Fluorine-substituted indazole compounds and uses thereof
Patent Information
- Application Number
- CA3056501
- Authority / Receiving Office
- CA · CA
- Patent Type
- Patents
- Current Assignee / Owner
- Priority Date
- 2017-04-11
- Filing Date
- 2018-04-10
- Publication Date
- 2026-10-13
- Estimated Expiration
- 2038-04-10
Abstract
Description
FLUORINE-SUBSTITUTED INDAZOLE COMPOUNDS AND USES THEREOF RELATED APPLICATION
[0001] This application claims priority and benefits of Chinese Patent Application No. 201710232060.X, filed with State Intellectual Property Office on April 11, 2017. FIELD
[0002] The invention belongs to the pharmaceutical field, specifically, it relates to fluorine- substituted indazole compounds and uses thereof, further to pharmaceutical compositions containing these compounds. These compounds and pharmaceutical compositions can be used as soluble guanylate cyclase stimulators. BACKGROUND
[0003] Cyclic guanosine monophosphate (cGMP) is a second messenger having action of intracellular signal transduction, and together with nitrogen monoxide (NO), which is released from the endothelium and transmits hormonal and mechanical signals, forms the NO / cGMP system. Guanylate cyclases catalyze the biosynthesis of cGMP from guanosine triphosphate (GTP). The known representatives of this family can be classified both according to structural features and according to the type of ligands into two groups: the particulate guanylate cyclases which can be stimulated by natriuretic peptides, and the soluble guanylate cyclases which can be stimulated by NO. The soluble guanylate cyclases consist of two subunits and very probably contain one heme per heterodimer, which is part of the regulatory site. NO is able to bind to the iron atom of haem and thus markedly increase the activity of the enzyme. Haem-free enzyme cannot, by contrast, be stimulated by NO. Carbon monoxide (CO) is also able to attach to the central iron atom of haem, but the stimulation by CO is distinctly less than that by NO.
[0004] By forming cGMP, and owing to the resulting regulation of phosphodiesterases, ion channels and protein kinases, guanylate cyclase plays an important role in various physiological processes, in particular in the relaxation and proliferation of smooth muscle cells, in platelet aggregation and platelet adhesion and in neuronal signal transmission, and also in disorders which are based on a disturbance of the above mentioned processes. Under pathophysiological conditions, the NO / cGMP system may be suppressed, which may lead for example to high blood pressure, platelet activation, increased cellular proliferation, endothelial dysfunction, atherosclerosis, angina pectoris, heart failure, myocardial infarction, thromboses, stroke and sexual dysfunction.
[0005] Owing to the expected high efficiency and few side effects, a treatment of such disorders which targets the influence of the cGMP signal path in organisms and is NO-independent is a promising approach. Therapeutic stimulation of soluble guanylate cyclase on NO-based compounds, such as organic nitrates, is formed by bioconversion to give NO and activate soluble guanylate cyclase by NO attacking at the central iron atom of heme. In addition to the side effects, the development of tolerance is one of the disadvantages of this type of treatment.
[0006] Soluble guanylate cyclase (sGC) is widely found in mammalian cytosols and has a relatively high content in lung and brain, and is a key signal transduction enzymes in nitric oxide (NO)-sGC-guanosine monophosphate (cGMP) signaling pathway, sGC is activated in the body and will catalyze GTP into cGMP. cGMP is an important second-class messenger molecule that activates several downstream effector molecules such as phosphodiesterase (PDE), cyclic nucleotide gated ion channels (CNG) and protein kinase G (PKG), etc., which in turn triggers a series of cascade reactions downstream to exert important physiological functions in the gastrointestinal system, the blood circulatory system and the nervous system such as promoting relaxation of blood vessels and smooth muscles, inhibiting platelet aggregation, vascular remodeling, apoptosis and inflammation and participation nerve delivery and more.
[0007] sGC is a NO sensor and receptor that contains two subunits: alpha and beta, each with three domains, including a heme domain, a central domain and a catalytic domain, wherein heme domains of two subunits share a heme. NO binds to heme of sGC, activates sGC and catalyzes the conversion of its substrate GTP into a secondary signaling molecule cGMP, opens the PKG signaling pathway and leads to vasodilation. As a receptor of NO, sGC plays an important role in the cardiovascular system and nervous system. Disorders of NO signal can lead to the imbalance of physiological functions and lead to various diseases. Therefore, as a new drug that can activate sGC directly, sGC stimulator has aroused increasingly more attention.
