2-arylbenzimidazoles as PPARGC1A activators for the treatment of neurodegenerative diseases

文档序号：554779 发布日期：2021-05-14 浏览：43次中文

阅读说明：本技术 作为ppargc1a激活剂用于治疗神经退行性疾病的2-芳基苯并咪唑 (2-arylbenzimidazoles as PPARGC1A activators for the treatment of neurodegenerative diseases ) 是由塞缪尔·D·尼斯特埃德加·英格曼科·D·阮马克·史密斯于 2019-08-06 设计创作，主要内容包括：本申请公开了由下式(III)所包含的一类化合物及其用途：这些化合物可激活Ppargc1a,因此可用于治疗多种神经退行性疾病,例如肌萎缩性脊髓侧索硬化症(ALS)、阿尔茨海默氏病、帕金森氏病、亨廷顿舞蹈病、额颞叶变性、路易体痴呆、运动神经元疾病和脱髓鞘疾病。(The present application discloses a class of compounds encompassed by the following formula (III) and uses thereof: these compounds activate Ppargc1a and are therefore useful in the treatment of various neurodegenerative diseases, such as Amyotrophic Lateral Sclerosis (ALS), alzheimer's disease, parkinson's disease, huntington's disease, frontotemporal lobar degeneration, dementia with lewy bodies, motor neuron disease, and demyelinating diseases.)

1. A compound of the following formula (I):

wherein:

W²is N or C-R²；

W³Is N or C-R³；

W⁴Is N or C-R⁴；

W⁵Is N or C-R⁵；

W⁶Is N or C-R⁶；

W⁷Is N or C-R⁷；

W⁸Is N or C-R⁸；

Wherein:

R¹is selected from-CH₂OC(＝O)R³⁰、–CH₂OP(＝O)OR⁴⁰OR⁴¹、-C(＝O)OR⁴²and-C (═ O) R⁴³；

Wherein:

R³⁰is selected from (C)₁-C₁₀) Hydrocarbyl, substituted by amino (C)₁-C₁₀) Hydrocarbyl, quilt (C)₁-C₄) Alkoxycarbonyl substituted (C)₁-C₁₀) Hydrocarbyl, substituted by carboxyl (C)₁-C₁₀) A hydrocarbon group, a carboxyl group and (C)₁-C₆) Alkoxycarbonyl, (C)₁-C₆) Alkoxycarbonylamino group, methylthio group, heterocyclic group, (C)₁-C₁₀) Oxaalkyl, CHR⁴⁴NHR⁴⁵And a guanidino group;

wherein:

R⁴⁴selected from any naturally occurring amino acid side chain; and

R⁴⁵selected from H, methyl and (C)₁-C₄) An alkoxycarbonyl group; and

R⁴⁰and R⁴¹Independently selected from hydrogen and (C)₁-C₆) A hydrocarbyl group;

R⁴²is (C)₁-C₅) An alkyl group; and

R⁴³is (C)₁-C₃) An alkyl group; and

R²、R³、R⁴and R⁵Independently selected from hydrogen, deuterium, halogen, perfluoro (C)₁-C₄) Alkyl, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy, perfluoro (C)₁-C₄) Alkoxy group, (C)₁-C₄) Acyl, (C)₁-C₄) Alkoxy (C)₁-C₄) Alkyl, hydroxy (C)₁-C₄) Alkyl, hydroxy, carboxy, (C)₁-C₄) Alkoxycarbonylamino [ -HNC (═ O) O-alkyl]Carboxamido [ -C (═ O) NH₂]、(C₁-C₄) Alkylaminocarbonyl [ -C (═ O) NH-alkyl]Cyano, acetoxy, nitro, amino, (C)₁-C₄) Alkylamino radical, di (C)₁-C₄) Alkylamino, mercapto, (C)₁-C₄) Alkylthio, aminosulfonyl, (C)₁-C₄) Alkylsulfonyl and (C)₁-C₄) An amide group;

R⁶and R¹⁰Independently selected from hydrogen, deuterium, halogen, (C)₁-C₃) Alkyl, perfluoro (C)₁-C₃) Alkyl, hydroxy, (C)₁-C₃) Alkoxy, perfluoro (C)₁-C₃) Alkoxy and amino;

R⁷and R⁹Independently selected from hydrogen, deuterium, hydroxy, cyano, amino, halogen, halo (C)₁-C₄) Alkyl, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy and halo (C)₁-C₄) An alkoxy group; and

R⁸selected from hydrogen, deuterium, halogen, halo (C)₁-C₄) Alkyl, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy, halo (C)₁-C₄) Alkoxy, cyano, phenyl, phenoxy, benzyloxy, and amino.

2. The compound of claim 1, wherein:

W⁶is C-H; w⁸Is C-R⁸；

R⁹And R¹⁰Is hydrogen;

R⁷is H or (C)₃-C₄) An alkyl group; and

R⁸selected from H, (C)₁-C₄) Alkyl, amino, (C)₁-C₄) Alkoxy, halo (C)₁-C₄) Alkoxy and hydroxy.

3. The compound of claim 2, wherein:

W²and W⁵Are each C-R²And C-R⁵；

R²、R³、R⁴And R⁵Independently selected from H, halogen and perfluoro (C)₁-C₃) An alkyl group; and

R¹is-CH₂OP(＝O)OR⁴⁰OR⁴¹。

4. The compound of claim 2, wherein:

W²and W⁵Are each C-R²And C-R⁵；

R²、R³、R⁴And R⁵Independently selected from H, halogen and perfluoro (C)₁-C₃) An alkyl group;

R¹is-CH₂OC(＝O)R³⁰(ii) a And

R³⁰selected from:

(a)(C₁-C₆) An alkyl group;

(b) quilt (C)₁-C₄) Alkyl amino substituted phenyl;

(d) substituted by carboxyl groups (C)₁-C₃) A hydrocarbyl group;

(e)(C₁-C₅) Oxaalkyl; and

(d) a pyridyl group.

5. The compound of claim 1, wherein:

W²and W⁵Independently selected from C-H, C-F, C-D, C-CF₃、C-CH₃、C-Cl、C-Br、C-OH、C-OCH₃、C-NH₂、C-CF₂H、C-OCF₃、C-OCF₂H、C-CD₃And C-CONH₂；

W³Selected from N, C-H, C-NH₂、C-F、C-CF₃、C-D、C-OCH₃、C-CN、C-OH、C-Cl、C-CH₃、C-CF₂H、C-OCF₃、C-OCF₂H、C-CD₃And C-Br;

W⁴selected from N, C-H, C-NH₂、C-F、C-CF₃、C-D、C-OCH₃、C-CN、C-OH、C-Cl、C-CH₃、C-CF₂H、C-OCF₃、C-OCF₂H、C-CD₃And C-Br;

W⁶is C-H;

W⁷is N or C-H;

W⁸is C-R⁸；

R⁸Selected from H, (C)₁-C₄) Alkyl, amino, (C)₁-C₄) Alkoxy, halo (C)₁-C₄) Alkoxy and hydroxy;

R⁹is H or (C)₁-C₄) An alkyl group; and

R¹⁰is H.

6. The compound of claim 5, wherein:

W²and W⁵Independently selected from C-H, C-F, C-D, C-CF₂H、C-CD₃And C-CF₃；

W³Selected from N, C-H, C-NH₂、C-F、C-CF₃、C-CF₂H、C-CD₃And C-D;

W⁴selected from N, C-H, C-NH₂、C-F、C-CF₃、C-CF₂H、C-CD₃And C-D;

W⁷is C-H;

R⁸selected from H, tert-butyl, amino and methoxy; and

R⁹is H or tert-butyl.

7. The compound of claim 1, wherein W²、W³、W⁴And W⁵1-4 of them are C-D or C-F.

8. The compound of claim 1, wherein R²、R³、R⁴And R⁵Is perfluoro (C)₁-C₄) Alkyl, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy, perfluoro (C)₁-C₄) Alkoxy, amino, hydroxy, nitrile, halogen or formamide, the remainder being hydrogen.

9. The compound of claim 8, wherein R²、R³、R⁴And R⁵Is trifluoromethyl, methyl, ethyl, methoxy, trifluoromethoxy, amino, hydroxy, nitrile, halogen or carboxamide.

10. The compound of claim 1, wherein W³Or W⁴One of which is N and the other together with W²And W⁵Is C-H.

11. The compound of claim 1, wherein W²、W³、W⁴、W⁵、W⁶And W⁷Is C-H.

12. The compound according to any one of claims 1-11, wherein R⁸Is a tert-butyl group.

13. A compound of the following formula (II):

wherein:

ar is

W¹Selected from O, S and N-R¹Or when W is⁹When is N, W¹May additionally be C-R⁵⁰；

W²Is N or C-R²；

W³Is N or C-R³；

W⁴Is N or C-R⁴；

W⁵Is N or C-R⁵；

W⁹Is C, or when W¹Is C-R⁵⁰When the current is over; w⁹May be N;

wherein:

R¹selected from H, (C)₁-C₃) alkyl-CH₂OC(＝O)R³⁰；CH₂OP(＝O)OR⁴⁰OR⁴¹、-C(＝O)OR⁴²and-C (═ O) R⁴³；

Wherein:

R³⁰is selected from (C)₁-C₁₀) Hydrocarbyl, substituted by amino (C)₁-C₁₀) Hydrocarbyl, quilt (C)₁-C₄) Alkoxycarbonylalkoxycarbonyl substituted (C)₁-C₁₀) Hydrocarbyl, substituted by carboxyl (C)₁-C₁₀) A hydrocarbon group, a carboxyl group and (C)₁-C₆) Alkoxycarbonyl group, (C)₁-C₆) Alkoxycarbonyl alkoxycarbonylamino group, methylthio group, heterocyclic group and (C)₁-C₁₀) Oxaalkoxy, CHR⁴⁴NHR⁴⁵And a guanidino group;

wherein:

R⁴⁴selected from any naturally occurring amino acid side chain; and

R⁴⁵selected from H, methyl and (C)₁-C₄) An alkoxycarbonyl group; and

R⁴⁰and R⁴¹Independently selected from hydrogen and (C)₁-C₆) A hydrocarbyl group;

R⁴²is (C)₁-C₅) An alkyl group; and

R⁴³is (C)₁-C₃) An alkyl group; and

R⁵⁰is H or (C)₁-C₃) An alkyl group; and

R²、R³、R⁴and R⁵Independently selectFrom hydrogen, deuterium, halogen, perfluoro (C)₁-C₄) Alkyl, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy, perfluoro (C)₁-C₄) Alkoxy group, (C)₁-C₄) Acyl, (C)₁-C₄) Alkoxy (C)₁-C₄) Alkyl, hydroxy (C)₁-C₄) Alkyl, hydroxy, carboxy, (C)₁-C₄) Alkoxycarbonylamino [ -HNC (═ O) O-alkyl]Carboxamido [ -C (═ O) NH₂]、(C₁-C₄) Alkylaminocarbonyl [ -C (═ O) NH-alkyl]Cyano, acetoxy, nitro, amino, (C)₁-C₄) Alkylamino radical, di (C)₁-C₄) Alkylamino, mercapto, (C)₁-C₄) Alkylthio, aminosulfonyl, (C)₁-C₄) Alkylsulfonyl and (C)₁-C₄) An amide group;

provided only that:

W⁹is C;

W¹is N-R¹(ii) a And

R¹is not H or (C)₁-C₃) When the alkyl group is used, the alkyl group,

ar comprises

14. The compound of claim 13, wherein:

W²and W⁵Are each C-R²And C-R⁵(ii) a And

R²、R³、R⁴and R⁵Independently selected from H, deuterium, halogen, (C)₁-C₃) Alkoxy, perfluoro (C)₁-C₃) Alkoxy, nitrile, amino, hydroxy, aminocarbonyl, (C)₁-C₃) Alkyl and perfluoro (C)₁-C₃) An alkyl group.

