TW201335149A - Methods for treating diseases of the retina - Google Patents

Abstract

Disclosed herein is a method of treating disorders of the retina comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of Formula I as defined herein. These compounds are useful as PDE10 inhibitors.

Description

Method for treating retinal diseases Reference related application

This application claims US Provisional Application Serial No. 61/444,587 filed on February 18, 2011, 61/482,106 submitted on May 3, 2011, and 61/444,602, and May 2011, submitted on February 18, 2011. The benefit of 61/482,097, filed on Jan. 3, which is incorporated herein in its entirety by reference.

The present invention relates to the use of aromatic heterocyclic compounds which are potent phosphodiesterase (PDE) inhibitors, in particular, selective PDE10 inhibitors for the treatment of retinal diseases.

Summary of invention

The invention provides a method for treating a condition of the retina comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula I

Or a pharmaceutically acceptable salt thereof, wherein: Z is

R ^{1 is} each independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, C ₁ to C ₈ alkyl, C ₂ to C ₈ alkenyl, C ₂ to C ₈ alkynyl, C ₁ to C ₈ alkoxy, C ₁ to C ₈ haloalkyl, C ₃ to C ₈ cycloalkyl, C ₃ to C ₈ cycloalkyl-C ₁ to C ₈ alkyl, 4 to 7-membered heterocycloalkyl, C ₁ to C ₈ thio An alkyl group, NR ³ R ³ , -O-CF ₃ , -S(O) _n -R ³ , C(O)-NR ³ R ³ , and a C ₁ to C ₈ alkyl group substituted with a hetero atom, wherein The hetero atom is selected from the group consisting of nitrogen, oxygen and sulfur, and wherein the hetero atom may be further selected from the group consisting of hydrogen, C ₁ to C ₈ alkyl, C ₃ to C ₈ cycloalkyl, C ₂ to C ₈ alkenyl, C ₂ to Substituted with a C ₈ alkynyl group and a C ₁ to C ₈ haloalkyl group; R ^{3 is} each independently selected from hydrogen, C ₁ to C ₈ alkyl, C ₂ to C ₈ alkenyl, C ₂ to C ₈ alkyne a C ₁ to C ₈ haloalkyl group, and a C ₃ to C ₈ cycloalkyl group; R ^{2 is} selected from the group consisting of hydrogen, C ₁ to C ₈ alkyl, C ₃ to C ₈ cycloalkyl-C ₁ to C ₈ alkyl a C ₂ to C ₈ alkenyl group, a C ₂ to C ₈ alkynyl group, a C ₁ to C ₈ haloalkyl group, and a C ₃ to C ₈ cycloalkyl group; HET ^{1 is} selected from the group consisting of a monocyclic heteroaryl group and a bicyclic heteroaryl group. group, wherein the monocyclic and bicyclic heteroaryl may be optionally substituted by at least one R ^4; R ⁴ is selected from Halogen, hydroxy, cyano, _{C. 1} to C ₈ alkyl, C ₂ to C ₈ alkenyl group, C ₂ to C ₈ alkynyl groups, C ₁ to C ₈ alkoxy, C ₃ to C ₈ cycloalkyl, C _{a 3-} to C ₈ cycloalkyl-C ₁ to C ₈ alkyl group, a C ₁ to C ₈ thioalkyl group, and a substituent selected from the group consisting of -OR ⁸ , -NR ⁸ R ⁸ , and -SR ⁸ a C ₁ to C ₈ alkyl group, wherein R ^{8 is} independently selected from hydrogen and a C ₁ to C ₈ alkyl group; and HET ² is a monocyclic or bicyclic heteroaryl group, wherein under the condition that HET ² is not tetrazole, Monocyclic and bicyclic heteroaryl are optionally substituted by at least one R ⁵ ; R ^{5 is} independently selected from halo, hydroxy, cyano, C ₁ to C ₈ alkyl, C ₂ to C ₈ alkenyl, C ₂ To C ₈ alkynyl, C ₁ to C ₈ alkoxy, C ₃ to C ₈ cycloalkyl, C ₃ to C ₈ cycloalkyl-C ₁ to C ₈ alkyl, C ₁ to C ₈ thioalkyl , -NR ⁷ R ⁷ , and C ₁ to C ₈ haloalkyl; B ¹ and B ² are adjacent atoms in Het ¹ , which are independently selected from carbon and nitrogen; and the bond j is between Z and B ² a valence bond; the bond k is a covalent bond between B ¹ and B ² in Het ¹ ; X and X ¹ are each independently selected from the group consisting of oxygen, sulfur, C(R ₂ ) ₂ and NR ₂ , with the proviso that X or X ¹ At least one of them is carbon; Y is selected from carbon and nitrogen, provided that Y is Carbon, which is used to replace R ^6; wherein R ⁶ is independently selected from hydrogen, halogen, hydroxy, cyano, C ₁ to C ₈ alkyl, C ₂ to C ₈ alkenyl group, C ₂ to C ₈ alkynyl , C ₁ to C ₈ alkoxy, C ₁ to C ₈ cycloalkyl, C ₃ to C ₈ cycloalkyl-C ₁ to C ₈ alkyl, C ₁ to C ₈ thioalkyl, C ₁ to C _8- haloalkyl, -NR ⁷ R ⁷ , -O-CF ₃ , -S(O) _m -R ⁷ , C(O)-NR ⁷ R ⁷ , and a C ₁ to C ₈ alkyl group substituted with a hetero atom, Wherein the hetero atom is selected from the group consisting of nitrogen, oxygen and sulfur, and wherein the hetero atom may be further selected from the group consisting of hydrogen, C ₁ to C ₈ alkyl, C ₃ to C ₈ cycloalkyl, C ₂ to C ₈ alkenyl, C Substituted with a substituent of ₂ to C ₈ alkynyl and C ₁ to C ₈ haloalkyl; and wherein R ⁷ are each independently selected from hydrogen and C ₁ to C ₈ alkyl; p is 1, 2 or 3, n is 0, 1 or 2; and m is 0, 1 or 2.