[0008] sGC stimulators have a dual mechanism of action on sGC in vivo. When the concentration of NO is low, sGC can be directly activated. When NO is at a certain level, sGC stimulators can cooperate with NO and then activates the sGC to catalyze substrate guanosine triphosphate (GTP) transfering into the second-class messenger molecule guanosine monophosphate (cGMP), and then involves in the regulation of many important physiological processes, such as promoting vascular and smooth muscle relaxation; inhibition of platelet aggregation, vascular remodeling, etc. sGC stimulator activates sGC will also mediate other signaling pathways such as TGF-β, which play anti-fibrosis, anti-tumor effect. Therefore, the NO / sGC / cGMP pathway is an effective target for the treatment of a variety of cardiovascular diseases such as pulmonary hypertension, acute heart failure, angina and myocardial infarction-induced vascular remodeling.
[0009] Over the years, many researchers have developed NO donors, phosphodiesterase inhibitors and non-NO-dependent sGC stimulators and other drugs, wherein the non-NO-dependent sGC stimulators can avoid the shortcomings of traditional NO donor drugs, such as prone tolerance, lack of specificity and short duration, thus has received widespread attention. SUMMARY OF THE INVENTION
[0010] The present invention provides a novel fluorine-substituted indazole compounds as sGC stimulators and pharmaceutical compositions thereof, and the use of the compounds or the pharmaceutical compositions in the manufacture of a medicament, wherein the medicament is used for the treatment and / or prevention of sGC-mediated diseases such as heart failure, sclerosis, systemic sclerosis, sickle cell anemia, achalasia of cardia, pulmonary fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis, pulmonary hypertension and the like.
[0011] In one aspect, provided herein is a compound having Formula (I) or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof, [Image disponible dans le document PDF, Image available in the PDF document] (I), wherein [Image disponible dans le document PDF, Image available in the PDF document] t is 1, 2, 3 or 4; each f is independently 0, 1, 2, 3 or 4; each R<com:Sup>a< / com:Sup> and R<com:Sup>b< / com:Sup> is independently H, D, F, Cl, Br, I, CN, amino, hydroxy, mercapto, C<com:Sub>1-6< / com:Sub> alkyl, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math> alkenyl, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math> alkynyl, halo <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkylamino, halo <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy, acyl, sulfonyl, C<com:Sub>3-6< / com:Sub> cycloalkyl, C<com:Sub>2-5< / com:Sub> heterocyclyl, C<com:Sub>6-10< / com:Sub> aryl or C<com:Sub>1-5< / com:Sub> heteroaryl; or, R<com:Sup>a< / com:Sup> and R<com:Sup>b< / com:Sup> together form carbonyl; or, R<com:Sup>a< / com:Sup> and R<com:Sup>b< / com:Sup>, together with the carbon atom to which they are attached, form a 3- to 8-membered carbocyclic ring or 3- to 8-membered heterocyclic ring; each R<com:Sup>c< / com:Sup> is independently H, D, C<com:Sub>1-6< / com:Sub> alkyl, C<com:Sub>2-6< / com:Sub> alkenyl, C<com:Sub>2-6< / com:Sub> alkynyl, halo C<com:Sub>1-6< / com:Sub> alkyl, C<com:Sub>3-6< / com:Sub> cycloalkyl, C<com:Sub>2-5< / com:Sub> heterocyclyl, C<com:Sub>6-10< / com:Sub> aryl or C<com:Sub>1-5< / com:Sub> heteroaryl; C1 is <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl, <com:Math><semantics>C1−9<annotation encoding="application / x-tex">C_{1-9}< / annotation>< / semantics>< / com:Math> heteroaryl or <com:Math><semantics>C2−9<annotation encoding="application / x-tex">C_{2-9}< / annotation>< / semantics>< / com:Math> heterocyclyl; C2 is <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl, <com:Math><semantics>C3−10<annotation encoding="application / x-tex">C_{3-10}< / annotation>< / semantics>< / com:Math> carbocyclyl, <com:Math><semantics>C2−9<annotation encoding="application / x-tex">C_{2-9}< / annotation>< / semantics>< / com:Math> heterocyclyl or 6- to 10-membered heteroaryl; each R<com:Sup>1< / com:Sup> is independently H, D, F, Cl, Br, I, CN, NO<com:Sub>2< / com:Sub>, amino, hydroxy, mercapto, C<com:Sub>1-6< / com:Sub> alkyl, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math> alkenyl, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math> alkynyl, halo <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy, halo <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkylamino, acyl, sulfonyl, <com:Math><semantics>−(CR10R11)u−C3−6<annotation encoding="application / x-tex">-(CR^{10}R^{11})_u-C_{3-6}< / annotation>< / semantics>< / com:Math> cycloalkyl, <com:Math><semantics>−(CR10R11)u−C2−5<annotation encoding="application / x-tex">-(CR^{10}R^{11})_u-C_{2-5}< / annotation>< / semantics>< / com:Math> heterocyclyl, <com:Math><semantics>−(CR10R11)u−C6−10<annotation encoding="application / x-tex">-(CR^{10}R^{11})_u-C_{6-10}< / annotation>< / semantics>< / com:Math> aryl or <com:Math><semantics>−<annotation encoding="application / x-tex">-< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(CR10R11)u<annotation encoding="application / x-tex">(CR^{10}R^{11})_{u}< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics>< / com:Math> heteroaryl; wherein each of the amino, hydroxy, mercapto, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math> alkenyl, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math> alkynyl, halo <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy, halo <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkylamino, acyl, sulfonyl, - <com:Math><semantics>(CR10R11)u<annotation encoding="application / x-tex">(CR^{10}R^{11})_u< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>< / com:Math> cycloalkyl, -<com:Math><semantics>(CR10R11)u<annotation encoding="application / x-tex">(CR^{10}R^{11})_u< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C2−5<annotation encoding="application / x-tex">C_{2-5}< / annotation>< / semantics>< / com:Math> heterocyclyl, -<com:Math><semantics>(CR10R11)u<annotation encoding="application / x-tex">(CR^{10}R^{11})_u< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl and -<com:Math><semantics>(CR10R11)u<annotation encoding="application / x-tex">(CR^{10}R^{11})_u< / annotation>< / semantics>< / com:Math>- <com:Math><semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics>< / com:Math> heteroaryl is unsubstituted or independently substituted with 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, CN, NO<com:Sub>2< / com:Sub>, amino, hydroxy, mercapto, oxo, C<com:Sub>1-6< / com:Sub> alkyl, C<com:Sub>2-6< / com:Sub> alkenyl, C<com:Sub>2-6< / com:Sub> alkynyl, halo C<com:Sub>1-6< / com:Sub> alkyl, C<com:Sub>1-6< / com:Sub> alkoxy, halo C<com:Sub>1-6< / com:Sub> alkoxy, C<com:Sub>1-6< / com:Sub> alkylamino, C<com:Sub>3-6< / com:Sub> cycloalkyl, C<com:Sub>2-5< / com:Sub> heterocyclyl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl and <com:Math><semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics>< / com:Math> heteroaryl; each R<com:Sup>2< / com:Sup> is independently H, D, F, Cl, Br, I, CN, NO<com:Sub>2< / com:Sub>, amino, hydroxy, mercapto, C<com:Sub>1-6< / com:Sub> alkyl, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math> alkenyl, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math> alkynyl, halo <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, halo <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkylamino, hydroxy <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, cyano C<com:Sub>1-6< / com:Sub> alkyl, amino C<com:Sub>1-6< / com:Sub> alkyl, hydroxy C<com:Sub>1-6< / com:Sub> alkoxy, amino C<com:Sub>1-6< / com:Sub> alkoxy, acyl, sulfonyl or C<com:Sub>1-6< / com:Sub> alkoxy; each R<com:Sup>3< / com:Sup> is independently oxo, H, D, F, Cl, Br, I, CN, NO<com:Sub>2< / com:Sub>, mercapto, C<com:Sub>1-6< / com:Sub> alkyl, C<com:Sub>2-6< / com:Sub> alkenyl, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math> alkynyl, halo <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>−(CR6aR6b)j−C3−10<annotation encoding="application / x-tex">-(CR^{6a}R^{6b})_j-C_{3-10}< / annotation>< / semantics>< / com:Math> cycloalkyl, <com:Math><semantics>−(CR6aR6b)j−C2−10<annotation encoding="application / x-tex">-(CR^{6a}R^{6b})_j-C_{2-10}< / annotation>< / semantics>< / com:Math> heterocyclyl, <com:Math><semantics>−(CR6aR6b)j<annotation encoding="application / x-tex">-(CR^{6a}R^{6b})_j< / annotation>< / semantics>< / com:Math> [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (CR<com:Sup>6a< / com:Sup>R<com:Sup>6b< / com:Sup>)<com:Sub>i< / com:Sub>C(=O)R<com:Sup>8< / com:Sup>; each R<com:Sup>3< / com:Sup> is unsubstitued or independently substituted with 1, 2, 3 or 4 R<com:Sup>x< / com:Sup>; or, any two adjacent R<com:Sup>3< / com:Sup>, together with the carbon atoms to which they are attached, form a 3- to 6-membered carbocyclic ring, heterocyclic ring, aromatic ring or heteroaromatic ring, and wherein each of 3- to 6-membered carbocyclic ring, heterocyclic ring, aromatic ring and heteroaromatic ring is unsubstituted or independently substituted with 1, 2, 3 or 4 R<com:Sup>z< / com:Sup>; R<com:Sup>4< / com:Sup> is D, F, Cl, Br, I, CN, NO<com:Sub>2< / com:Sub>, mercapto, C<com:Sub>1-6< / com:Sub> alkyl, C<com:Sub>2-6< / com:Sub> alkenyl, C<com:Sub>2-6< / com:Sub> alkynyl, halo C<com:Sub>1-6< / com:Sub> alkyl, [Image disponible dans le document PDF, Image available in the PDF document] 5 [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] unsubstituted or substituted with 1, 2, 3 or 4 R<com:Sup>y< / com:Sup>; each R<com:Sup>5< / com:Sup> and R<com:Sup>5e< / com:Sup> is independently H, D, C<com:Sub>1-6< / com:Sub> alkyl, hydroxy C<com:Sub>1-6< / com:Sub> alkyl, amino C<com:Sub>1-6< / com:Sub> alkyl, cyano <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, halo <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy-<com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>< / com:Math> cycloalkyl, <com:Math><semantics>C2−5<annotation encoding="application / x-tex">C_{2-5}< / annotation>< / semantics>< / com:Math> heterocyclyl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> 5 heteroaryl, C<com:Sub>3-6< / com:Sub> cycloalkyl-C<com:Sub>1-6< / com:Sub>-alkyl, C<com:Sub>2-5< / com:Sub> heterocyclyl-C<com:Sub>1-6< / com:Sub>-alkyl, C<com:Sub>6-10< / com:Sub> aryl-C<com:Sub>1-6< / com:Sub>-alkyl or C<com:Sub>1-5< / com:Sub> heteroaryl-<com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl; each R<com:Sup>5a< / com:Sup>, R<com:Sup>5b< / com:Sup>, R<com:Sup>5c< / com:Sup> and R<com:Sup>5d< / com:Sup> is independently H, D, C<com:Sub>1-6< / com:Sub> alkyl, C<com:Sub>2-6< / com:Sub> alkenyl, C<com:Sub>2-6< / com:Sub> alkynyl, hydroxy C<com:Sub>1-6< / com:Sub> alkyl, amino C<com:Sub>1-6< / com:Sub> alkyl, cyano C<com:Sub>1-6< / com:Sub> alkyl, halo C<com:Sub>1-6< / com:Sub> alkyl, C<com:Sub>1-6< / com:Sub> alkoxy-C<com:Sub>1-6< / com:Sub>-alkyl, C<com:Sub>1-6< / com:Sub> alkoxycarbonyl, C<com:Sub>1-6< / com:Sub> alkylcarbonyl, C<com:Sub>1-6< / com:Sub> alkylaminocarbonyl, C<com:Sub>3-6< / com:Sub> cycloalkyl, C<com:Sub>2-5< / com:Sub> heterocyclyl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl, <com:Math><semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics>< / com:Math> heteroaryl, <com:Math><semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>< / com:Math> cycloalkylcarbonyl, <com:Math><semantics>C2−5<annotation encoding="application / x-tex">C_{2-5}< / annotation>< / semantics>< / com:Math> heterocyclylcarbonyl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> arylcarbonyl, C<com:Sub>1-5< / com:Sub> heteroarylcarbonyl, C<com:Sub>3-6< / com:Sub> cycloalkyl-C<com:Sub>1-6< / com:Sub>-alkyl, C<com:Sub>2-5< / com:Sub> heterocyclyl-C<com:Sub>1-6< / com:Sub>-alkyl, C<com:Sub>6-10< / com:Sub> aryl-C<com:Sub>1-6< / com:Sub>- alkyl or C<com:Sub>1-5< / com:Sub> heteroaryl-C<com:Sub>1-6< / com:Sub>-alkyl; or, R<com:Sup>5a< / com:Sup> and R<com:Sup>5b< / com:Sup>, together with the N atom