15. The compound of claim 13, wherein:

R²、R³、R⁴and R⁵Independently selected from H, halogen and perfluoro (C)₁-C₃) An alkyl group.

16. The compound of claim 15, wherein:

W¹is N-H or C-H;

W²and W⁵Independently selected from C-H, C-F, C-D, C-CF₃、C-CH₃、C-Cl、C-Br、C-OH、C-OCH₃、C-NH₂、C-CF₂H、C-OCF₃、C-OCF₂H、C-CD₃And C-CONH₂；

W³Selected from N, C-H, C-NH₂、C-F、C-CF₃、C-D、C-OCH₃、C-CN、C-OH、C-Cl、C-CH₃、C-CF₂H、C-OCF₃、C-OCF₂H、C-CD₃And C-Br; and

W⁴selected from N, C-H, C-NH₂、C-F、C-CF₃、C-D、C-OCH₃、C-CN、C-OH、C-Cl、C-CH₃、C-CF₂H、C-OCF₃、C-OCF₂H、C-CD₃And C-Br.

17. The compound of claim 16, wherein:

W²and W⁵Independently selected from C-H, C-F, C-D, C-CF₂H、C-CD₃And C-CF₃；

W³Selected from N, C-H, C-NH₂、C-F、C-CF₃、C-CF₂H、C-CD₃And C-D;

W⁴selected from N, C-H, C-NH₂、C-F、C-CF₃、C-CF₂H、C-CD₃And C-D.

18. The compound of claim 13, wherein W²、W³、W⁴And W⁵1-4 of them are C-D or C-F.

19. The compound of claim 13, wherein R²、R³、R⁴And R⁵Is perfluoro (C)₁-C₄) Alkyl, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy, perfluoro (C)₁-C₄) Alkoxy, amino, hydroxy, nitrile, halogen or formamide, the remainder being hydrogen.

20. The compound of claim 19, wherein R²、R³、R⁴And R⁵Is trifluoromethyl, methyl, ethyl, methoxy, trifluoromethoxy, amino, hydroxy, nitrile, halogen or carboxamide.

21. The compound of claim 13, wherein W³Or W⁴One of which is N and the other together with W²And W⁵Is C-H.

22. The compound of claim 13, wherein W²、W³、W⁴And W⁵Is C-H.

23. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to any one of claims 1-11 and 13-22.

24. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 12.

25. A method of treating a neurodegenerative disease, comprising administering to a subject having a neurodegenerative disease an effective amount of a compound of formula (III):

wherein:

W¹selected from O, S and N-R¹Or when W⁹When is N, W¹May additionally be C-R⁵⁰；

W²Is N or C-R²；

W³Is N or C-R³；

W⁴Is N or C-R⁴；

W⁵Is N or C-R⁵；

W⁶Is N or C-R⁶；

W⁷Is N or C-R⁷；

W⁸Is N or C-R⁸；

W⁹Is C, or when W¹Is C-R⁵⁰When W is⁹May be N;

wherein:

R¹selected from H, (C)₁-C₃) Alkyl, -CH₂OC(＝O)R³⁰、-CH₂OP(＝O)OR⁴⁰OR⁴¹、-C(＝O)OR⁴²and-C (═ O) R⁴³；

Wherein:

R³⁰is selected from (C)₁-C₁₀) Hydrocarbyl, substituted by amino (C)₁-C₁₀) Hydrocarbyl, quilt (C)₁-C₄) Alkoxycarbonylalkoxycarbonyl substituted (C)₁-C₁₀) Hydrocarbyl, quilt (C)₁-C₄) Alkoxycarbonylalkoxycarbonyl substituted (C)₁-C₁₀) A hydrocarbon group, a carboxyl group and (C)₁-C₁₀) Alkoxycarbonyl group, (C)₁-C₆) Alkoxycarbonyl alkoxycarbonylamino group, methylthio group, heterocyclic group and (C)₁-C₁₀) Oxaalkoxy, CHR⁴⁴NHR⁴⁵And a guanidino group;

wherein:

R⁴⁴selected from any naturally occurring amino acid side chain; and

R⁴⁵selected from H, methyl and (C)₁-C₄) An alkoxycarbonyl group; and

R⁴⁰and R⁴¹Independently of each otherSelected from hydrogen and (C)₁-C₆) A hydrocarbyl group;

R⁴²is (C)₁-C₅) An alkyl group; and

R⁴³is (C)₁-C₃) An alkyl group; and

R⁵⁰is H or (C)₁-C₃) An alkyl group;

R⁶and R¹⁰Independently selected from hydrogen, deuterium, halogen, (C)₁-C₃) Alkyl, perfluoro (C)₁-C₃) Alkyl, hydroxy, (C)₁-C₃) Alkoxy, perfluoro (C)₁-C₃) Alkoxy and amino;

R⁸selected from hydrogen, deuterium, halogen, halo (C)₁-C₄) Alkyl, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkane (I) and its preparation methodOxy, halo (C)₁-C₄) Alkoxy, cyano, phenyl, phenoxy, benzyloxy, and amino;

with the following conditions: when the following is the case, R⁸Is not hydrogen or (C)₁-C₄) Alkyl groups:

(a)W¹is N-R¹；

(b)R¹Is hydrogen;

(c)W²、W³、W⁴、W⁵、W⁶and W⁷Is C-H;

(d)W⁸is C-R⁸；

(e)W⁹Is C; and

(f)R⁹and R¹⁰Is hydrogen.

26. The method of claim 25, wherein the neurodegenerative disease is selected from the group consisting of: amyotrophic Lateral Sclerosis (ALS), Alzheimer's disease, Parkinson's disease, Huntington's disease, frontotemporal degeneration, dementia with Lewy bodies, motor neuron disease, and demyelinating disease.

27. A method of treating aging-related cognitive disorders and neuroinflammation comprising administering to a subject suffering from aging-related cognitive disorders and neuroinflammation an effective amount of a compound of formula III as defined in claim 25.

Technical Field

The present application relates to the use of 2-arylbenzimidazoles, 2-arylbenzoxazoles, 2-arylbenzothiazoles, 2-arylimidazo [1,2-a ] pyridines, and prodrug derivatives thereof, as chemical activators of Ppargc1a for the treatment of neurodegenerative diseases.

Background

Amyotrophic lateral sclerosis

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of motor neurons, resulting in a gradual decline in motor function and ultimately death. The motor symptoms of ALS include muscle weakness, convulsions, and wasting, which in turn lead to difficulties in speaking, swallowing, and breathing. The cause of motor neuron death in ALS is unknown, and 5-10% of ALS cases are inherited.

Activation of immune cells in the central and peripheral nervous systems has been suggested to be a key determinant of disease progression in ALS (Phani et al, Front Pharmacol, 3:150, 2012). In particular, microglia and macrophages have been shown to play different roles in the development of neuroinflammation in the disease (Dibaj et al, PLoS One, 6 (3): e17910, 2011; Boillee et al, Science, 312: 1389-. Notably, replacement of host myeloid cells by Bone Marrow Transplantation (BMT) has been shown to prolong survival in an ALS animal model, which is thought to be mediated by replacement of CNS microglia (Beers et al, Proc Natl Acad Sci U S A.103: 16021-6, 2006). However, recent studies have shown that these cells develop not from bone marrow cells, but from more primitive yolk sac progenitor cells (Ginhoux et al, Science, 330: 841-5, 2110), suggesting that bone marrow-derived cells mediating the therapeutic effects of BMT in the above studies are more likely to be peripheral or pericerebrovascular macrophages. However, the specific signaling pathways in ALS that lead to innate immune cell-mediated inflammation are not fully understood.

At present, ALS is not yet cured. Certain therapies, such as riluzole, bone marrow transplantation (Deda, Cytotherapy, 11: 18-25, 2009), and non-invasive ventilation (McDeRmott et al, BMJ, 336: 658-62, 2008) have been shown to have some effect in improving quality of life and prolonging survival, but no therapy can cure or provide significant benefits.

Alzheimer's disease

Alzheimer's Disease (AD) is a degenerative brain disease characterized clinically by a gradual loss of motor function with concomitant loss of memory, cognition, reasoning, judgment and emotional stability, gradually leading to severe neurodegeneration and ultimately death. It has been proposed that neuronal metabolic dysfunction in the form of oxidative stress is the underlying cause of neurodegeneration in AD (Friedland-Leuner et al, Mol Biol Transl Sci, 127: 183-.

Although the progression of AD varies from individual to individual, there are many common symptoms. Early symptoms are often mistakenly considered as age-related problems or stress manifestations. In the early stages, the most common symptom is reduced motor ability, difficulty remembering what happened recently, which is called short term memory loss (Buchman et al, Exp Rev neuron, 11: 665-76, 2011). When AD is suspected, diagnosis is usually based on tests that assess behavioral and mental abilities, and if possible, brain scans are usually performed. However, brain tissue examination is required to make a clear diagnosis. As the disease progresses, symptoms may include confusion, irritability, aggression, mood swings, language disturbances, and long-term memory impairment. As the individual's condition deteriorates, he/she will often evade families and society. Then, the body's function is gradually lost, eventually leading to death.

Parkinson's disease

Parkinson's Disease (PD), also known as idiopathic or primary parkinson's disease, is a degenerative nervous system disease of the central nervous system. Motor symptoms of PD are caused by the death of dopamine-producing cells in the substantia nigra of the midbrain region, and the cause of this cell death is not known. In the early stages of the disease, the most obvious symptoms are those associated with exercise. These symptoms include tremors, stiffness, slowness of movement and difficulty performing fine motor movements, difficulty walking and gait abnormalities. Later, thought and behavioral problems may arise, dementia usually occurring in the late stages of the disease, and depression is the most common mental symptom. Other symptoms include sensory, sleep and emotional problems.

PD is characterized by progressive motor injury and neuroinflammation caused by microglia, an innate immune cell of the central nervous system (Aguzzi et al, Science, 339: 156-61, 2013). Inflammatory mediators produced by dysfunctional microglia have been shown to lead to neuronal cell death, which is the basis for progressive impairment of cognitive and behavioral performance in neurodegenerative diseases (Czirr et al, J Clin Invest, 122: 1156-63, 2012). However, the specific signaling pathways leading to microglia-mediated inflammation remain elusive.

Huntington's chorea

Huntington's Disease (HD) is the central nervous system autosomal dominant degenerative disease, wherein the Huntington gene mutations. HD is a genetic disease that leads to progressive depletion (degeneration) of nerve cells in the brain. HD has a wide range of effects on human functional abilities, often leading to motor, mental (cognitive) and psychiatric disorders.

Symptoms of HD vary from patient to patient, but the progression of the disease is relatively predictable (Mason S et al, J Neurol, 2015). In the early stages of the disease, the symptoms are mild, e.g. mood changes. Later, cognitive and motor problems may occur, and dementia usually occurs in the late stages of the disease. Chorea (involuntary movements) is the most common motor symptom. Other complications include pneumonia, heart disease, and physical injury from falls.