Retinal disease

The compounds of the invention may be used to treat diseases of the retina. By "lesion of the retina", the present application means any condition of the retina that impairs the normal function of the retina, the tissue surrounding it, or the eye. These include macular degeneration, approximate retinal degeneration, diabetic retinopathy, choroidal neovascularization, macular edema (also known as cystoid macular edema and macular swelling), preretinal membrane (macular wrinkles), macular hole, retinitis ( For example, retinitis pigmentosa, macular dystrophy (such as Stargard's adolescent macular degeneration, Best's yolk dystrophy, pyramidal dystrophy, and graphic malnutrition of the retinal pigment epithelium (pattern Dystrophy)), retinal detachment, retinal trauma, retinal neoplasms and their associated retinal diseases, congenital hypertrophy of the retinal pigment epithelium, acute posterior multifocal squamous pigment epithelial lesions, acute retinal pigment epitheliitis, and uveitis ( Includes iritis, flattened ciliary body inflammation, choroiditis, retinitis, and chorioretinitis.

Among Americans 50 years of age or older, macular degeneration (also known as age-related macular degeneration) is the most common cause of vision loss and is becoming more common with age. AMD can be divided into wet (new blood vessels) or dry (non-new blood vessels). The most common is the dry form of the disease. When the central retina becomes distorted, pigmented, or most commonly thinned, the disease occurs in association with atrophy of omental pigment epithelial cells and loss of macular photoreceptors. The result is a central geographic atrophy. The wet form of macular degeneration causes the most severe loss of vision. The wet form of macular degeneration is generally associated with aging, but other diseases that cause wet macular degeneration include severe myopia and some intraocular infections such as histoplasmosis, which can be exacerbated in individuals with AIDS. The wet form is characterized by abnormal blood vessels that grow through the retinal pigment epithelial cells, which results in bleeding, exudation, scarring or retinal detachment.

Retinopathy associated with diabetes is the leading cause of blindness in type 1 diabetes and is also common in type 2 diabetes. The extent of retinopathy depends on the duration of diabetes and usually begins 10 years or more after the onset of diabetes. Diabetic retinopathy can be divided into (1) non-proliferative or background retinopathy characterized by capillary permeability, edema, hemorrhage, small aneurysms, and an increase in exudate; or (2) proliferative retinopathy, It is characterized by the potential for extending neovascularization, scarring, fibrous tissue formation, and retinal detachment from the retina to the vitreous. It is believed that diabetic retinopathy is caused, at least in part, by the development of glycosylated proteins caused by hyperglycemia. Glycosylated proteins produce free radicals that result in oxidative tissue damage and depletion of cellular reactive oxygen species (ROS) scavengers such as glutathione.

In the choroidal neovascular membrane, abnormal blood vessels originating from the choroid grow through the retinal layer. The fragile new blood vessel is easily broken, causing blood or body fluids to accumulate in the retinal layer.

In macular edema, it can occur as a disease, injury or after surgery, and body fluids are accumulated in the macular layer, causing blurring and distortion of the central vision.

The anterior membrane of the retina is a cellophane-form formed on the macula (cellophane- Like membrane), which affects central vision by causing turbidity and distortion. As it progresses, the contraction of the membrane on the macula can cause swelling. The disease is most common in people over the age of 75.

Retinitis pigmentosa is a retinal degeneration characterized by nighttime blindness and gradual loss of peripheral vision, which ultimately leads to complete blindness; ophthalmoscopic changes include dark mosaic-like retinal pigmentation, retinal vascular thinning, optic disc wax Pale pale, and in advanced forms, macular degeneration. In some cases, pigmentation can be lacking. Retinitis pigmentosa can be associated with degenerative opacity of the vitreous and cataract.

Macular dystrophy is a term applied to heterogeneous groups of diseases that are common causes of visual loss in many people. A common feature of macular dystrophy is the gradual loss of central vision caused by the degeneration of photoreceptor cells in the macula. In many forms of macular dystrophy, the final stage of the disease leads to legal blindness. More than 20 types of macular dystrophy are known. Some of these are, for example, age-related macular dystrophy, Stargardt-like dominant macular dystrophy, recessive stagart's disease, atypical yolk-like macula Malnutrition (VMDI), Usher Syndrome Type 1B, autosomal neovascular inflammatory vitreoretinopathy, familial exudative vitreoretinopathy, and Best Yolk-like dystrophy (VMD2).

Stargard-like dominant macular dystrophy (also known as autosomal dominant) Autosomal dominant macular atrophy is adolescent macular degeneration. Patients with this disease usually have normal vision in young children, but in childhood, vision loss begins, and it rapidly develops to legal blindness. It is clinically characterized by atrophic macular degeneration with sharp boundaries and is usually associated with yellow fundus spots.

Boster's macular dystrophy is a hereditary autosomal dominant macular dystrophy of unknown biochemical causes. The disease has an age of onset from childhood to 40 years of age. Early clinical symptoms include abnormal aggregation of the yellow substance lipofuscin in the sub-macular retinal pigment epithelium (RPE). This results in a gradual loss of the characteristic "yolk" appearance and visual acuity of the RPE. With age, RPE becomes more and more disordered due to aggregation and dispersal of lipofuscin and scarring and neovascularization. These changes are accompanied by further loss of vision.

The pathological features observed in Stargard-like dominant macular dystrophy and Beste's macular dystrophy are similar in many ways to age-related macular dystrophy (AMD) (in elderly patients in developed areas) The characteristics observed in the primary cause of blindness.

Retinal detachment occurs when the sensory layers of the retina are separated from their retinal pigment epithelial cells and supporting tissues under the choroid. Typically, retinal detachment is caused by the appearance of retinal tears or vitreous contractions, either of which may occur simultaneously or by trauma. Retinal detachment can also be caused by pathology, such as retinopathy of premature birth in premature infants or retinopathy of diabetes in individuals with diabetes. Symptoms of retinal detachment are painless and sudden or partial loss of vision in one eye. When there is Upon tearing, or when there is a contraction that causes the retina to separate from the underlying structure, the liquid vitreous passes through the opening and then into the subretinal space, resulting in further exudation in the subretinal space. The retina gradually separates and separates from the underlying retinal pigment epithelial cells. This causes the outer retina to lose its normal supply of oxygen and nutrients from the choroid. Over time, retinal detachment can also result in loss of vision due to damage to photoreceptor cells located outside the retina.

By "treatment," the application means the use of medical treatment. The term encompasses administration of a compound of the invention to alleviate the symptoms of retinal diseases (e.g., a decrease in visual acuity associated with macular degeneration), and thereby to address pathological changes associated with the disease (e.g., abnormal blood vessel growth associated with the condition).

