。

Embodiment mode 6-2

A compound described in the above embodiment 6-1, wherein R is³And R⁴As described in embodiment mode 3-1.

Embodiment modes 6 to 3

A compound described in the above embodiment 6-2, wherein R is³And R⁴As described in embodiment 4-1.

Embodiment 7-1

A compound or salt thereof selected from

(-) -2- (difluoromethyl) -8-ethyl-8- (2-hydroxyethyl) -6H-spiro [1, 6-naphthyridine-5, 3' -oxetane ] -7(8H) -one,

4, 4-diethyl-1, 1-dimethyl-3-oxo-1, 2,3, 4-tetrahydroisoquinoline-6-carbonitrile,

8, 8-diethyl-5, 5-dimethyl-7-oxo-5, 6,7, 8-tetrahydro-1, 6-naphthyridine-2-carbonitrile,

(-) -6-bromo-4-ethyl-4- (2-hydroxyethyl) -1, 1-dimethyl-1, 4-dihydroisoquinolin-3 (2H) -one,

(+) -6-bromo-4-ethyl-4- (2-hydroxyethyl) -1, 1-dimethyl-1, 4-dihydroisoquinolin-3 (2H) -one,

8, 8-diethyl-7-oxo-7, 8-dihydro-6H-spiro [1, 6-naphthyridine-5, 3' -oxetane ] -2-carbonitrile,

8',8' -diethyl-7 '-oxo-7', 8 '-dihydro-6' H-spiro [ oxetane-3, 5 '-pyrido [3,4-b ] pyrazine ] -2' -carbonitrile,

4, 4-diethyl-3-oxo-3, 4-dihydro-2H-spiro [ isoquinoline-1, 3' -oxetane ] -6-carbonitrile,

6-chloro-4, 4-dimethyl-2H-spiro [ isoquinoline-1, 3' -oxetane ] -3(4H) -one,

4, 4-dimethyl-3-oxo-3, 4-dihydro-2H-spiro [ isoquinoline-1, 3' -oxetane ] -6-carbonitrile,

2- (difluoromethoxy) -8, 8-dimethyl-6H-spiro [1, 6-naphthyridine-5, 3' -oxetane ] -7(8H) -one,

(+) -6-chloro-4- (2-hydroxyethyl) -4-methyl-2H-spiro [ isoquinoline-1, 3' -oxetane ] -3(4H) -one,

(-) -6-chloro-4- (2-hydroxyethyl) -4-methyl-2H-spiro [ isoquinolin-1, 3' -oxetan ] -3(4H) -one, and

(-) -2- (difluoromethoxy) -8-ethyl-8- (2-hydroxyethyl) -6H-spiro [1, 6-naphthyridine-5, 3' -oxetane ] -7(8H) -one.

Embodiment 7-2