At present, no method for curing HD exists, and patients with advanced disease need full-time nursing.

Frontotemporal lobar degeneration

Frontotemporal lobar degeneration (FTD) is a disease closely associated with AD, with progressive degeneration of AD occurring in the frontal and temporal lobes of the brain. Gliosis and inflammatory activation of microglia have been documented in human and animal FTD models (Cagnin et al Annals of Neurol, 20046: 894-. The behavioral and linguistic abilities of FTD patients gradually decline, and memory is usually relatively preserved. As the disease progresses, it becomes increasingly difficult for the patient to perform activities, hold themselves, and care for himself. There is currently no therapeutic method available to slow or stop the progression of the disease.

Dementia with lewy bodies

Dementia with lewy bodies (DLB) is a dementia associated with PD. The hallmark of this disease is the presence of alpha synuclein aggregates in the brain of the patient. These patients experience PD-like symptoms including kyphosis, muscle stiffness, gait distortion and difficulty moving, as well as changes in mental and thinking, hypomnesis (but less pronounced than AD). Since lewy bodies are also present in PD, both diseases may be associated with the same underlying abnormalities in the way the brain processes the protein a-synuclein. Furthermore, similar to PD, there is microglial-associated neuroinflammation in the brain of DLB patients, although this pathological feature occurs more extensively (Iannaccone et al, Parkinsonism relat. dis, 201319: 47-52).

Motor neuron disease

Motor Neuron Disease (MND) is a neurological disease similar to ALS that selectively affects motor neurons, cells that control autonomic muscle activity, including speech, walking, swallowing, and motor activity, and there is no effective MND treatment currently available. They are neurodegenerative in nature and lead to progressive disability and death. Furthermore, in animal models of MND, a specific pathway called granule protein precursor can trigger the inflammatory activation of microglia, and gene ablation of this pathway can slow disease progression (Philips et al, J neuropathohol Exp Neurol, 201069: 1191-200).

Demyelinating diseases

Demyelinating diseases, such as Guillain-Barre syndrome and Multiple Sclerosis (MS), are degenerative diseases in which the myelin sheath of neurons is damaged. This damage impairs signal transduction of the affected nerve, resulting in inadequate sensory, motor, cognitive or other functions, which are not curable. It is most notably MS, a disease involving a subpopulation of cells of the immune system. For example, persistent demyelination is often associated with infiltration of circulating T cells and macrophages and inflammatory activation of microglia (Kutzelnigg et al, handb. Clin. neurol, 2014, 122: 15-58).

The compounds described herein activate Ppargc1a and are useful for treating the neurodegenerative diseases described above.

Disclosure of Invention

It has been found that 2-arylbenzimidazoles, 2-arylbenzoxazoles, 2-arylbenzothiazoles, and 2-arylimidazo [1,2-a ] pyridines activate PPargc1 a. These compounds and their prodrug derivatives are useful in the treatment of neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (ALS), Alzheimer's disease, Parkinson's disease, Huntington's disease, frontotemporal lobar degeneration, dementia with Lewy bodies, motor neuron disease and demyelinating diseases.

In a first aspect, the present application relates to compounds of the following formula (I):

wherein:

W²is N or C-R²；

W³Is N or C-R³；

W⁴Is N or C-R⁴；

W⁵Is N or C-R⁵；

W⁶Is N or C-R⁶；

W⁷Is N or C-R⁷；

W⁸Is N or C-R⁸；

R¹Is selected from-CH₂OC(＝O)R³⁰、-CH₂OP(＝O)OR⁴⁰OR⁴¹、-C(＝O)OR⁴²and-C (═ O) R⁴³；

Wherein:

wherein:

R⁴⁴selected from any naturally occurring amino acid side chain; and

R⁴⁵selected from H, methyl and (C)₁-C₄) An alkoxycarbonyl group; and

R⁴⁰and R⁴¹Independently selected from hydrogen and (C)₁-C₆) A hydrocarbyl group;

R⁴²is (C)₁-C₅) An alkyl group; and

R⁴³is (C)₁-C₃) An alkyl group; and

R⁶and R¹⁰Independently selected from hydrogen, deuterium, halogen, (C)₁-C₃) Alkyl, perfluoro (C)₁-C₃) Alkyl, hydroxy, (C)₁-C₃) Alkoxy, perfluoro (C)₁-C₃) Alkoxy and amino;

R⁸selected from hydrogen, deuterium, halogen, halo (C)₁-C₄) Alkyl, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy, halo (C)₁-C₄) Alkoxy, cyano, phenyl, phenoxy, benzyloxy, and amino.

In a second aspect, the present application relates to a compound represented by the following formula (II):

wherein:

ar is

W¹Selected from O, S and N-R¹Or when W⁹When is N, W¹May additionally be C-R⁵⁰；

W²Is N or C-R²；

W³Is N or C-R³；

W⁴Is N or C-R⁴；

W⁵Is N or C-R⁵；

W⁹Is C, or when W¹Is C-R⁵⁰When the current is over; w⁹May be N;

wherein:

R¹selected from H, (C)₁-C₃) Alkyl, -CH₂OC(＝O)R³⁰、-CH₂OP(＝O)OR⁴⁰OR⁴¹、-C(＝O)OR⁴²and-C (═ O) R⁴³；

Wherein:

wherein:

R⁴⁴selected from any naturally occurring amino acid side chain; and

R⁴⁵selected from H, methyl and (C)₁-C₄) An alkoxycarbonyl group; and

R⁴⁰and R⁴¹Independently selected from hydrogen and (C)₁-C₆) A hydrocarbyl group;

R⁴²is (C)₁-C₅) An alkyl group; and

R⁴³is (C)₁-C₃) An alkyl group; and

R⁵⁰is H or (C)₁-C₃) An alkyl group; and

R²、R³、R⁴and R⁵Independently selected from hydrogen, deuterium, halogen, perfluoro (C)₁-C₄) Alkyl, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy, perfluoro (C)₁-C₄) Alkoxy group, (C)₁-C₄) Acyl, (C)₁-C₄) Alkoxy (C)₁-C₄) Alkyl, hydroxy (C)₁-C₄) Alkyl, hydroxy, carboxy, (C)₁-C₄) Alkoxycarbonylamino [ -HNC (═ O) O-Alkyl radical]Carboxamido [ -C (═ O) NH₂]、(C₁-C₄) Alkylaminocarbonyl [ -C (═ O) NH-alkyl]Cyano, acetoxy, nitro, amino, (C)₁-C₄) Alkylamino radical, di (C)₁-C₄) Alkylamino, mercapto, (C)₁-C₄) Alkylthio, aminosulfonyl, (C)₁-C₄) Alkylsulfonyl and (C)₁-C₄) An amide group;

provided only that:

W⁹is C;

W¹is N-R¹(ii) a And

R¹is not H or (C)₁-C₃) When the alkyl group is used, the alkyl group,

ar comprises

In a third aspect, the present application relates to a method of treating a neurodegenerative disease comprising administering a compound represented by the following formula (III):

wherein:

W¹selected from O, S and N-R¹Or when W⁹When is N, W¹May additionally be C-R⁵⁰；

W²Is N or C-R²；

W³Is N or C-R³；

W⁴Is N or C-R⁴；

W⁵Is N or C-R⁵；

W⁶Is N or C-R⁶；

W⁷Is N or C-R⁷；

W⁸Is N or C-R⁸；

W⁹Is C, or when W¹Is C-R⁵⁰When the current is over; w⁹May be N;

wherein:

R¹selected from H, (C)₁-C₃) Alkyl, -CH₂OC(＝O)R³⁰、-CH₂OP(＝O)OR⁴⁰OR⁴¹、-C(＝O)OR⁴²and-C (═ O) R⁴³；

Wherein:

R³⁰is selected from (C)₁-C₁₀) Hydrocarbyl, substituted by amino (C)₁-C₁₀) Hydrocarbyl, quilt (C)₁-C₁₀) Alkoxycarbonyl substituted (C)₁-C₁₀) Hydrocarbyl, substituted by carboxyl (C)₁-C₁₀) A hydrocarbon group, a carboxyl group and (C)₁-C₁₀) Alkoxycarbonyl, (C)₁-C₆) Alkoxycarbonylamino group, methylthio group, heterocyclic group, (C)₁-C₁₀) Alkoxy, CHR⁴⁴NHR⁴⁵And a guanidino group;

wherein:

R⁴⁴selected from any naturally occurring amino acid side chain; and

R⁴⁵selected from H, methyl and (C)₁-C₄) An alkoxycarbonyl group; and

R⁴⁰and R⁴¹Independently selected from hydrogen and (C)₁-C₆) A hydrocarbyl group;

R⁴²is (C)₁-C₅) An alkyl group; and

R⁴³is (C)₁-C₃) An alkyl group; and

R⁵⁰is H or (C)₁-C₃) An alkyl group;

R⁶and R¹⁰Independently selected from hydrogen, deuterium, halogen, (C)₁-C₃) Alkyl, perfluoro (C)₁-C₃) Alkyl, hydroxy, (C)₁-C₃) Alkoxy, perfluoro (C)₁-C₃) Alkoxy and amino;

R⁸selected from hydrogen, deuterium, halogen, halo (C)₁-C₄) Alkyl, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy, halo (C)₁-C₄) Alkoxy, cyano, phenyl, phenoxy, benzyloxy, and amino;

provided that, when the following is the case, R⁸Is not hydrogen or (C)₁-C₄) Alkyl groups:

(a)W¹is N-R¹；

(b)R¹Is hydrogen;

(c)W²、W³、W⁴、W⁵、W⁶and W⁷Is C-H;

(d)W⁸is C-R⁸；

(e)W⁹Is C; and

(f)R⁹and R¹⁰Is hydrogen.

In a fourth aspect, the present application relates to methods and uses of compounds according to formula I, II or III as described above, or pharmaceutical compositions comprising compounds according to formula I, II or III, in medicine, in particular for the treatment of neurodegenerative diseases. Such neurodegenerative diseases include Amyotrophic Lateral Sclerosis (ALS), Alzheimer's disease, Parkinson's disease, Huntington's disease, frontotemporal lobar degeneration, Lewy body dementia, motor neuron disease, and demyelinating diseases. The method comprises administering an effective amount of a compound or pharmaceutical composition described herein.

In a fifth aspect, the present application relates to methods and uses of compounds according to formula I, II or III as described above, or pharmaceutical compositions comprising compounds according to formula I, II or III, in medicine, in particular for treating age-related cognitive disorders and neuroinflammation in a patient. These methods comprise administering to a patient a therapeutically effective amount of a pharmaceutical composition of a compound described herein.

Drawings

Figure 1 shows plasma API levels of prodrug examples 6-P, 8-P and 11-P.

Figure 2 shows brain tissue API levels for prodrug examples 6-P, 8-P and 11-P.

Figure 3 shows the liver API levels of prodrug examples 6-P, 8-P and 11-P.

Detailed Description

Substituents are generally defined at the time of introduction and this definition is maintained throughout the specification and all independent claims.

In a first compositional aspect, the present application relates to a compound of the following formula (I) as described herein:

in a second compositional aspect, the present application relates to a compound represented by the following formula (II) as described herein:

in a method aspect, the present application relates to a compound as described herein represented by the following formula (III):

in the examples described below, unless otherwise indicated, the compound may be a compound as shown in formula I, II or III.