Compound of the invention

As set forth in the Summary of the Invention, the invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of a retinal disorder.

In another embodiment of the invention, in Formula I, HET ¹ is a 5-membered heteroaryl.

In another embodiment of the invention, in Formula I, HET ^{1 is} selected from the group consisting of pyrazole, isoxazole, triazole, oxazole, thiazole, and imidazole.

In another embodiment of the invention, in Formula I, HET ^{2 is} selected from the group consisting of 4-pyridyl, 4-pyridazine, and isoxazole.

In another embodiment of the invention, in Formula I, HET ² is 4-pyridyl.

In another embodiment, in Formula I, the compound is selected from the group consisting of

Or a pharmaceutically acceptable salt thereof, wherein j, k, Z HET ² and R ⁴ are as defined above in formula I.

In another embodiment, the compound of Formula I has the structure:

Or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula I has the structure:

Or a pharmaceutically acceptable salt thereof.

In another embodiment of the method of the present invention, in Formula I, Y is selected from the group consisting of carbon and nitrogen, with the proviso that no more than one Y is nitrogen.

In another embodiment of the present invention, in formula I, X ¹ is carbon, and X is oxygen.

In another embodiment of the invention, all Y are carbon (ie, the heteroaryl is quinoline).

In another embodiment, in Formula I, HET ¹ is not a tetrazole.