to which they are attached, form a 3- to 10-membered heterocyclic ring or 3- to 10-membered heteroaromatic ring; or, R<com:Sup>5c< / com:Sup> and R<com:Sup>5d< / com:Sup>, together with the N atom to which they are attached, form a 3- to 10-membered heterocyclic ring or 3- to 10-membered heteroaromatic ring; eachR<com:Sup>6a< / com:Sup>, R<com:Sup>6b< / com:Sup>, R<com:Sup>6c< / com:Sup> and R<com:Sup>6d< / com:Sup> is independently H, D, F, Cl, Br, I, CN, amino, hydroxy, mercapto, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math> alkenyl, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math> alkynyl, hydroxy <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, amino <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, cyano <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, halo C<com:Sub>1-6< / com:Sub> alkyl, C<com:Sub>1-6< / com:Sub> alkoxy, halo C<com:Sub>1-6< / com:Sub> alkoxy, C<com:Sub>1-6< / com:Sub> alkylamino, acyl, sulfonyl, C<com:Sub>3-6< / com:Sub> cycloalkyl, C<com:Sub>2-5< / com:Sub> heterocyclyl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl or <com:Math><semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics>< / com:Math> heteroaryl; each <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R7a<annotation encoding="application / x-tex">R^{7a}< / annotation>< / semantics>< / com:Math> is independently H, D, amino, hydroxy, mercapto, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math> alkenyl, C<com:Sub>2-6< / com:Sub> alkynyl, halo C<com:Sub>1-6< / com:Sub> alkyl, C<com:Sub>1-6< / com:Sub> alkoxy, halo C<com:Sub>1-6< / com:Sub> alkoxy, C<com:Sub>1-6< / com:Sub> alkylamino, C<com:Sub>3-6< / com:Sub> cycloalkyl, C<com:Sub>2-5< / com:Sub> heterocyclyl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl or <com:Math><semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics>< / com:Math> heteroaryl; each R<com:Sup>8< / com:Sup> and R<com:Sup>8a< / com:Sup> is independently H, D, amino, hydroxy, mercapto, C<com:Sub>1-6< / com:Sub> alkyl, C<com:Sub>2-6< / com:Sub> alkenyl, C<com:Sub>2-6< / com:Sub> alkynyl, halo C<com:Sub>1-6< / com:Sub> alkyl, C<com:Sub>1-6< / com:Sub> alkoxy, halo C<com:Sub>1-6< / com:Sub> alkoxy, C<com:Sub>1-6< / com:Sub> alkylamino, C<com:Sub>3-6< / com:Sub> cycloalkyl, C<com:Sub>2-5< / com:Sub> heterocyclyl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl or <com:Math><semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics>< / com:Math> heteroaryl; each R<com:Sup>9< / com:Sup> and R<com:Sup>9a< / com:Sup> is independently H, D, C<com:Sub>1-6< / com:Sub> alkyl, C<com:Sub>2-6< / com:Sub> alkenyl, C<com:Sub>2-6< / com:Sub> alkynyl, halo C<com:Sub>1-6< / com:Sub> alkyl, acyl, sulfonyl, C<com:Sub>3-6< / com:Sub> cycloalkyl, C<com:Sub>2-5< / com:Sub> heterocyclyl, C<com:Sub>6-10< / com:Sub> aryl, C<com:Sub>1-5< / com:Sub> heteroaryl, C<com:Sub>3-6< / com:Sub> cycloalkyl-C<com:Sub>1-6< / com:Sub>- alkyl, C<com:Sub>2-5< / com:Sub> heterocyclyl-C<com:Sub>1-6< / com:Sub>-alkyl, C<com:Sub>6-10< / com:Sub> aryl-C<com:Sub>1-6< / com:Sub>-alkyl or C<com:Sub>1-5< / com:Sub> heteroaryl-C<com:Sub>1-6< / com:Sub> alkyl; each R<com:Sup>10< / com:Sup> and R<com:Sup>11< / com:Sup> is independently H, D, F, Cl, Br, I, CN, amino, hydroxy, mercapto, C<com:Sub>1-6< / com:Sub> alkyl, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math> alkenyl, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math> alkynyl, hydroxy <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, amino <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, cyano <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, halo <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, C<com:Sub>1-6< / com:Sub> alkoxy, halo C<com:Sub>1-6< / com:Sub> alkoxy, C<com:Sub>1-6< / com:Sub> alkylamino, acyl, sulfonyl, C<com:Sub>3-6< / com:Sub> cycloalkyl, C<com:Sub>2-5< / com:Sub> heterocyclyl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl or <com:Math><semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics>< / com:Math> heteroaryl; or, <com:Math><semantics>R10<annotation