In some embodiments of formulas II and III, W¹Is N-R¹. In other embodiments of formulas II and III, W¹Is O. In other embodiments of formulas II and III, W¹Is S. In still other embodiments of formulas II and III, it is preferred when W⁹When is N, W¹Is C-R⁵⁰. At W¹Is C-R⁵⁰In some embodiments, R⁵⁰Is H. At W¹Is C-R⁵⁰In other embodiments of (5), R⁵⁰Is (C)₁-C₃) An alkyl group.

In some embodiments of formulas I, II and III, R¹is-CH₂OC(＝O)R³⁰(ii) a Wherein R is³⁰Is selected from (C)₁-C₁₀) Hydrocarbyl, substituted by amino (C)₁-C₁₀) Hydrocarbyl, quilt (C)₁-C₄) Alkoxycarbonyl substituted (C)₁-C₁₀) Hydrocarbyl, substituted by carboxyl (C)₁-C₁₀) A hydrocarbon group, a carboxyl group and (C)₁-C₆) Alkoxycarbonyl, (C)₁-C₆) Alkoxycarbonylamino group, methylthio group, heterocyclic group, (C)₁-C₁₀) Oxaalkyl and guanidino.

In some embodiments, when R¹is-CH₂OC(＝O)R³⁰When R is³⁰Selected from: (a) (C)₁-C₆) An alkyl group; (b) quilt (C)₁-C₄) Alkyl amino substituted phenyl; (c) decarboxylated residues of natural amino acids; (d) substituted by carboxyl groups (C)₁-C₃) A hydrocarbyl group; (e) (C)₁-C₅) Oxaalkyl; and (d) a pyridyl group.

In some embodiments of formulas II and III, R¹Is H. In other embodiments of formulas II and III, R¹Is (C)₁-C₃) An alkyl group.

In some embodiments of formulas I, II and III，W²Is N. In other embodiments of formulas I, II and III, W²Is C-R². In some embodiments, W²Selected from C-H, C-F, C-D, C-CF₃、C-CH₃、C-Cl、C-Br、C-OH、C-OCH₃、C-NH₂、C-CF₂H、C-OCF₃、C-OCF₂H、C-CD₃And C-CONH₂. In some embodiments, W²Selected from C-H, C-F, C-D, C-CF₂H、C-CD₃And C-CF₃。

At W²Is C-R²In the examples of (1), R²Selected from hydrogen, deuterium, halogen, perfluoro (C)₁-C₄) Alkyl, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy, perfluoro (C)₁-C₄) Alkoxy group, (C)₁-C₄) Acyl, (C)₁-C₄) Alkoxy (C)₁-C₄) Alkyl, hydroxy (C)₁-C₄) Alkyl, hydroxy, carboxy, (C)₁-C₄) Alkoxycarbonylamino [ -HNC (═ O) O-alkyl]Carboxamido [ -C (═ O) NH₂]、(C₁-C₄) Alkylaminocarbonyl [ -C (═ O) NH-alkyl]Cyano, acetoxy, nitro, amino, (C)₁-C₄) Alkylamino radical, di (C)₁-C₄) Alkylamino, mercapto, (C)₁-C₄) Alkylthio, aminosulfonyl, (C)₁-C₄) Alkylsulfonyl and (C)₁-C₄) An amide group.

At W²Is C-R²In some embodiments, R²Selected from hydrogen, perfluoro (C)₁-C₄) Alkyl, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy, perfluoro (C)₁-C₄) Alkoxy, amino, hydroxy, nitrile, halogen or carboxamide. In some embodiments, R²Selected from hydrogen, trifluoromethyl, methyl, ethyl, methoxy, trifluoromethoxy, amino, hydroxy, nitrile, halogen or carboxamide. In some embodiments, R²Selected from hydrogen, halogen and perfluoro (C)₁-C₃) An alkyl group.

In some embodiments of formulas I, II and III, W³Is N. In other embodiments of formulas I, II and III, W³Is C-R³. In some embodiments, W³Selected from N, C-H, C-NH₂、C-F、C-CF₃、C-D、C-OCH₃、C-CN、C-OH、C-Cl、C-CH₃、C-CF₂H、C-OCF₃、C-OCF₂H、C-CD₃And C-Br. In some embodiments, W³Selected from N, C-H, C-NH₂、C-F、C-CF₃、C-CF₂H、C-CD₃And C-D.

At W³Is C-R³In some embodiments, R³Selected from hydrogen, deuterium, halogen, perfluoro (C)₁-C₄) Alkyl, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy, perfluoro (C)₁-C₄) Alkoxy group, (C)₁-C₄) Acyl, (C)₁-C₄) Alkoxy (C)₁-C₄) Alkyl, hydroxy (C)₁-C₄) Alkyl, hydroxy, carboxy, (C)₁-C₄) Alkoxycarbonylamino [ -HNC (═ O) O-alkyl]Carboxamido [ -C (═ O) NH₂]、(C₁-C₄) Alkylaminocarbonyl [ -C (═ O) NH-alkyl]Cyano, acetoxy, nitro, amino, (C)₁-C₄) Alkylamino radical, di (C)₁-C₄) Alkylamino, mercapto, (C)₁-C₄) Alkylthio, aminosulfonyl, (C)₁-C₄) Alkylsulfonyl and (C)₁-C₄) An amide group.

At W³Is C-R³In some embodiments, R³Selected from hydrogen, perfluoro (C)₁-C₄) Alkyl, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy, perfluoro (C)₁-C₄) Alkoxy, amino, hydroxy, nitrile, halogen or carboxamide. At W³Is C-R³In some embodiments, R³Selected from hydrogen, trifluoromethyl, methyl, ethyl, methoxy, trifluoromethoxy, amino, hydroxy, nitrile, halogen or carboxamide. At W³Is C-R³ToIn some embodiments, R³Selected from H, halogen and perfluoro (C)₁-C₃) An alkyl group.

In some embodiments of formulas I, II and III, W⁴Is N. In other embodiments of formulas I, II and III, W⁴Is C-R⁴. In some embodiments, W⁴Selected from N, C-H, C-NH₂、C-F、C-CF₃、C-D、C-OCH₃、C-CN、C-OH、C-Cl、C-CH₃、C-CF₂H、C-OCF₃、C-OCF₂H、C-CD₃And C-Br. In some embodiments, W⁴Selected from N, C-H, C-NH₂、C-F、C-CF₃、C-CF₂H、C-CD₃And C-D.

At W⁴Is C-R⁴In some embodiments, R⁴Selected from hydrogen, deuterium, halogen, perfluoro (C)₁-C₄) Alkyl, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy, perfluoro (C)₁-C₄) Alkoxy group, (C)₁-C₄) Acyl, (C)₁-C₄) Alkoxy (C)₁-C₄) Alkyl, hydroxy (C)₁-C₄) Alkyl, hydroxy, carboxy, (C)₁-C₄) Alkoxycarbonylamino [ -HNC (═ O) O-alkyl]Carboxamido [ -C (═ O) NH₂]、(C₁-C₄) Alkylaminocarbonyl [ -C (═ O) NH-alkyl]Cyano, acetoxy, nitro, amino, (C)₁-C₄) Alkylamino radical, di (C)₁-C₄) Alkylamino, mercapto, (C)₁-C₄) Alkylthio, aminosulfonyl, (C)₁-C₄) Alkylsulfonyl and (C)₁-C₄) An amide group.

At W⁴Is C-R⁴In some embodiments, R⁴Selected from hydrogen, perfluoro (C)₁-C₄) Alkyl, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy, perfluoro (C)₁-C₄) Alkoxy, amino, hydroxy, nitrile, halogen or carboxamide. At W⁴Is C-R⁴In some embodiments, R⁴Selected from hydrogen, trifluoromethyl, methylEthyl, methoxy, trifluoromethoxy, amino, hydroxy, nitrile, halogen, or carboxamide. At W⁴Is C-R⁴In some embodiments, R⁴Selected from H, halogen and perfluoro (C)₁-C₃) An alkyl group.

In some embodiments of formulas I, II and III, W⁵Is N. In other embodiments of formulas I, II and III, W⁵Is C-R⁵. In some embodiments, W⁵Selected from C-H, C-F, C-D, C-CF₃、C-CH₃、C-Cl、C-Br、C-OH、C-OCH₃、C-NH₂、C-CF₂H、C-OCF₃、C-OCF₂H、C-CD₃And C-CONH₂. In some embodiments, W⁵Selected from CH, CF, CD, C-CF₂H、C-CD₃And C-CF₃。

At W⁵Is C-R⁵In the examples of (1), R⁵Selected from hydrogen, deuterium, halogen, perfluoro (C)₁-C₄) Alkyl, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy, perfluoro (C)₁-C₄) Alkoxy group, (C)₁-C₄) Acyl, (C)₁-C₄) Alkoxy (C)₁-C₄) Alkyl, hydroxy (C)₁-C₄) Alkyl, hydroxy, carboxy, (C)₁-C₄) Alkoxycarbonylamino [ -HNC (═ O) O-alkyl]Carboxamido [ -C (═ O) NH₂]、(C₁-C₄) Alkylaminocarbonyl [ -C (═ O) NH-alkyl]Cyano, acetoxy, nitro, amino, (C)₁-C₄) Alkylamino radical, di (C)₁-C₄) Alkylamino, mercapto, (C)₁-C₄) Alkylthio, aminosulfonyl, (C)₁-C₄) Alkylsulfonyl and (C)₁-C₄) An amide group.

At W⁵Is C-R⁵In some embodiments, R⁵Selected from hydrogen, perfluoro (C)₁-C₄) Alkyl, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy, perfluoro (C)₁-C₄) Alkoxy, amino, hydroxy, nitrile, halogen or carboxamide.In some embodiments, R⁵Selected from hydrogen, trifluoromethyl, methyl, ethyl, methoxy, trifluoromethoxy, amino, hydroxy, nitrile, halogen or carboxamide. In some embodiments, R⁵Selected from hydrogen, halogen and perfluoro (C)₁-C₃) An alkyl group.

In some embodiments of formulas I and III, W⁶Is N. In other embodiments of formulas I and III, W⁶Is C-R⁶Preferably C-H.

At W⁶Is C-R⁶In some embodiments, R⁶Selected from hydrogen, deuterium, halogen, (C)₁-C₃) Alkyl, perfluoro (C)₁-C₃) Alkyl, hydroxy, (C)₁-C₃) Alkoxy, perfluoro (C)₁-C₃) Alkoxy and amino.

In some embodiments of formulas I and III, W⁷Is N. In other embodiments of formulas I and III, W⁷Is C-R⁷. At W⁷Is C-R⁷In some embodiments, R⁷Selected from hydrogen, deuterium, hydroxy, cyano, amino, halogen (C)₁-C₄) Alkyl, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy and halogen (C)₁-C₄) An alkoxy group. At W⁷Is C-R⁷In some embodiments, R⁷Is hydrogen or (C)₃-C₄) An alkyl group.

In some embodiments of formulas I and III, W⁸Is N. In other embodiments of formulas I and III, W⁸Is C-R⁸. At W⁸Is C-R⁸In some embodiments, R⁸Selected from hydrogen, deuterium, halogen, halo (C)₁-C₄) Alkyl, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy, halo (C)₁-C₄) Alkoxy, cyano, phenyl, phenoxy, benzyloxy, and amino. At W⁸Is C-R⁸In some embodiments, R⁸Selected from H, (C)₁-C₄) Alkyl, amino, (C)₁-C₄) Alkoxy, halo (C)₁-C₄) Alkoxy and hydroxy. In thatW⁸Is C-R⁸In some embodiments, R⁸Selected from H, tert-butyl, amino and methoxy, when W⁷Is N or R⁷When it is hydrogen, R⁸Preferably a tert-butyl group.