In another embodiment, the compound of formula I is selected from the group consisting of: 2-[-4-(4-pyridin-4-yl-2H-pyrazol-3-yl)-phenoxymethyl]-quinoline; -[4-(2-methyl-4-pyridin-4-yl-2H-pyrazol-3-yl)-phenoxymethyl]-quinoline; 2-[4-(1-methyl-4- Pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl 1-quinoline; 2-[4-(2-ethyl-4-pyridin-4-yl-2H-pyrazole-3 -yl)-phenoxymethyl]-quinoline; 2-[4-(1-ethyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline ; dimethyl-(2-{4-pyridin-4-yl-3-[4-(quinolin-2-ylmethoxy)-phenyl]-pyrazol-1-yl}-ethyl)- Amine; dimethyl-(2-{4-pyridin-4-yl-5-[4-(quinolin-2-ylmethoxy)-phenyl]-pyrazol-1-yl}-ethyl) -amine; 1-{4-pyridin-4-yl-3-[4-(quinolin-2-ylmethoxy)-phenyl]-pyrazol-1-yl}-propan-2-ol; -{4-pyridin-4-yl-5-[4-(quinolin-2-ylmethoxy)-phenyl]-pyrazol-1-yl}-propan-2-ol; 2-[4- (2-isopropyl-4-pyridin-4-yl- 2H -pyrazol-3-yl)-phenoxymethyl]-quinoline; 2-[4-(4-pyridin-4-yl-iso Oxazol-5-yl)-phenoxymethyl]-quinoline; 2-[4-(5-pyridin-4-yl-pyrimidin-4-yl)-phenoxymethyl]-quinoline; 2-[ 4-(2-methyl-5-pyridin-4-yl-pyrimidin-4-yl)-phenoxymethyl]-quin ;2-[4-(2-methyl-6-pyridin-4-yl-pyrazolo[1,5-a]pyrimidin-7-yl)-phenoxymethyl]-quinoline; 2-[4 -(2-methyl-6-pyridin-4-yl-[1,2,4]triazolo[1.5-a]pyrimidin-7-yl)-phenoxymethyl]-quinoline; 2-[4 -(4-pyridazin-4-yl-2H-pyrazol-3-yl)-phenoxymethyl]-quinoline; 2-[4-(1-methyl-4-pyridazin-4-yl- 1 H -pyrazol-3-yl)-phenoxymethyl]-quinoline; 2-[4-(2-methyl-4-pyridazin-4-yl- 2H -pyrazol-3-yl) -phenoxymethyl]-quinoline; 2-[-4-(4-pyrimidin-4-yl-2H-pyrazol-3-yl)-phenoxymethyl]-quinoline; 2-[4-(4 -pyridazin-3-yl-2H-pyrazol-3-yl)-phenoxymethyl]-quinoline; 2-{4-[4-(3-methyl-isoxazol-5-yl)- 2H-pyrazol-3-yl]-phenoxymethyl}-quinoline; 2-{4-[2-methyl-4-(3-methyl-isoxazol-5-yl)-2 H - Pyrazol-3-yl]-phenoxymethyl}-quinoline; 2-{4-[1-methyl-4-(3-methyl-isoxazol-5-yl)-1 H -pyrazole 3-yl]-phenoxymethyl}-quinoline 2-{4-[2-methyl-5-(3-methyl-isoxazol-5-yl)-pyrimidin-4-yl]-benzene Oxymethyl}-quinoline; 2-[4-(2-pyridin-4-yl-2H-pyrazol-3-yl)-phenoxymethyl]-quinoline; 2-[4-(3-A 5-[pyridin-4-yl[1,2,4]triazol-4-yl)-phenoxymethyl]-quinoline; 2-[4-(1-methyl-4-pyridine-4- yl -1 H - Zyrid-3-yl)-phenoxymethyl]-quinoline; 7-chloro-2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-benzene Oxymethyl]-quinoline hydrochloride; 6-fluoro-2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]- Quinoline hydrochloride; 2-[2-fluoro-4-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline; 2-[2-fluoro- 4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline; 2-[2,3-difluoro-4-(1- Methyl-4-pyridin-4}-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline; 2-[3-fluoro-4-(4-pyridin-4-yl-1H -pyrazol-3-yl)-phenoxymethyl]-quinoline; 2-[4-(5-pyridin-4-yl-1H-pyrazol-4-yl)-phenoxymethyl]-quinoline ;2-[4-(1-methyl-5-pyridin-4-yl-1H-pyrazol-4-yl)-phenoxymethyl]-quinoline; 2-[4-(methyl-3- Pyridin-4-yl-1H-pyrazol-4-yl)-phenoxymethyl]-quinoline; 2-methyl-1-{4-pyridin-4-yl-3-[4-(quinoline- 2-ylmethoxy)-phenyl]-pyrazol-1-yl}-propan-2-ol; 2-methyl-1-{4-pyridin-4-yl-5-[4-(quinoline -2-ylmethoxy)-phenyl]-pyrazol-1-yl}-propan-2-ol; (R)-1-{4-pyridin-4-yl-3-[4-(quinoline -2-ylmethoxy)-phenyl]-pyrazol-1-yl}-propan-2-ol; (S)-1-{4-pyridin-4-yl-3-[4-(quinoline -2- Methoxy)-phenyl]-pyrazol-1-yl}-propan-2-ol; 2-[4-(1-isopropyl-4-pyridin-4-yl-1H-pyrazole-3- Benzyloxymethyl]-quinoline; 2-[4-(1-isobutyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline ;2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-[1.8]diazepine; 2-{2-[4 -(4-pyridin-4-yl-2H-pyrazol-3-yl)-phenyl]-ethyl}-quinoline; 2-{2-[4-(1-methyl-4-pyridine-4 -yl-1H-pyrazol-3-yl)-phenyl]-ethyl}-quinoline; 2-{4-[4-(2-chloro-pyridin-4-yl)-1H-pyrazole-3 -yl]-phenoxymethyl}-quinoline; 2-{4-[4-(2-chloro-pyridin-4-yl)-1-methyl-1H-pyrazol-3-yl]-phenoxy Methyl}-quinoline; 2-{4-[1-methyl-4-(2-methyl-pyridin-4-yl)-1H-pyrazol-3-yl]-phenoxymethyl}-quin Phenanthine; dimethyl-(4-{1-methyl-3-[4-(quinolin-2-ylmethoxy)-phenyl]-1H-pyrazol-4-yl}-pyridine-2- Base;-amine; 2-[4-(5-pyridin-4-yl-pyrazol-1-yl)-phenoxymethyl]-quinoline; 2-[4-(3-methyl-5-pyridine 4-yl-pyrazol-1-yl)-phenoxymethyl]-quinoline; 2-[2-chloro-4-(4-pyridin-4-yl-1H-pyrazol-3-yl)- Phenoxymethyl]-quinoline; 2-[2-chloro-4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quin Porphyrin; 2-[4-(4-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-phenoxymethyl]-quinoline; 2-[4-(5- Pyridin-4-yl-[1,2,4]triazol-1-yl)-phenoxymethyl]-quinoline; 2-[4-(3-methyl-5-pyridin-4-yl-[ 1,2,4]triazol-1-yl)-phenoxymethyl]-quinoline; 2-[4-(2-pyridin-4-yl-2H-[1,2,4]triazole-3 -yl)-phenoxymethyl]-quinoline; 2-[4-(5-methyl-2-pyridin-4-yl-2H-[1,2,4]triazol-3-yl)-benzene Oxymethyl]-quinoline; 8-methoxy-2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quin Porphyrin; 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-pyrido[1,2-a]pyrimidine-4- Ketone; 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline; 2-[3-fluoro-4-( 1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline; 4-chloro-2-[4-(1-methyl-4-pyridine 4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline; 4-methoxy-2-[4-(1-methyl-4-pyridin-4-yl-1H -pyrazol-3-yl)-phenoxymethyl]-quinoline; dimethyl-{2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl) )-phenoxymethyl]-quinolin-4-yl}-amine; 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxy Quinoline Persole; 2-((4-(5-(pyridin-4-yl)oxazol-4-yl)phenoxy)methyl)quinoline; 2-((4-(2-methyl-5) -(pyridin-4-yl)oxazol-4-yl)phenoxy)methyl)quinoline; 2-((4-(3-methyl-4-(pyridin-4-yl)-1H-pyridyl) Zyrid-5-yl)phenoxy)methyl)quinoline; 2-((4-(1,3-dimethyl-4-(pyridin-4-yl)-1H-pyrazol-5-yl)) Phenoxy)methyl)quinoline; 2-((4-(1,5-dimethyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl Quinoline; 2-(1-(4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)ethyl)quinoline; 2-( (4-(5-(pyridin-4-yl)-1,2,3-triazol-4-yl)phenoxy)methyl)quinoline; 2-((4-(2-methyl-5) -(pyridin-4-yl)-2H-1,2,3-triazol-4-yl)phenoxy)methyl)quinoline; 2-((4-(3-methyl-5-(pyridine) 4-yl)-3H-1,2.3-triazol-4-yl)phenoxy)methyl)quinoline; 2-((4-(1-(pyridin-4-yl)-1H-imidazole-) 2-yl)phenoxy)methyl)quinoline; 2-((4-(5-(pyridin-4-yl)-1H-imidazol-1-yl)phenoxy)methyl)quinoline; -((4-(2-methyl-5-(pyridin-4-yl)-1H-imidazol-1-yl)phenoxy)methyl)quinoline; 2-((4-(2-ethyl) -5-(pyridin-4-yl)-1H-imidazol-1-yl)phenoxy)methyl)quinoline; 2-((4-(2-(pyridin-4-yl)-1H-) Imidazolyl-1-yl)phenoxy)methyl)quinoline; and a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of formula I is selected from the group consisting of: 2-{4-[pyridin-4-yl-2-(2,2,2-trifluoro-ethyl)-2H-pyrazole-3- Methyl-phenoxymethyl}-quinoline; 2-{4-[pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline; 2-{ 3-fluoro-4-[4-pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline; 2-{3-Fluoro-4-[4-pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenoxymethyl}- Quinoline; 2-{4-[4-pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quin a porphyrin; and a pharmaceutically acceptable salt thereof.

The above compounds are described in WO 2006/072828 A2.

In a preferred embodiment, the compound of formula I is administered as a succinate salt.

In another preferred embodiment, the compound of formula I has the structure:

Or a pharmaceutically acceptable salt thereof, and in one embodiment, a succinate salt of the compound.

The chemical name of this compound (free oxime form) is 2-[4-(1-methyl-4-pyridin-4-yl-1 H -pyrazol-3-yl)-phenoxymethyl]-quinoline. A method of preparing the compound (also known as PF-2545920 or MP-10) can be found in U.S. Patent No. 7,429,665, the disclosure of which is incorporated herein in its entirety by reference.

The succinate salt of this compound can be prepared as follows, in accordance with U.S. Patent Application Publication No. 2010/063,089, the disclosure of which is incorporated herein by reference. 2-((4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy) A in ethyl acetate (75 ml) at 25 ° To a solution of quinoline (3.0 g, 7.6 mmol) in free hydrazine, 900 mg (7.6 mmol) of succinic acid in 75 ml of ethyl acetate was added at 25 °C. The mixture was then stirred at 25 ° C for 12 h. The resulting precipitate was filtered, washed with diethyl ether then dried in vacuo. The amount specified in the procedure was used to produce 3.13 g of the title compound as a white prism-shaped crystal.