encoding="application / x-tex">R^{10}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R11<annotation encoding="application / x-tex">R^{11}< / annotation>< / semantics>< / com:Math> together form carbonyl; or, <com:Math><semantics>R10<annotation encoding="application / x-tex">R^{10}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R11<annotation encoding="application / x-tex">R^{11}< / annotation>< / semantics>< / com:Math>, together with the carbon atom to which they are attached, form a 3- to 8-membered carbocyclic ring or 3- to 8- membered heterocyclic ring; each R<com:Sup>x< / com:Sup> is independently oxo, H, D, F, Cl, Br, I, CN, amino, hydroxy, mercapto, C<com:Sub>1-6< / com:Sub> alkyl, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math> alkenyl, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math> alkynyl, hydroxy <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, amino <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, cyano <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, halo <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy, halo <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkylamino, acyl, sulfonyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkylcarbonyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkylsulfonyl, C<com:Sub>1-6< / com:Sub> alkylcarbonylamino, C<com:Sub>1-6< / com:Sub> alkylsulfonylamino, C<com:Sub>1-6< / com:Sub> alkoxycarbonylamino, C<com:Sub>3-6< / com:Sub> cycloalkyl, C<com:Sub>2-5< / com:Sub> heterocyclyl, C<com:Sub>6-10< / com:Sub> aryl or C<com:Sub>1-5< / com:Sub> heteroaryl; each R<com:Sup>y< / com:Sup> is independently oxo, H, D, F, Cl, Br, I, CN, amino, hydroxy, mercapto, C<com:Sub>1-6< / com:Sub> alkyl, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math> alkenyl, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math> alkynyl, hydroxy <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, amino <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, cyano <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, halo <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy, halo <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkylamino, acyl, sulfonyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkylcarbonyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkylsulfonyl, C<com:Sub>1-6< / com:Sub> alkylcarbonylamino, C<com:Sub>1-6< / com:Sub> alkylsulfonylamino, C<com:Sub>1-6< / com:Sub> alkoxycarbonylamino, C<com:Sub>3-6< / com:Sub> cycloalkyl, <com:Math><semantics>C2−5<annotation encoding="application / x-tex">C_{2-5}< / annotation>< / semantics>< / com:Math> heterocyclyl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl or <com:Math><semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics>< / com:Math> heteroaryl; each R<com:Sup>z< / com:Sup> is independently oxo, H, D, F, Cl, Br, I, CN, amino, hydroxy, mercapto, C<com:Sub>1-6< / com:Sub> alkyl, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math> alkenyl, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math> alkynyl, hydroxy <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, amino <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, cyano <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, halo <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy, halo <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkylamino, acyl, sulfonyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkylcarbonyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkylsulfonyl, C<com:Sub>1-6< / com:Sub> alkylcarbonylamino, C<com:Sub>1-6< / com:Sub> alkylsulfonylamino, C<com:Sub>1-6< / com:Sub> alkoxycarbonylamino, C<com:Sub>3-6< / com:Sub> cycloalkyl, C<com:Sub>2-5< / com:Sub> heterocyclyl, C<com:Sub>6-10< / com:Sub> aryl or C<com:Sub>1-5< / com:Sub> heteroaryl; n is 0, 1, 2, 3 or 4; m is 0, 1, 2 or 3; r is 0, 1, 2, 3, 4, 5 or 6; each u, j and g is independently 0, 1, 2, 3 or 4; and each h, i, k and p is independently 0, 1, 2, 3 or 4.