In some embodiments of formulas II and III, when W¹Is CR⁵⁰When W is⁹Is N. In other embodiments of formulas II and III, when W¹Is NR¹When O or S is, W⁹Is C.

In some embodiments of formulas I and III, R⁹Selected from hydrogen, deuterium, hydroxy, cyano, amino, halogen, halo (C)₁-C₄) Alkyl, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy and halo (C)₁-C₄) An alkoxy group. In a preferred embodiment, when R⁷Is hydrogen and R⁸When is H, R⁹Is a tert-butyl group.

In some embodiments of formulas I and III, R¹⁰Selected from hydrogen, deuterium, halogen, (C)₁-C₃) Alkyl, perfluoro (C)₁-C₃) Alkyl, hydroxy, (C)₁-C₃) Alkoxy, perfluoro (C)₁-C₃) Alkoxy and amino, preferably H.

In some embodiments of formula II, Ar isIn other embodiments of formula II, Ar isIn other embodiments of formula II, Ar isIn other embodiments of formula II, Ar isIn other embodiments of formula II, Ar is

Examination will reveal that certain species and genera are not patentable by the inventors of the present application. In this case, the exclusion of these species and genera in the applicant's claims is intended to comply with the patent examination requirements and does not reflect the conception or description of the invention by the inventor, which includes all members of genera I, II and III that are not members of the public.

As used herein, and as will be understood by those of skill in the art, unless explicitly further limited, the term "compound" is intended to include salts of the compound. In a particular embodiment, the term "compound of formula (la)" refers to the compound or a pharmaceutically acceptable salt thereof.

The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic acid or base (including inorganic acids and bases as well as organic acids and bases). When the compounds of the present application are basic, salts can be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Suitable pharmaceutically acceptable acid addition salts for the compounds of the present application include acetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid (benzenesulfonate), benzoic acid, boric acid, butyric acid, camphoric acid, camphorsulfonic acid, carbonic acid, citric acid, ethanedisulfonic acid, ethanesulfonic acid, ethylenediaminetetraacetic acid, formic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalenesulfonic acid, nitric acid, oleic acid, pamoic acid, pantothenic acid, phosphoric acid, trimethylacetic acid, polygalacturonic acid, salicylic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, tartaric acid, teracolanic acid (Teoclatic), p-toluenesulfonic acid and the like. When the compounds contain acidic side chains, pharmaceutically acceptable base addition salts suitable for use in the compounds of the present application include, but are not limited to, metal salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, arginine, N' -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. Further, where appropriate, pharmaceutically acceptable salts include non-toxic ammonium cations and carboxylate, sulfonate and phosphonate anions attached to alkyl groups having from 1 to 20 carbon atoms.

Although it is possible for the compounds of formulae I, II and III to be administered as starting chemicals, it is preferred that they be present as pharmaceutical compositions. According to another aspect, the present application provides a pharmaceutical composition comprising a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers thereof, and optionally one or more other therapeutic ingredients. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

Formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal and topical (including dermal, buccal, sublingual and intraocular) administration. The most suitable route depends on the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the compound of formula I, II or III, or a pharmaceutically-acceptable salt thereof ("active ingredient"), with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.

Formulations suitable for oral administration herein may be presented as discrete units, such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient; a powder or granules; solutions or suspensions in aqueous or non-aqueous liquids; or an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be provided in the form of pills, suppositories, or pastes.

Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricant, surfactant or dispersing agent. Molded tablets may be prepared by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide sustained, delayed or controlled release of the active ingredient therein.

Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient. Formulations for parenteral administration also include aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. The formulations described above may be presented in unit dose in multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example physiological saline, Phosphate Buffered Saline (PBS), immediately prior to use. Emergency injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the type described previously.

It will be appreciated that the compounds of the present application may exist in radiolabeled form, i.e., the compounds may contain one or more atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Radioisotopes of hydrogen, carbon, phosphorus, fluorine and chlorine, respectively, include²H、³H、¹³C、¹⁴C、¹⁵N、³⁵S、¹⁸F and³⁶and (4) Cl. Compounds containing these radioisotopes and/or other radioisotopes of other atoms are within the scope of this application. Tritium (i.e. tritium³H) And carbon-14 (i.e.¹⁴C) It is particularly preferred because of its ease of preparation and detectability. Containing isotopes¹¹C、¹³N、¹⁵O and¹⁸the compounds of F are well suited for positron emission computed tomography. The radiolabeled compounds of formulae I, II and III herein and prodrugs thereof may generally be prepared by methods well known to those skilled in the artTo prepare the compound. Conveniently, such radiolabeled compounds may be prepared by methods disclosed in the examples and schemes below, by replacing the non-radiolabeled reagent with a readily available radiolabeled reagent.

The compounds provided herein are useful for treating neurodegenerative diseases in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of formula I, II or III.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. A complete list of abbreviations used by organic chemists (i.e., those of ordinary skill in the art) is presented inJournal of organic chemistryThe first phase of each reel. This list is typically presented in a table entitled "abbreviated standard list," which is incorporated herein by reference. If there are multiple definitions of a term recited herein, the definitions in this section prevail unless otherwise stated.

As used herein, the terms "comprises," "comprising," or any other variation thereof, are intended to cover a stated feature, integer, step, or component, but do not preclude the addition of one or more additional features, integers, steps, components, or groups thereof. The term includes the terms "consisting of … …" and "consisting essentially of … …".

As used herein, the phrase "consisting essentially of … …" or grammatical variations thereof is to be taken as specifying the stated features, integers, steps or components but does not preclude the addition of one or more additional features, integers, steps, components or groups thereof (only if the additional features, integers, steps, components or groups thereof do not materially alter the basic and novel characteristics of the claimed composition or method).

As used herein, "patient" includes humans and other animals, particularly mammals. Thus, the method is suitable for human therapy and veterinary applications. In some embodiments, the patient is a mammal, e.g., a primate. In some embodiments, the patient is a human.

Treatment may include administering a compound described herein to a patient diagnosed with a disease, and may include administering the compound to a patient without effective symptoms. Conversely, treatment may include administering the composition to a patient at risk of developing a particular disease, or to a patient suffering from one or more physiological symptoms of a disease, even though a diagnosis of the disease may not have been made.

The term "administration" with respect to a dosage form of the present application refers to the act of introducing the dosage form into the system of a subject in need of treatment. When a dosage form of the present application is administered in combination with one or more other active agents (in their respective dosage forms), "administering" and variations thereof are understood to include the simultaneous and/or sequential introduction of the dosage form and another active agent. Administration of any of the dosage forms includes parallel administration, co-administration, or sequential administration. In some cases, these treatments are performed at about the same time, e.g., within about a few seconds to several hours of each other.

A "therapeutically effective" amount of a compound described herein is generally an amount sufficient to achieve the desired effect, and may vary depending on the nature and severity of the disease condition and the potency of the compound. It will be appreciated that concentrations other than those used to treat active disease may be used for prophylaxis. Therapeutic benefit is achieved by alleviating one or more of the physiological symptoms associated with the underlying disease such that an improvement in the condition is observed despite the fact that the patient may still have the underlying disease.

Throughout the specification, the terms and substituents retain their definitions.

C₁-C₂₀Hydrocarbons include alkyl, cycloalkyl, polycycloalkyl, alkenyl, alkynyl, aryl, and combinations thereof. Examples include benzyl, phenethyl, cyclohexylmethyl, adamantyl, camphoryl, and naphthylethyl. Hydrocarbyl refers to any substituent consisting of hydrogen and carbon as the only elements. Aliphatic hydrocarbons are hydrocarbons without aromaticity; they may be saturated or unsaturated, cyclic, linear or branched. Examples of aliphatic hydrocarbons include isopropyl, 2-butenyl, 2-butynyl, cyclopentyl, norbornyl, and the like. Aromatic hydrocarbons include benzene (phenyl), naphthalene (naphthyl), anthracene, and the like.

Unless otherwise specified, alkyl (or alkylene) groups are intended to include straight or branched chain saturated hydrocarbon structures and combinations thereof. Alkyl means an alkyl group comprising from 1 to 20 carbon atoms, preferably from 1 to 10 carbon atoms, more preferably from 1 to 6 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, and the like.

Cycloalkyl groups are a subset of hydrocarbons, including cyclic hydrocarbon groups of 3 to 8 carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, norbornyl, and the like.

Unless otherwise indicated, the term "carbocyclic" is intended to include ring systems in which the ring atoms are all carbon, but do not have any oxidation state. Thus, (C)₃-C₁₀) Carbocycle refers to non-aromatic and aromatic systems, including cyclopropane, benzene, and cyclohexene; (C)₈-C₁₂) Carbocycles refer to systems such as norbornane, decalin, indene dioxide, and naphthalene. Unless otherwise defined, carbocycle refers to monocyclic, bicyclic, and polycyclic.

Heterocycle refers to an aliphatic or aromatic carbocyclic residue in which 1 to 4 carbon atoms are substituted with a heteroatom selected from the group consisting of N, O and S. The nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatoms may optionally be quaternized. Unless otherwise specified, the heterocyclic ring may be non-aromatic (heteroaliphatic) or aromatic (heteroaryl). Examples of heterocycles include pyrrolidine, pyrazole, pyrrole, indole, quinoline, isoquinoline, tetrahydroisoquinoline, benzofuran, benzodioxane, benzodioxole (commonly referred to as methylenedioxyphenyl when occurring as a substituent), tetrazole, morpholine, thiazole, pyridine, pyridazine, pyrimidine, thiophene, furan, oxazole, oxazoline, isoxazole, dioxane, tetrahydrofuran, and the like. Examples of heterocyclyl residues include piperazinyl, piperidinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, tetrahydrofuranyl, tetrahydropyranyl, thienyl (historically also referred to as thiophenyl), benzothienyl, thiomorpholinyl, oxadiazolyl, triazolyl, and tetrahydroquinolinyl.

Hydrocarbyloxy or alkoxy refers to a group having a straight or branched chain configuration of 1 to 20 carbon atoms (preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms) attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, and the like. Lower alkoxy means a group containing 1 to 4 carbons. For the purposes of this application, alkoxy and lower alkoxy include methylenedioxy and ethylenedioxy.

Oxaalkyl refers to an alkyl residue in which one or more carbons (and their associated hydrogen) have been replaced with oxygen. Examples include methoxypropoxy, 3,6, 9-trioxadecyl, and the like. The term "oxaalkyl" is understood in the art [ see nomenclature and the index of chemicals of the Chemical Abstracts published by the american Chemical society (Naming and expressing of Chemical substructures for Chemical Abstracts), 196, but not limited by 127(a) ], i.e. it refers to a compound in which oxygen is bound to its adjacent atoms by single bonds (forming ether bonds); it does not refer to double-bonded oxygen as found in carbonyl groups. Similarly, thioalkyl and azaalkyl refer to alkyl residues in which one or more carbons are substituted with sulfur or nitrogen, respectively. Examples include ethylaminoethyl and methylthiopropyl.