The compounds of formula I may have optical centers, and thus the configuration of different enantiomers and diastereomers may occur. The present invention includes all enantiomers, diastereomers, and other stereoisomers of these compounds of Formula I, as well as stereoisomers thereof, racemic compounds, racemic mixtures, and other mixtures.

The pharmaceutically acceptable salts of the compounds of formula I include the acid addition salts and basic salts thereof. A suitable acid addition salt is formed from the acid forming the non-toxic salt. Examples include, but are not limited to, acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, hydrogen sulfate/sulfate, borate, camphorsulfonic acid Salt, citrate, cyclamate, ethanedisulfonate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, Hexafluorophosphate, hydroxyphenyl benzoate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, hydroxyethyl Sulfonate, lactate, malate, maleate, malonate, mandelate, methanesulfonate, methyl sulfate, naphthylate, 2-naphthalenesulfonate, smoke Acid salt, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, salicylate, sucrose salt, hard Fatty acid, succinate, sulfonate, stannate, tartrate, tosylate, trifluoroacetate and xinafoate. A suitable base salt is formed from the formation of a non-toxic salt. Examples include, but are not limited to, aluminum salts, arginine salts, benzathine salts, calcium salts, choline salts, diethylamine salts, diethanolamine salts, glycinates, lysine salts, magnesium salts, alcohol amine salts, Potassium salt, sodium salt, tromethamine salt and zinc salt. It is also possible to form hemisalt of acids and hydrazines, such as hemisulfate and hemi-calcium salts. For a review of suitable salts, see Handol of Pharmaceutical Salts: Properties, Selection by Stahl and Wermuth (Wiley-VCH, 2002).

The compounds of the present invention can exist continuously from a completely amorphous to a fully crystalline solid. The term "amorphous" refers to a state in which the material lacks long-range order at the molecular level and depending on the temperature, the material may exhibit physical properties of solid or liquid. Typically, these materials do not give a unique X-ray diffraction pattern, and although they exhibit solid nature, it is more formal to describe these materials as liquid. Once heated, a change from solid to liquid nature occurs, characterized by a change in state, typically second order ("glass transition"). The term "crystalline" refers to a solid phase in which the material has a regularly ordered internal structure at the molecular level and a unique X-ray diffraction pattern with defined peaks. These materials also exhibit a liquid state when heated sufficiently Properties, but changes from solid to liquid are characterized by phase transitions, typically first order ("melting point"). The compounds of the invention may also exist in unsolvated solvated forms. The term "solvate" as used herein describes a molecular complex comprising a compound of the invention and one or more pharmaceutically acceptable solvent molecules. When the solvent is water, the term "hydrate" is used.

The compounds of the invention may also exist in a mesomorphic state (intermediate phase or liquid crystal) when subjected to suitable conditions. The mesomorphic state is an intermediate between the true crystalline state and the true liquid state (melt or solution). The mesogenicity caused by the change in temperature is described as "temperature", and the mesogenicity due to the addition of the second component such as water or another solvent is described as "easy to dissolve". A compound having the possibility of forming a readily soluble intermediate phase is described as "amphiphilic" and the compound is made of an ion (eg, -COO ^- Na ⁺ , -COO ^- K ⁺ , or -SO ₃ ^- Na ⁺ ) or The molecular composition of a non-ionic (eg, -N ^- N ⁺ (CH ₃ ) ₃ ) polar head group. For more information, see NH Hartshorne and A. Stuart, Crystals and the Polarizing Microscope, Fourth Edition (Edward Arnold, 1970).

In the following, all references to compounds of the formula I include references to their salts, solvates, multi-component complexes and liquid crystals and solvates of their salts, multi-component complexes and liquid crystals.

The compounds of the invention include a compound of formula I as defined above, which compounds of formula I include all polymorphs as defined below and their crystal habits, prodrugs and isomers thereof (including optical isomerism) Isomers, geometric isomers, and tautomers, and isotope-labeled compounds of Formula I.

As indicated, the so-called "prodrug" of the compound of formula I is also in the hair Within the scope of the Ming Dynasty. Thus, when administered into or onto the body, for example, by hydrolytic cleavage, certain derivatives of a compound of formula I which may itself have little or no pharmacological activity can be converted to a compound of formula I having the desired activity. These derivatives are referred to as "prodrugs" for short. Further information on the use of prodrugs can be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (Ed. EB Roche Found in , American Pharmaceutical Association).

For example, the proper functionality of a compound of formula I will be known by the skilled artisan as "pre-part" (as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985). Instead, a prodrug in accordance with the invention can be prepared.

Some examples of prodrugs in accordance with the present invention include, but are not limited to:

(i) wherein the compound of formula I contains a carboxylic acid functionality (-COOH), an ester thereof, for example, a compound in which the hydrogen of the carboxylic acid functionality of the compound of formula (I) is substituted with a (C ₁ -C ₈ )alkyl group.

(ii) a compound wherein the compound of formula I contains an alcohol functionality (-OH), an ether thereof, for example, a hydrogen of an alcohol functionality of a compound of formula I is substituted with a (C ₁ -C ₆ ) alkoxymethyl group; and

(iii) wherein the compound of formula I contains primary or secondary amino functionality (-NH ₂ or -NHR, wherein R ≠ H), its guanamine, for example one or two of the amino functionality of the compound of formula I, as the case may be A compound in which a hydrogen is substituted with a (C ₁ -C ₁₀ ) alkenyl group.

Further examples of substituents in accordance with the foregoing examples and examples of other prodrug forms can be found in the aforementioned references. Moreover, certain compounds of formula I are themselves useful as prodrugs of other compounds of formula I.