[0012] In some embodiments, each R<com:Sup>a< / com:Sup> and R<com:Sup>b< / com:Sup> is independently H, D, F, Cl, Br, I, CN, amino, hydroxy, mercapto, methyl, ethyl, propyl, butyl, C<com:Sub>2-4< / com:Sub> alkenyl, C<com:Sub>2-4< / com:Sub> alkynyl, halo C<com:Sub>1-4< / com:Sub> alkyl, C<com:Sub>1-4< / com:Sub> alkoxy, C<com:Sub>1-4< / com:Sub> alkylamino, halo C<com:Sub>1-4< / com:Sub> alkoxy, C<com:Sub>3-6< / com:Sub> cycloalkyl, C<com:Sub>2-5< / com:Sub> heterocyclyl, phenyl or C<com:Sub>1-5< / com:Sub> heteroaryl; or, R<com:Sup>a< / com:Sup> and R<com:Sup>b< / com:Sup> together form carbonyl; or, R<com:Sup>a< / com:Sup> and R<com:Sup>b< / com:Sup>, together with the carbon atom to which they are attached, form a 3- to 6-membered carbocyclic ring or 3- to 6-membered heterocyclic ring; and each R<com:Sup>c< / com:Sup> is independently H, D, methyl, ethyl, propyl, butyl, C<com:Sub>2-4< / com:Sub> alkenyl, C<com:Sub>2-4< / com:Sub> alkynyl, halo <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>< / com:Math> cycloalkyl, <com:Math><semantics>C2−5<annotation encoding="application / x-tex">C_{2-5}< / annotation>< / semantics>< / com:Math> heterocyclyl, phenyl or <com:Math><semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics>< / com:Math> heteroaryl.
[0013] In some embodiments, C1 is: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>(C1−1),<annotation encoding="application / x-tex">(C1-1),< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(C1−2),<annotation encoding="application / x-tex">(C1-2),< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(C1−3)<annotation encoding="application / x-tex">(C1-3)< / annotation>< / semantics>< / com:Math> or <com:Math><semantics>(C1−4);<annotation encoding="application / x-tex">(C1-4);< / annotation>< / semantics>< / com:Math> wherein, each <com:Math><semantics>X1<annotation encoding="application / x-tex">X^1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>X2<annotation encoding="application / x-tex">X^2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>X3<annotation encoding="application / x-tex">X^3< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>X4<annotation encoding="application / x-tex">X^4< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>X5<annotation encoding="application / x-tex">X^5< / annotation>< / semantics>< / com:Math> is independently N or CH; each <com:Math><semantics>Y1<annotation encoding="application / x-tex">Y^1< / annotation>< / semantics>< / com:Math> is independently <com:Math><semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>C(=O)<annotation encoding="application / x-tex">C(=O)< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NH<annotation encoding="application / x-tex">NH< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>S<annotation encoding="application / x-tex">S< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>S(=O)<annotation encoding="application / x-tex">S(=O)< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>S(=O)2<annotation encoding="application / x-tex">S(=O)_2< / annotation>< / semantics>< / com:Math> or <com:Math><semantics>O<annotation encoding="application / x-tex">O< / annotation>< / semantics>< / com:Math>; [Image disponible dans le document PDF, Image available in the PDF document] wherein, is the bond through which C1 is attached to L. [Image disponible dans le document PDF, Image available in the PDF document] bond through which C1 is attached to L.