The term "halogen" refers to a fluorine, chlorine, bromine or iodine atom. In one embodiment, the halogen may be a fluorine or chlorine atom.

Unless otherwise specified, acyl refers to formyl, as well as straight, branched, cyclic configurations, saturated, unsaturated, and aromatic groups having 1,2, 3,4, 5, 6, 7, and 8 carbon atoms and combinations thereof attached to the parent structure through a carbonyl functionality. Examples include acetyl, benzoyl, propionyl, isobutyryl, and the like. Lower acyl refers to a group containing 1 to 4 carbons. When the double-bonded oxygen itself is referred to as a substituent, it is referred to as "oxo".

As used herein, the term "optionally substituted" may be used interchangeably with "unsubstituted or substituted". The term "substituted" refers to the replacement of one or more hydrogen atoms in a particular group with a particular group. For example, substituted alkyl, aryl, cyclicAlkyl, heterocyclyl and the like refer to alkyl, aryl, cycloalkyl or heterocyclyl groups in which one or more H atoms in each residue are substituted by: halogen, haloalkyl, alkyl, acyl, alkoxyalkyl, hydroxy lower alkyl, carbonyl, phenyl, heteroaryl, phenylsulfonyl, hydroxy, lower alkoxy, haloalkoxy, oxaalkyl, carboxy, alkoxycarbonyl [ -C (═ O) O-alkyl]Alkoxycarbonylamino [ HNC (═ O) O-alkyl]Aminocarbonyl (also known as carboxamido) [ -C (═ O) NH₂]Alkylaminocarbonyl [ -C (═ O) NH-alkyl]Cyano, acetoxy, nitro, amino, alkylamino, dialkylamino, (alkyl) (aryl) aminoalkyl, alkylaminoalkyl (including cycloalkylaminoalkyl), dialkylaminoalkyl, dialkylaminoalkoxy, heterocycloalkoxy, mercapto, alkylthio, sulfoxide, sulfone, sulfonamide, alkylsulfinyl, alkylsulfonyl, amidoalkyl, amidoalkoxy, amide, amidino, aryl, benzyl, heterocyclyl, heterocyclylalkyl, phenoxy, benzyloxy, heteroaryloxy, hydroxyimino, alkoxyimino, oxaalkyl, sulfonamide, trityl, amidino, guanidino, ureido, benzyloxyphenyl, and benzyloxy. Also included in the substituents referred to as "optionally substituted" are "oxo"; it will be appreciated by those skilled in the art that since oxo is a divalent group, there may be instances where it is not suitable as a substituent (e.g. on phenyl). In one embodiment, 1,2, or 3 hydrogen atoms are substituted with a particular group. In the case of alkyl and cycloalkyl groups, three or more hydrogen atoms may be substituted with fluorine; in fact, all available hydrogen atoms may be substituted by fluorine.

Substituent RⁿIs generally defined at the time of introduction and is to be maintained throughout the specification and all independent claims. For any and all compounds shown or claimed that may exist as tautomers, all possible tautomers are meant to be included.

Experimental part

The preparation of compounds may involve the protection and deprotection of various chemical groups. One skilled in the art can readily determine whether protection and deprotection are required and select the appropriate protecting group. Suitable groups suitable for this purpose are discussed in standard textbooks in the chemical field, for example in Organic synthetic Protecting groups (Protective Group in Organic Synthesis) by T.W.Greene and P.G.M.Wuts (John Wiley & Sons, New York, 1999), in chemical Protecting groups (Protective Group in Chemistry, 1 st edition, Oxford university Press, 2000), and in March advanced Organic Chemistry: reactions, Mechanisms and structures (March's Advanced Organic chemistry: Reactions, mechanics, and Structure, 5 th edition, Wiley-Interscience, 2001) are discussed.

The benzimidazole compound can be synthesized by any one of the following methods: i) reacting an optionally substituted 2-nitroaniline with an arylaldehyde in the presence of sodium bisulfite (D.Fokas et al, Synthesis 2005, 1, 47-56); ii) reacting the acid chloride with an optionally substituted 1, 2-phenylenediamine followed by cyclocondensation of the intermediate amide.

Method A-2-nitroaniline reacts with aromatic aldehyde to generate benzimidazole

Example 1: 2- (4- (tert-butyl) phenyl) -1H-benzo [ d ] imidazole

A solution of 2-nitroaniline (691mg, 5.00mmol) and 4-tert-butylbenzaldehyde (836. mu.L, 5.00mmol, 1.0 equiv.) in ethanol (20mL) was treated with freshly prepared aqueous 1M sodium bisulfite (15mL, 15.0mmol, 3.0 equiv.) and the mixture was heated at 70 ℃ for 14 h. The mixture was cooled to ambient temperature, quenched by the addition of 5M aqueous ammonium hydroxide (10mL), and the solid formed was collected by filtration and washed several times with water. The product was purified by ethanol-water recrystallization to give an off-white solid (739mg, 59%).¹H NMR(500MHz,DMSO-d₆):δ12.84(1H,br s),8.10(2H,d,J＝8.4Hz),7.57(4H,app d,J＝8.4Hz,overlapping br),7.21-7.17(2H,m),1.33(9H,s)；LCMS:rt 2.48-2.52min,+ve ESI m/z 250.8([M+H]⁺,100％),-ve ESI m/z 248.7(M–H]^-,100％)。

Method for preparing benzimidazole compound by performing cyclocondensation reaction of intermediate amide after reaction of B-acyl chloride and 1, 2-phenylenediamine

Example 2: 2- (4- (tert-butyl) phenyl) -1H-imidazo [4,5-c ] pyridine

To a cooled (0 ℃ C.) solution of 3, 4-diaminopyridine (437mg, 4.00mmol) and triethylamine (669. mu.L, 4.80mmol, 1.2 equivalents) in Dimethylformamide (DMF) (15mL) was added 4-tert-butylbenzoyl chloride (781. mu.L, 4.00mmol, 1.0 equivalents) in DMF (1mL) dropwise. The mixture was allowed to warm to ambient temperature and stirred for 12 hours. The mixture was slowly added to vigorously stirred ice water (240mL) and the solid formed was collected by filtration. Purification by flash chromatography (hexanes-EtOAc, 100:0 to 0:100) afforded N- (4-aminopyridin-3-yl) -4- (tert-butyl) benzamide (369mg, 34%) as a white solid.¹H NMR(500MHz,DMSO-d₆):δ9.66(1H,s),8.09(1H,s),7.89(2H,d,J＝8.4Hz),7.80(1H,d,J＝5.2Hz),7.55(2H,d,J＝8.4Hz),7.44(1H,d,J＝5.2Hz),5.17(2H,s),1.32(9H,s)；LCMS:rt 2.46-2.50min,+ve ESI m/z 269.7([M+H]⁺,100％),-ve ESI m/z 267.7(M–H]^-,100％)。

A solution of N- (4-aminopyridin-3-yl) -4- (tert-butyl) benzamide (135mg, 0.50mmol) in glacial acetic acid (5mL) was heated at 70 ℃ for 14 h. The solution was cooled to ambient temperature and poured into ethyl acetate (50 mL). The organic layer was washed with water (2X 5mL), saturated aqueous sodium bicarbonate (2X 5mL), brine (5mL) and dried (Na)₂SO₄) And the solvent was evaporated under reduced pressure. The residue was resuspended in a small amount of ethyl acetate (. about.0.5 mL) and treated with stirring by dropwise addition of hexane, the precipitate formed was filtered and dried to give 2- (4- (tert-butyl) phenyl) -1H-imidazo [4,5-c ] as a white solid]Pyridine (34mg, 27%).¹H NMR(500MHz,CD₃OD):δ8.88(1H,s),8.32(1H,d,J＝5.6Hz),8.09(2H,d,J＝8.4Hz),7.64(3H,app d,J＝8.4Hz,overlapping),1.39(9H,s)；LCMS:rt 2.41-2.45min,+ve ESI m/z 251.8([M+H]⁺,100％),-ve ESI m/z 249.7(M–H]^-,100％)。

Optionally substituted 2-aminothiophenols are reacted with acid chlorides and then heated to synthesize benzothiazole compounds.

Method for generating benzothiazole compound by reacting C-acyl chloride with 2-aminothiophenol

Example 3: 2- (4-tert-butylphenyl) -1, 3-benzothiazole

To a solution of 2-aminothiophenol (1.070mL, 10mmol) in NMP (20mL) was added 4-tert-butylbenzoyl chloride (2.930mL, 15mmol, 1.5 equiv.) dropwise and the solution was heated to 100 ℃ for 6 hours. The cooled reaction was poured into ice water (300mL) and concentrated NH was added₄The pH of the OH aqueous solution is adjusted to 9-10. The mixture was filtered and washed several times with water. Purification by flash chromatography (hexanes-EtOAc, 100:0 to 70:30) gave a white crystalline solid (1.831g, 65%).¹H NMR(500MHz,CDCl₃):δ8.07(1H,d,J＝8.1Hz),8.03(2H,d,J＝8.4Hz),7.90(1H,d,J＝8.1Hz),7.52(2H,d,J＝8.4Hz),7.49(1H,td,J＝7.8,0.8Hz),7.37(1H,td,J＝7.8,0.8Hz),1.37(9H,s)；LCMS:rt 4.58-4.62min,+ve ESI m/z 268.1([M+H]⁺,100％)。

Optionally substituted 2-aminophenol is reacted with acyl chloride and then heated to synthesize the benzoxazole compound.

Method for reacting D-acyl chloride with 2-aminophenol to generate benzoxazole

Example 4: 2- (4-tert-butylphenyl) -1, 3-benzoxazole

To a cooled (0 ℃ C.) solution of 2-aminophenol (1.091mL, 10mmol) in NMP (5mL) was added dropwise4-tert-butylbenzoyl chloride (1.953mL, 10mmol, 1.0 equiv.), then pyridine (1.011mL, 12.5mmol, 1.25 equiv.) is added and the solution is stirred at 180 ℃ for 3 hours. The reaction was poured into water-MeOH (80:20, 20mL) and the mixture was cooled to 0 ℃. The precipitated product was filtered and purified by flash chromatography (hexane-EtOAc, 100:0 to 75:25) to give a white solid (1.977g, 75%).¹H NMR(500MHz,CDCl₃):δ8.19(2H,d,J＝8.5Hz),7.79-7.75(1H,m),7.59-7.57(1H,m),7.55(2H,d,J＝8.5Hz),7.36-7.33(2H,m),1.38(9H,s)；LCMS:rt 4.38-4.42min,+ve ESI m/z 252.1([M+H]⁺,100％)。

The imidazo [1,2-a ] pyridine is synthesized by heating 2-aminopyridine and 2-bromo-1-phenylethanol-1-one in the presence of a base.