Metabolites of the compounds of formula I are also included within the scope of the invention, i.e., compounds formed in vivo by administration of a drug. Some examples of metabolites in accordance with the present invention include, but are not limited to: (i) where a compound of Formula I contains a methyl group, an hydroxymethyl derivative thereof _{(-CH 3 → -CH 2 OH)} ; compound (ii) of formula I wherein Containing an alkoxy group, a hydroxy derivative thereof (-OR→-OH); (iii) wherein the compound of formula I contains a tertiary amino group, a secondary amino derivative thereof (-NR ¹ R ² →-NHR ¹ or -NHR ² ); (iv) wherein the compound of formula I contains a secondary amino group, a primary amino group thereof (-NHR ¹ →-NH ₂ ); (v) wherein the compound of formula I contains a phenyl moiety, a phenol derivative thereof (-Ph→-PhOH); And (vi) wherein the compound of formula I contains a guanamine group, a carboxylic acid derivative thereof (-CONH ₂ →-COOH); (vii) wherein the compound of formula I contains an aromatic nitrogen atom or an aliphatic tertiary amine function, which is N- Oxide derivative.

The compound of formula I having one of the nitrogen atoms in the tertiary amine function may be further substituted by oxygen (i.e., N-oxide).

A compound of formula I containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Wherein the compound of formula I contains Alkenyl or alkenylene, geometric cis/trans (or Z/E) isomers, this is possible. Tautomerism ("tautomerism") can occur through structural isomers that can be converted by low energy barriers. This can occur in the form of a proton tautomerism in a compound of formula I containing, for example, an imino group, a keto group, or a fluorenyl group, or a so-called valence tautomerism in a compound containing an aryl moiety. It follows that a single compound can exhibit more than one type of isomerism.

In the process of the invention, all stereoisomers, geometric isomers and tautomeric forms of the compounds of formula I may be employed, including compounds which exhibit more than one form of isomerism, and mixtures of one or more thereof. Also included are acid addition salts or base salts wherein the counterion is optical, for example, d -lactate or l -lysine, or racemic, such as dl -tartrate or dl -arginine.

A method of preparing a compound for use in the method of the present invention is described in U.S. Patent No. 7,429,665 and International Application Publication No. WO 2006/072828, the entire disclosure of which is incorporated herein by reference.

The term "alkyl" as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having a straight or branched chain moiety. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, and t-butyl.

The term "alkenyl" as used herein, unless otherwise indicated, includes alkyl moieties having at least one carbon-carbon double bond, wherein alkyl is as defined above. Examples of alkenyl groups include, but are not limited to, vinyl and propenyl.

The term "alkynyl" as used herein, unless otherwise indicated, includes alkyl moieties having at least one carbon-carbon triple bond, wherein alkyl is as defined above. Examples of alkynyl groups include, but are not limited to, ethynyl and 2-propynyl.

The term "alkoxy" as used herein, alone or as part of another group, as used herein, unless otherwise indicated, refers to an alkyl group attached to an oxygen atom.

The term "thioalkyl" as used herein, alone or as part of another group, unless otherwise indicated, includes any of the above alkyl groups attached through a sulfur atom.

Unless otherwise indicated, the terms "halogen" or "halo", as used alone or as part of another group, mean chloro, bromo, fluoro, and iodo.

The term "haloalkyl" as used herein, unless otherwise indicated, refers to at least one halo group attached to an alkyl group. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, trifluoroethyl, difluoromethyl, and fluoromethyl. The term "cycloalkyl" as used herein, unless otherwise indicated, includes a non-aromatic saturated cycloalkyl moiety, wherein the alkyl group is as defined above. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

The term "aryl" as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl, naphthyl, anthryl, fluorenyl. "Aryl" encompasses a fused ring group in which at least one ring is an aromatic ring.

The terms "heterocycle", "heterocycloalkyl" and like terms, as used herein, mean a non-aromatic ring group containing one or more heteroatoms (preferably from 1 to 4 heteroatoms), preferably each preferably. Selected from oxygen, sulfur and nitrogen. The heterocyclic group of the present invention can also include a ring system substituted with one or more oxo moieties. Examples of non-aromatic heterocyclic groups are azacyclopropyl, azetidinyl, pyrrolidine Base, acridinyl, azepine, pyridazinyl, 1,2,3,6-tetrahydropyridyl, oxiranyl, propylene oxide, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyridyl Benzyl, tetrahydrothiopyranyl, morpholino, thiomorpholino, thiamethane, pyrrolinyl, indanyl, 2H-pyranyl, 4H-pyranyl, dioxoalkyl , 1,3-dioxolanyl, pyrazolinyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-nitrogen heterocycle [3.1.0]hexyl, 3-azacyclo[4.1.0]heptyl, quinazolidinyl, quinuclidinyl, 1,4-dioxospiro[4.5]decyl, 1,4-dioxen Snail [4.4] fluorenyl, 1,4-dioxaspiro[4.3]octyl and 1,4-dioxaspiro[4.2]heptyl.

The term "heteroaryl" as used herein refers to an aromatic group (preferably 1 to 4 heteroatoms) containing one or more heteroatoms, preferably oxygen, sulfur and nitrogen. A polycyclic group containing one or more hetero atoms (wherein at least one ring of the group is an aromatic ring) is a "heteroaryl" group. The heteroaryl groups of the present invention can also include ring systems substituted with one or more oxo moieties. The heteroaryl group containing a tertiary nitrogen may also be further substituted by oxygen (i.e., N-oxide).

Examples of heteroaryl groups are pyridyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolinyl, isoquinolyl, tetrazolyl, furyl, thienyl, Isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, porphyrinyl, oxazolyl, pyridazinyl, pyridazinyl, tri Azinyl, isodecyl, decyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazyl, benzothienyl, benzotriazolyl, benzothiazolyl, benzox Azolyl, quinazolinyl, quinoxalinyl, diazonaphthyl, dihydroquinolyl, tetrahydroquinolyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, benzofuranyl, furan Pyridyl, pyrrole Pyrimidinyl, and azaindolyl. For clarity, the term heteroaryl includes heteroaryl structures in substituent Z in formula I (ie, heteroaryl structures containing Y).

The term "one or more" substituents, or "at least one" substituent, as used herein, unless otherwise indicated, refers to the maximum number of substituents from one to the possible (based on the number of bonding points available).

Unless otherwise indicated, all of the above groups derived from a hydrocarbon may have up to 1 to about 20 carbon atoms (eg, C ₁ -C ₂₀ alkyl, C ₂ -C ₂₀ alkenyl, C ₃ -C ₂₀ cycloalkyl) a 3-20 membered heterocycloalkyl group, a C ₆ -C ₂₀ aryl group, a 5-20 membered heteroaryl group, or the like) or 1 to about 15 carbon atoms (eg, C ₁ -C ₁₅ alkyl group, C _{2 )} -C ₁₅ alkenyl, C ₃ -C ₁₅ cycloalkyl, 3-15 membered heterocycloalkyl, C ₆ -C ₁₅ aryl, 5-15 membered heteroaryl, etc.), or 1 to about 12 A carbon atom, or from 1 to about 8 carbon atoms, or from 1 to about 6 carbon atoms.

Preparation and application

The compounds of the invention may be administered orally, transdermally (e.g., by the use of a patch), intranasal, sublingual, rectal, parenteral, or topical routes. In one embodiment, the compound is delivered by injecting the compound into the eye; topical administration is less likely to achieve a dose that is sufficiently high for the compound to effectively treat the condition of the retina.

In one embodiment, the compound is administered at a dose ranging from about 0.25 mg to about 1500 mg per day; in another embodiment, administered in a single or divided dose at a dose of from 0.25 to about 300 mg per day. a compound; in another embodiment, the compound is administered at a dose of from 0.01 mg to about 10 mg/kg body weight per day, however, depending on the weight and condition of the subject to be treated and the choice The particular route of administration, as well as the response to the individual being treated, selected, and the length of time the patient is treated, will inevitably change. In some cases, doses below 0.25 mg/day may be sufficient, however in other cases larger doses may be used without causing any harmful side effects, provided that these larger doses are first taken within one day Divided into several small doses for administration.

The active compound can be administered alone or in combination with a pharmaceutically acceptable carrier or diluent by any of the routes previously indicated. More particularly, the active compound can be administered in a wide variety of dosage forms, for example, in the form of tablets, capsules, transdermal patches, lozenges, lozenges, hard candies, powders, sprays, emulsions, ointments, suppositories, Pectin, gel, paste, lotion, ointment, aqueous solution, aqueous suspension, injectable solution, elixirs, syrups and the like may be combined with various pharmaceutically acceptable inert carriers. These carriers include solid diluents or fillers, sterile aqueous media, and various non-toxic organic solvents. Furthermore, the oral pharmaceutical composition can be suitably sweetened and/or flavored. Generally, the active compounds will be present in these dosage forms at levels ranging from about 5.0% to about 70% by weight.

For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be combined with various disintegrating agents such as starch (preferably corn, potato or tapioca). Starch), alginic acid and certain complex citrates, and granular binders such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic are used together. Further, a lubricant such as magnesium stearate, sodium lauryl sulfate and talc can be used for tableting. Solid compositions of a similar form may also be used in capsules Fillers; preferred materials in this regard also include lactose or milk sugar, as well as high molecular weight polyethylene glycols. When desired for oral administration of aqueous suspensions and/or elixirs, the active ingredient can be combined with various sweetening or flavoring agents, coloring agents, and, if desired, emulsifiers and/or suspensions, such as water These diluents are combined with ethanol, propylene glycol, glycerin, and various combinations thereof.

For parenteral administration, solutions of the active compounds in pharmaceutically acceptable oily or aqueous vehicles such as, but not limited to, sesame oil, peanut oil or aqueous propylene glycol can be employed. If necessary, the aqueous solution should be properly buffered and the liquid diluent first rendered isotonic.

The preparation of the solution is carried out under sterile conditions and is readily accomplished by standard pharmaceutical techniques known to those skilled in the art. Parenteral administration can be by injection, including intravenous, intra-articular, intramuscular, and subcutaneous forms. The aqueous solution is suitable for intravenous injection. The oily solution is suitable for intra-articular, intramuscular and subcutaneous injection purposes.

It is also possible to administer the active compound topically, and this topical administration can be carried out by means of emulsions, patches, pectins, pastes, creams and the like in accordance with standard pharmaceutical procedures.

example

The invention is illustrated by the following examples. The compounds of the invention were tested using the following experimental protocol:

(1) Mice (or vehicle) were administered twice daily at 10 mg/kg, IP.

(2) On day 3, mice were exposed to 10,000 lux of light for 30 minutes, 2 hours after the first dose and 6 hours before the last dose.

(3) On the 11th day, ERG measurement was performed.

(4) On day 12, the mice were sacrificed for retinal histology.

Analysis of the ERG function measures the integrity of the function of the retina. In this analysis, drug-treated mice showed a very small loss of function, however, vehicle-treated mice showed a severe loss of function (Fig. 1). Furthermore, as shown in Figure 2, photoreceptor cells were also significantly protected in this study. In the model, autofluorescence appears as retinal degeneration. Figure 3 shows that the compounds of the invention are capable of reducing this self-fluorescence.

In immunohistochemical studies of rabbits, non-human primates and human retinas, the inventors demonstrated that PDE10A protein is expressed in photoreceptors and RPE/choroid (Fig. 4).

These data confirm the utility of the compounds of the invention in the treatment of retinal diseases.

Each and every reference (whether disclosed in a patent publication or scientific/journal publication) disclosed herein is hereby incorporated by reference.

The details of the specific embodiments described in the present invention are not to be construed as limiting. Various equivalents and modifications can be made without departing from the spirit and scope of the invention, and it should be understood that these equivalent embodiments are part of the invention.

Figure 1 shows that Compound MP-10 prevents loss of ERG function in the ABCA4/RDH8 mouse model.

Figure 2 shows that compound MP-10 is protected in the ABCA4/RDH8 mouse model. Photoreceptor loss. Higher levels indicate more loss of photoreceptor cells. Drug vs. vehicle was counted by one-way analysis of variance: P < 0.005, higher grade = more death.

Figure 3 shows that the compound MP-10 reduced the expression of self-fluorescence in the retina of model mice by measurement of SLO self-fluorescence. The drug vs. 0 mg was counted by one-way analysis of variance: P < 0.05.

Figure 4 shows that PDE10A is expressed in photoreceptors of human and non-human primates, as also by immunohistochemistry with anti-human PDE10A Ab. (Abcam 14622-100).