Method for producing imidazo [1,2-a ] pyridine by reacting E-2-aminopyridine with 2-bromo-1-phenylethanol-1-one

Example 5: 2- (4-tert-butylphenyl) imidazo [1,2-a ] pyridine

Pyridin-2-amine (63.8mg, 0.68mmol) and 2-bromo-1- (4-tert-butylphenyl) ethanone (0.136mL, 0.68mmol) were added to the flask and dissolved in acetonitrile (2.7mL), followed by sodium bicarbonate (114mg, 1.36 mmol). The reaction was refluxed for 1 hour and then cooled. The precipitate was removed by filtration and the filtrate was evaporated under reduced pressure. The crude product was purified by flash chromatography (50:50EtOAC: hexane) to give 2- (4-tert-butylphenyl) imidazo [1,2-a as a yellow solid]Pyridine (0.061g, 35%).¹H NMR(500MHz,CD₃OD):δ8.42(1H,d,J＝6.9Hz),8.16(1H,s),7.85(2H,d,J＝8.4Hz),7.55(1H,d,J＝9.1Hz),7.49(2H,d,J＝8.4Hz),7.32(1H,t,J＝7.9Hz),6.92(1H,t,J＝6.8Hz),1.36(9H,s)；LCMS:rt 2.51-2.55min,+ve ESI m/z 250.8([M+H]⁺,100％)。

Method for obtaining 1-alkyl-benzimidazoles by alkylation of F-benzimidazoles

The 1-alkyl-benzimidazoles are synthesized by dropwise addition of alkyl halides in the presence of sodium bicarbonate or sodium carbonate.

Example 6: 2- (4-tert-butylphenyl) -1-methyl-benzo [ d ] imidazole

A white solid.¹H NMR(500MHz,CD₃OD):δ7.73(2H,d,J＝8.4Hz),7.68(1H,d,J＝7.9Hz),7.65(2H,d,J＝8.4Hz),7.55(1H,d,J＝7.9Hz),7.35(1H,t,J＝7.8Hz),7.31(1H,t,J＝7.8Hz),3.90(3H,s),1.40(9H,s)；LCMS:rt 2.63-2.67min,+ve ESI m/z 264.8([M+H]⁺,100％)。

Table 1 shows the compound names, structures, spectral data and synthetic methods (S.M.) for examples 7-78.

TABLE 1

Benzimidazole prodrugs were synthesized by methods G and H described below.

Process for the reaction of G-halomethyl esters with halomethyl carbonates to form benzimidazole prodrugs

Benzimidazole prodrugs are prepared by heating benzimidazole and chloromethyl ester in the presence of sodium iodide and sodium carbonate in refluxing acetone; alternatively, benzimidazole prodrugs can be prepared by heating benzimidazole with methyl chloride carbonate in the presence of sodium iodide and sodium carbonate in refluxing acetone (examples 6-P to 9-P and 11-P).

In a typical procedure described below, a solution of benzimidazole (1.0mmol) in acetone (10mL) is treated with sodium carbonate (2.0-3.0 mmol), sodium iodide (1.0-1.5mmol) and optionally protected chloromethyl ester (1.0-1.5 mmol). The mixture was heated under reflux until the reaction was complete. The mixture was then filtered and the solvent was evaporated and then purified using silica gel flash chromatography. Deprotection of the product was accomplished using standard protocols known in the art (examples 10-P and 12-P).

Alternatively, treatment of benzimidazole with sodium hydride followed by addition of bromomethyl ester provided the desired prodrug (example 5-P).

Example 1-P: (2-4- (tert-butyl) phenyl) -1H-benzo [ d ] imidazol-1-yl) acetic acid methyl ester

A cooled (0 ℃) solution of 2- (4-tert-butylphenyl) -1H-benzimidazole (250mg, 1.00mmol) in DMF (5mL) was treated portionwise with sodium hydride (60% dispersed in mineral oil, 40 mg, 1.00mmol, 1.0 eq.) and stirred at ambient temperature for 1H. The mixture was cooled to 0 ℃, methyl bromide acetate (98uL, 1.00mmol, 1.0 eq) was added dropwise, and stirred at ambient temperature for 48 hours. The reaction was poured into water (100mL) and extracted with EtOAc (4X 25 mL). The combined organic layers were washed with brine (25mL) and dried (Na)₂SO₄) And the solvent was evaporated under reduced pressure. The crude residue was purified by flash chromatography on silica eluting with hexanes-EtOAc (100:0 to 60:40) to give the title compound as a white crystalline solid (108mg, 32%).¹H NMR(500MHz,CDCl₃):δ7.83-7.81(1H,m),7.80(2H,d,J＝8.4Hz),7.62-7.60(1H,m),7.57(2H,d,J＝8.4Hz),7.36-7.33(2H,m),6.18(2H,s),2.18(3H,s),1.38(9H,s).LCMS:rt 3.27-3.47min,+ve ESI m/z 322.8([M+H]⁺,100％)。

Example 2-P: (2- (4- (tert-butyl) phenyl) -1H-benzo [ d ] imidazol-1-yl) butanoic acid methyl ester

A mixture of 2- (4-tert-butylphenyl) -1H-benzimidazole (501mg, 2.00mmol), sodium carbonate (636mg, 6.00mmol, 3.0 equiv.), and sodium iodide (450mg, 3.00mmol, 1.5 equiv.) in acetone (20mL) was treated with chloromethyl butyrate (382. mu.L, 3.00mmol, 1.5 equiv.), and the mixture was heated under reflux for 24 hours. The mixture was cooled to ambient temperature, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography (hexane-EtOAc, 100:0 to 70:30) to give a waxy solid which was triturated with hexane to give a white solid (143mg, 20%)。¹H NMR(500MHz,CDCl₃):δ7.83-7.81(1H,m),7.80(2H,d,J＝8.4Hz),7.62-7.60(1H,m),7.56(2H,d,J＝8.4Hz),7.35-7.33(2H,m),6.18(2H,s),2.41(2H,t,J＝7.4Hz),1.74-1.67(2H,app.sextet,J＝7.4Hz),1.38(9H,s),0.96(3H,t,J＝7.4Hz)；LCMS:rt 3.62-3.78min,+ve ESI m/z 350.9([M+H]⁺,100％)。

Example 3-P: (2- (4- (tert-butyl) phenyl) -1H-benzo [ d ] imidazol-1-yl) isobutyric acid methyl ester

A mixture of 2- (4-tert-butylphenyl) -1H-benzimidazole (501mg, 2.00mmol), sodium carbonate (636mg, 6.00mmol, 3.0 equivalents), and sodium iodide (450mg, 3.00mmol, 1.5 equivalents) in acetone (20mL) was treated with methyl 2-methylpropionate (379. mu.L, 3.00mmol, 1.5 equivalents), and the mixture was heated at reflux for 24 hours. The mixture was cooled to ambient temperature, filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography (hexane-EtOAc, 100:0 to 70:30) to give a waxy solid, triturated with hexane to give a white solid. Example 4-P: (2- (4- (tert-butylphenyl) -1H-benzo [ d ] imidazol-1-yl) pivalic acid methyl ester

A mixture of 2- (4-tert-butylphenyl) -1H-benzimidazole (250mg, 1.00mmol), sodium carbonate (159mg, 1.50mmol, 1.5 equivalents), and sodium iodide (165mg, 1.10mmol, 1.1 equivalents) in acetone (10mL) was treated with chloromethyl pivalate (159. mu.L, 1.10mmol, 1.1 equivalents), and the mixture was heated at reflux for 24 hours. The mixture was cooled to ambient temperature, filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography (hexanes-EtOAc, 100:0 to 70:30) to give a white solid (41mg, 11%). LCMS rt 3.87-3.91min, + ve ESI M/z 364.9([ M + H)]⁺,100％)。

Example 5-P: tert-butyl ((2- (4- (tert-butyl) phenyl) -1H-benzo [ d ] imidazol-1-yl) methyl) succinate

A mixture of 2- (4-tert-butylphenyl) -1H-benzimidazole (1001mg, 4.00mmol), sodium carbonate (848mg, 8.00mmol, 2.0 equiv.) and sodium iodide (660mg, 4.40mmol, 1.1 equiv.) in acetone (40mL) was treated with tert-butylchloromethylsuccinate (ClCH)₂OC(＝O)CH₂CH₂C(＝O)OC(CH₃)₃) (980mg, 4.40mmol, 1.1 equiv.) and the mixture heated to reflux for 48 h. The mixture was cooled to ambient temperature, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography (hexanes-EtOAc, 100:0 to 70:30) to give a waxy solid, triturated with hexanes to give a white solid (487mg, 28%).¹H NMR(500MHz,CDCl₃):δ7.83-7.80(3H,m,overlapping),7.61-7.59(1H,m),7.57(2H,d,J＝8.4Hz),7.35-7.33(2H,m),6.20(2H,s),2.69(2H,t,J＝6.5Hz),2.60(2H,t,J＝6.5Hz),1.41(9H,s),1.38(9H,s)；LCMS:rt 3.80-3.90min,+ve ESI m/z 437.1([M+H]⁺,100％)。

Example 6-P: 4- ((2- (4- (tert-butyl) phenyl) -1H-benzo [ d ] imidazol-1-yl) methoxy) -4-oxobutanoic acid

Tert-butyl ((2- (4- (tert-butyl) phenyl) -1H-benzo [ d) in dichloromethane (0.5mL)]Imidazol-1-yl) methyl) succinate (example 9-P, 87mg, 0.200mmol) was treated with trifluoroacetic acid (0.5mL) and the solution was stirred at ambient temperature for 4 hours. The solution was evaporated under reduced pressure and dried under high vacuum to give a white crystalline solid (70mg, 92%).¹H NMR(500MHz,CDCl₃):δ8.02(1H,m),7.92(2H,d,J＝8.1Hz),7.86-7.84(1H,m),7.71(2H,d,J＝8.1Hz),7.61-7.60(2H,m),6.32(2H,s),6.01(1H,br s),2.73(4H,s),1.39(9H,s).LCMS:rt 2.90-2.94min,+ve ESI m/z 380.9([M+H]⁺,100％)。

Example 7-P: (2- (4- (tert-butyl) phenyl) -1H-benzo [ d ] imidazol-1-yl) methyl 4- (((tert-butoxycarbonyl) amino) methyl) benzoate

A mixture of 2- (4-tert-butylphenyl) -1H-benzimidazole (1001mg, 4.00mmol), sodium carbonate (1272mg, 12.00mmol, 3.0 equiv.) and sodium iodide (660mg, 4.40mmol, 1.1 equiv.) in acetone (40mL) was treated with 4- (((tert-butoxycarbonyl) amino) methyl) benzoate (1319mg, 4.40mmol, 1.1 equiv.), and the mixture was heated under reflux for 48 hours. The mixture was cooled to ambient temperature, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography (hexanes-EtOAc, 100:0 to 70:30) to give a white solid (532mg, 26%).¹H NMR(500MHz,CDCl₃):δ8.04(2H,d,J＝8.3Hz),7.87-7.83(3H,m,overlapping),7.68-7.66(1H,m),7.58(2H,d,J＝8.3Hz),7.39-7.34(4H,m,overlapping),6.43(2H,s),4.93(1H,br s),4.38(2H,d,J＝5.2Hz),1.46(9H,s),1.38(9H,s)；LCMS:rt 3.88-3.92min,+ve ESI m/z 514.1([M+H]⁺,100％)。

Example 8-P: (4- (((2- (4- (tert-butyl) phenyl) -1H-benzo [ d ] imidazol-1-yl) methoxy) carbonyl) -phenyl) methylamine hydrochloride

(2- (4- (tert-butyl) phenyl) -1H-benzo [ d ] in ethyl acetate (13.5mL)]A solution of imidazol-1-yl) methyl 4- (((tert-butoxycarbonyl) amino) methyl) benzoate (462mg, 0.90mmol) was treated with a solution of 2.5M hydrogen chloride in ethanol (3.6mL, 9.00mmol, 10.0 equiv.) and the solution was stirred at ambient temperature for 24 h. The solution was evaporated under reduced pressure and dried under vacuum. The obtained solid was recrystallized from methanol-ether to give fine white needles (337mg, 93%).¹H NMR(500MHz,CD₃OD):δ8.24-8.22(1H,m),8.14(2H,d,J＝8.3Hz),8.01-7.99(2H,m),7.90-7.87(3H,m),7.76-7.70(2H,m),7.63-7.60(2H,m),6.69(2H,s),4.21(2H,s),1.45(9H,s).LCMS:rt 2.66-2.70min,+ve ESI m/z 414.0([M+H]⁺,20％)。

Process for the preparation of benzimidazole prodrugs by reaction of H-with dialkyl chloromethyl phosphates

Benzimidazole prodrugs are prepared by treating benzimidazole with an excess of sodium hydride, followed by treatment with dialkyl chloromethyl phosphate. In the case of di-tert-butyl chloromethyl phosphate, the resulting product can be subjected to acid-mediated hydrolysis to obtain the dihydrogen phosphate prodrug. The method was adjusted according to the methods reported by Chassaing et al (J Med chem.2008,51,1111) and Flores-Ramos et al (Bioorg Med Chem Lett.2014,24,5814).