Claims (15)

A use of a compound of formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating the retina: Where: Z is R ^{1 is} each independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, C ₁ to C ₈ alkyl, C ₂ to C ₈ alkenyl, C ₂ to C ₈ alkynyl, C ₁ to C ₈ alkoxy, C ₁ to C ₈ haloalkyl, C ₃ to C ₈ cycloalkyl, C ₃ to C ₈ cycloalkyl-C ₁ to C ₈ alkyl, 4 to 7-membered heterocycloalkyl, C ₁ to C ₈ thio An alkyl group, NR ³ R ³ , -O-CF ₃ , -S(O) _n -R ³ , C(O)-NR ³ R ³ , and a C ₁ to C ₈ alkyl group substituted with a hetero atom, wherein The hetero atom is selected from the group consisting of nitrogen, oxygen and sulfur, and wherein the hetero atom may be further selected from the group consisting of hydrogen, C ₁ to C ₈ alkyl, C ₃ to C ₈ cycloalkyl, C ₂ to C ₈ alkenyl, C ₂ to Substituted with a C ₈ alkynyl group and a C ₁ to C ₈ haloalkyl group; R ^{3 is} each independently selected from hydrogen, C ₁ to C ₈ alkyl, C ₂ to C ₈ alkenyl, C ₂ to C ₈ alkyne a C ₁ to C ₈ haloalkyl group, and a C ₃ to C ₈ cycloalkyl group; R ^{2 is} selected from the group consisting of hydrogen, C ₁ to C ₈ alkyl, C ₃ to C ₈ cycloalkyl-C ₁ to C ₈ alkyl a C ₂ to C ₈ alkenyl group, a C ₂ to C ₈ alkynyl group, a C ₁ to C ₈ haloalkyl group, and a C ₃ to C ₈ cycloalkyl group; HET ^{1 is} selected from the group consisting of a monocyclic heteroaryl group and a bicyclic ring aryl group, wherein the monocyclic and bicyclic heteroaryl may be optionally substituted by at least one R ^4; R ⁴ From halogen, hydroxy, cyano, C ₁ to C ₈ alkyl, C ₂ to C ₈ alkenyl group, C ₂ to C ₈ alkynyl groups, C ₁ to C ₈ alkoxy, C ₃ to C ₈ cycloalkyl, a C ₃ to C ₈ cycloalkyl-C ₁ to C ₈ alkyl group, a C ₁ to C ₈ thioalkyl group, and a substituent selected from the group consisting of -OR ⁸ , -NR ⁸ R ⁸ , and -SR ⁸ a C ₁ to C ₈ alkyl group, wherein R ^{8 is} independently selected from hydrogen and C ₁ to C ₈ alkyl; HET ² is a monocyclic or dicyclic heteroaryl group, wherein the condition for HET ² is not tetrazolium The monocyclic and bicyclic heteroaryl is optionally substituted with at least one R ⁵ ; R ^{5 is} independently selected from halo, hydroxy, cyano, C ₁ to C ₈ alkyl, C ₂ to C ₈ alkenyl , C ₂ to C ₈ alkynyl, C ₁ to C ₈ alkoxy, C ₃ to C ₈ cycloalkyl, C ₃ to C ₈ cycloalkyl-C ₁ to C ₈ alkyl, C ₁ to C ₈ sulfur Alkenyl, -NR ⁷ R ⁷ , and C ₁ to C ₈ haloalkyl; B ¹ and B ² are adjacent atoms in Het ¹ , which are independently selected from carbon and nitrogen; and the bond j is in Z and B ² a covalent bond between; a bond k is a covalent bond between B ¹ and B ² in Het ¹ ; X and X ¹ are each independently selected from the group consisting of oxygen, sulfur, C(R ₂ ) ₂ and NR ₂ , with the proviso that X or at least one of X ¹ is carbon; the Y is selected from carbon and nitrogen, with the proviso When Y is carbon, R ⁶ which is substituted use; wherein R ⁶ is independently selected from hydrogen, halogen, hydroxy, cyano, C to _{C. 1. 8} alkyl, C ₂ to _{C. 8} alkenyl, C ₂ to C ₈ alkynyl, C ₁ to C ₈ alkoxy, C ₁ to C ₈ cycloalkyl, C ₃ to C ₈ cycloalkyl-C ₁ to C ₈ alkyl, C ₁ to C ₈ thioalkyl, C ₁ to C ₈ haloalkyl, -NR ⁷ R ⁷ , -O-CF ₃ , -S(O) _m -R ⁷ , C(O)-NR ⁷ R ⁷ , and C ₁ to C ₈ substituted with a hetero atom An alkyl group, wherein the hetero atom is selected from the group consisting of nitrogen, oxygen and sulfur, and wherein the hetero atom may be further selected from the group consisting of hydrogen, C ₁ to C ₈ alkyl, C ₃ to C ₈ cycloalkyl, C ₂ to C ₈ olefin Substituted with a substituent of a C ₂ to C ₈ alkynyl group, and a C ₁ to C ₈ haloalkyl group; and wherein R ⁷ are each independently selected from hydrogen and C ₁ to C ₈ alkyl; p is 1, 2 or 3, n is 0, 1 or 2; and m is 0, 1 or 2. The use of the first item of the patent application, wherein HET ¹ is a 5-membered heteroaryl group. The use of claim 1 wherein HET ^{1 is} selected from the group consisting of pyrazole, isoxazole, triazole, oxazole, thiazole and imidazole. The use of claim 1 wherein HET ^{2 is} selected from the group consisting of 4-pyridyl, 4-pyridazine and isoxazole. The use of claim 1 wherein HET ² is 4-pyridyl. The use of the first item of the patent application, wherein the compound is selected from the group consisting of: Or a pharmaceutically acceptable salt thereof. The use of the first item of the patent application, wherein the compound has the following structure: Or a pharmaceutically acceptable salt thereof. The use of the first item of the patent application, wherein the compound has the following structure: Or a pharmaceutically acceptable salt thereof. The use of claim 1 wherein Y is selected from the group consisting of carbon and nitrogen, with the proviso that no more than one Y is nitrogen. The use of claim 1 wherein X ¹ is carbon and X is oxygen. For example, the application of the scope of claim 1 wherein all Y are carbon. The use of the first item of the patent application, wherein the compound has the following structure: Or a pharmaceutically acceptable salt thereof. The use of claim 1 wherein the compound is administered as a succinate. For example, the use of the first item of the patent scope, wherein the retinal disease is selected From: Aging-related macular degeneration, retinitis pigmentosa, Stargardt's disease and other retinal dystrophy, macular edema, retinal detachment, retinal trauma, retinal neoplasms and their associated retinal diseases, retinal pigment epithelium congenital Hypertrophy, acute posterior multifocal squamous pigment epithelial lesions, and acute retinal pigment epitheliitis. The use of claim 1, wherein the compound is administered orally or by injecting it into the eye.