Example 9-P: di-tert-butyl ((2- (4- (tert-butyl) phenyl) -1H-benzo [ d ] imidazol-1-yl) methyl) phosphate

To a cooled (0 ℃) solution of 2- (4-tert-butylphenyl) -1H-benzimidazole (2.00g, 8.00mmol) in DMF (35mL) was added sodium hydride (60% oil dispersion, 1.12g, 28.0mmol, 3.5 eq.) in portions, and the mixture was stirred at ambient temperature for 1H. The mixture was cooled (0 deg.C), a solution of di-tert-butyl chloromethyl phosphate (2.41mL, 10.4mmol, 1.3 equiv.) in DMF (5mL) was added dropwise, and stirred at ambient temperature for 12 h. The mixture was cooled (0 ℃ C.), diluted with DCM (150mL) and carefully added dropwise and then treated with water (50mL) in portions. The layers were separated and the organic layer was washed with water (3X 50mL), brine (2X 50mL) and dried (Na)₂SO₄) And the solvent was evaporated. The crude product was purified by flash chromatography on silica gel (hexane-EtOAc, 100:0 to 50:50) and the resulting oil crystallized at-20 ℃ overnight. The crystalline material was triturated with hexane (3X 10mL) to give a white solid (2.54g, 64%).¹H NMR(500MHz,CDCl₃):δ7.87(2H,d,J＝8.4Hz),7.82-7.80(1H,m),7.76-7.74(1H,m),7.56(2H,d,J＝8.4Hz),7.36-7.32(2H,m),6.00(2H,d,J＝8.2Hz),1.43(18H,s),1.38(9H,s)；LCMS:rt 3.7-3.8min,+ve ESI m/z 473.0([M+H]⁺,100％)。

Example 10-P: dihydro ((2- (4- (tert-butyl) phenyl) -1H-benzo [ d ] imidazol-1-yl) methyl) phosphate

To a di-tert-butyl group ((2- (4- (tert-butyl) phenyl) -1H-benzo [ d) in 1, 4-dioxane (0.5mL) at room temperature]Imidazol-1-yl) methyl) phosphate (118mg, 0.25mmol) was added dropwise to a solution of 4M hydrogen chloride in 1, 4-dioxane (0.5mL), and the mixture was stirred for 20 hours. The reaction mixture was diluted with 1, 4-dioxane (0.5mL) and the precipitate was filtered, washed with cold dioxane (1.0mL), cold diethyl ether (1.0mL) and dried under high vacuum to give white crystals (69mg, 73%).¹H NMR(500MHz,DMSO-d₆):δ8.04(1H,d,J＝7.9Hz),7.96(2H,d,J＝8.4Hz),7.87(1H,d,J＝7.9Hz),7.76(2H,d,J＝8.4Hz),7.62-7.56(2H,m),6.05(2H,d,J＝9.0Hz),1.37(9H,s)；LCMS:rt 2.1-2.2min,+ve ESI m/z 360.8([M+H]⁺,100％),-ve ESI m/z 358.7([M-H]^-,100％)。

Example 11-P: ((2- (4- (tert-butyl) phenyl) -1H-benzo [ d ] imidazol-1-yl) methyl ] methyl) phosphate disodium salt

To ((2- (4- (tert-butyl) phenyl) -1H-benzo [ d) in methanol (5mL) at ambient temperature]Imidazol-1-yl) methyl) dihydrogen phosphate suspension (180mg, 0.500mmol) was added dropwise to a 0.5M solution of sodium methoxide (2mL, 1.00mmol, 2.0 equiv.) in methanol. The resulting clear solution was evaporated under reduced pressure and dried under high vacuum to give a white solid (196mg, 96%).¹H NMR(500MHz,D₂O):δ7.92-7.89(3H,m,overlapping),7.79-7.77(3H,m,overlapping),7.50(1H,t,J＝7.5Hz),7.46(1H,t,J＝7.5Hz),5.88(2H,d,J＝4.3Hz),1.40(9H,s)；LCMS:rt 2.06-2.10min,+ve ESI m/z 360.8([M+H]⁺,100％),-ve ESI m/z 358.7([M-H]^-,100％)。

Other prodrug derivatives were synthesized as shown below. Examples of carbamates are typically formed by treating benzimidazole precursors with the appropriate chloroformate in pyridine/dichloromethane.

Example 12-P: (2- (4- (tert-butyl) phenyl) -1H-benzo [ d ] imidazol-1-yl) methyl (tert-butoxycarbonyl) -L-alanine ester

Example 13-P: 2- (4- (tert-butyl) phenyl) -1H-benzo [ d ] imidazole-1-carboxylic acid ethyl ester

Example 14-P: 2- (4- (tert-butyl) phenyl) -1H-benzo [ d ] imidazole-1-carboxylic acid methyl ester

Example 15-P: 2- (4- (tert-butyl) phenyl) -1H-benzo [ d ] imidazole-1-carboxylic acid ethyl ester

Example 16-P: 2- (4- (tert-butyl) phenyl) -1H-benzo [ d ] imidazole-1-carboxylic acid propyl ester

Example 17-P: 1- (2- (4- (tert-butyl) phenyl) -1H-benzo [ d ] imidazol-1-yl) ethan-1-one

Biological assay

Oxidative metabolism exerts an anti-inflammatory effect on myeloid cell phenotype (O' Neill LA, Front immunol.2014), Ppargc1a may promote this energy metabolism pathway (Spiegelman BM, Novartis Found symp.2007). Thus, pharmacological activation of Ppargc1a would be expected to suppress the inflammatory response of bone marrow cells. This phenomenon can be measured in culture by the TNF- α inhibition assay.

Cell assay method for measuring TNF-alpha inhibition

Murine bone marrow cells BV2 or human Peripheral Blood Mononuclear Cells (PBMC) were cultured in RPMI 1640 medium (Cat #11875119, Gibco) supplemented with 10% fetal bovine serum and 1% L-glutamine 1% penicillin. These cells were then stimulated with 100ng/ml lipopolysaccharide (LPS, O111: B4, Cat # L2630, Sigma) over 24 hours. LPS stimulation resulted in secretion of the inflammatory cytokine TNF-. alpha.by BV2 cells or PBMC, which was quantitated by ELISA according to the manufacturer's protocol (Cat #558273 for BV2 and Cat #558299 for PBMC, BD biosciences). To determine whether exemplary compounds 1-78 inhibited TNF- α production by BV2 cells or PBMCs, cells were cultured in the presence of different concentrations of the compounds and the rate of decrease in TNF- α production relative to TNF- α production in the same cells cultured in the presence of dimethyl sulfoxide (as a vehicle control) was determined. The results are shown in Table 2.

TABLE 2 TNF-inhibition

Microsomal stability and Caco-2 permeability assays were performed on selected compounds of the present application.

Microsome stability test method

Human liver microsomes (Corning #452117 batch 38291) or mouse liver microsomes (Corning #452701 batch 6328004) were combined with KxPO at a final concentration of 11.25mg protein/compound, respectively₄ pH 7.4(100mM)、MgCl₂(10mM) and test compound (1. mu.M) were mixed and pre-incubated (10 min, 37 ℃). Next, NADPH (1mM) was addedTo start the reaction (total volume 100. mu.L). At each time point (0, 10, 20 and 40 min), the reaction was quenched with a solution of Clem in acetonitrile (100. mu.L, 625ng/mL) (Cyprotex). The samples were centrifuged at 4000g for 20 min, diluted (75. mu.L in 75. mu.L of 0.1% aqueous formic acid) and analyzed by LC-MS/MS. The results are shown in Table 3.

Caco-2 permeability test method

Caco-2 cells were maintained at 5% CO₂DMEM under gas. For the transportation experiments, 5X 10⁵Cells/well cells were seeded on a polycarbonate filter pad and allowed to grow and differentiate for 21 ± 4 days before cell monolayers were used for experiments. The apparent permeability coefficients in the a → B and B → a directions were determined with and without the presence of elacridar as transporter inhibitor. Up to three test items and reference compounds were dissolved in Hank's balanced salt solution at pH 7.4 to a final concentration of 10 μ M. The assay was performed in HBSS containing 25mM HEPES (pH 7.4) at 37 ℃. Prior to the study, monolayer cells were washed in pre-warmed HBSS. At the start of the experiment, pre-heated HBSS containing the test item was added to the donor side of the monolayer, and HBSS without test item was added to the receiver side. Remove receiver-side aliquots over a 2 hour incubation period; aliquots of the donor side were taken at 0 and 2 hours. Aliquots were diluted with equal volumes of methanol/water and 0.1% formic acid containing the internal standard. The mixture was analyzed by LC-MS/MS. The apparent permeability coefficient (Papp) was calculated using the following formula: p_app＝(dC_rec/dt)/(A×C_0,donor)]X 106, wherein dC_revDt is the change in concentration in the receiver compartment with time, C_0,donorConcentration in the donor compartment at 0, and A is the area of cells in the compartment. The results are shown in Table 3.

TABLE 3 microsomal stability and Caco-2 Permeability

Pharmacokinetic studies (in mice) were performed on the compounds of examples 1, 6-P, 8-P and 11-P of the present application. The dose of the compounds of examples 1, 6-P, 8-P and 11-P in mice was 10mg/kgp.o. (n-2). Plasma, brain tissue and liver sampling was performed at 0.5 hours, 1 hour, 2 hours and 4 hours. Samples were analyzed by LCMS to determine the level of the compound of example 1, the Active Pharmaceutical Ingredient (API) of prodrugs examples 6-P, 8-P and 11-P.

Figure 1 shows plasma API levels of prodrug examples 6-P, 8-P and 11-P.

Figure 2 shows brain tissue API levels for prodrug examples 6-P, 8-P and 11-P.

Figure 3 shows the liver API levels of prodrug examples 6-P, 8-P and 11-P.

In general, figures 1-3 show that prodrug examples 6-P, 8-P, and 11-P result in measurable API content in plasma, brain tissue, and liver in mouse PK studies.

While typical embodiments have been set forth for the purpose of illustration, the foregoing descriptions and examples should not be deemed to be a limitation on the scope of the application. Accordingly, various modifications, adaptations, and alternatives may occur to one skilled in the art without departing from the spirit and scope herein.

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