[0015] In some embodiments, C2 is: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>(C2−1),<annotation encoding="application / x-tex">(C2-1),< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(C2−2),<annotation encoding="application / x-tex">(C2-2),< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(C2−3),<annotation encoding="application / x-tex">(C2-3),< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(C2−4),<annotation encoding="application / x-tex">(C2-4),< / annotation>< / semantics>< / com:Math> [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>(C2−5),<annotation encoding="application / x-tex">(C2-5),< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(C2−6),<annotation encoding="application / x-tex">(C2-6),< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(C2−7),<annotation encoding="application / x-tex">(C2-7),< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(C2−8)<annotation encoding="application / x-tex">(C2-8)< / annotation>< / semantics>< / com:Math> or [Image disponible dans le document PDF, Image available in the PDF document] 4 <com:Math><semantics>(C2−9);<annotation encoding="application / x-tex">(C2-9);< / annotation>< / semantics>< / com:Math> 5 wherein, each X<com:Sup>6< / com:Sup>, X<com:Sup>7< / com:Sup>, X<com:Sup>8< / com:Sup>, X<com:Sup>9< / com:Sup>, X<com:Sup>10< / com:Sup> and X<com:Sup>11< / com:Sup> is independently N or CH; 6 each Y<com:Sup>6< / com:Sup>, Y<com:Sup>7< / com:Sup> and Y<com:Sup>8< / com:Sup> is independently CH<com:Sub>2< / com:Sub>, C(=O), NH, S, S(=O), S(=O)<com:Sub>2< / com:Sub> or O; 7 each Y<com:Sup>5< / com:Sup> is independently CH<com:Sub>2< / com:Sub>, NH, S or O; 8 e is 0, 1, 2, 3 or 4; wherein, \( \frac{1}{2} \) is the bond through which C2 is attached to indazole. 9 [Image disponible dans le document PDF, Image available in the PDF document] which C2 is attached to indazole.
[0017] In some embodiments, the compound having Formula (I) of the invention has Formula (II), Formula (IIa), Formula (IIb) or Formula (IIc), or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof, [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] 6 (II), (IIa), [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (IIb) or (IIc), wherein each <com:Math><semantics>X1<annotation encoding="application / x-tex">X^1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>X2<annotation encoding="application / x-tex">X^2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>X3<annotation encoding="application / x-tex">X^3< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>X4<annotation encoding="application / x-tex">X^4< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>X5<annotation encoding="application / x-tex">X^5< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>X6<annotation encoding="application / x-tex">X^6< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>X7<annotation encoding="application / x-tex">X^7< / annotation>< / semantics>< / com:Math> is independently N or CH.
[0018] In some embodiments, each R<com:Sup>1< / com:Sup> is independently H, D, F, Cl, Br, I, CN, NO<com:Sub>2< / com:Sub>, amino, hydroxy, mercapto, C<com:Sub>1-4< / com:Sub> alkyl, C<com:Sub>2-4< / com:Sub> alkenyl, C<com:Sub>2-4< / com:Sub> alkynyl, halo C<com:Sub>1-4< / com:Sub> alkyl, C<com:Sub>1-4< / com:Sub> alkoxy, halo C<com:Sub>1-4< / com:Sub> alkoxy, C<com:Sub>1-4< / com:Sub> alkylamino, C<com:Sub>3-6< / com:Sub> cycloalkyl, C<com:Sub>2-5< / com:Sub> heterocyclyl, C<com:Sub>6-10< / com:Sub> aryl or C<com:Sub>1-5< / com:Sub> heteroaryl; wherein each of the C<com:Sub>1-4< / com:Sub> alkyl, C<com:Sub>2-4< / com:Sub> alkenyl, C<com:Sub>2-4< / com:Sub> alkynyl, halo C<com:Sub>1-4< / com:Sub> alkyl, C<com:Sub>1-4< / com:Sub> alkoxy, halo C<com:Sub>1-4< / com:Sub> 4 alkoxy, C<com:Sub>1-4< / com:Sub> alkylamino, C<com:Sub>3-6< / com:Sub> cycloalkyl, C<com:Sub>2-5< / com:Sub> heterocyclyl, C<com:Sub>6-10< / com:Sub> aryl and C<com:Sub>1-5< / com:Sub> heteroaryl is unsubstituted or independently substituted with 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, CN, NO<com:Sub>2< / com:Sub>, amino, hydroxy, mercapto, oxo, C<com:Sub>1-4< / com:Sub> alkyl, C<com:Sub>2-4< / com:Sub> alkenyl, C<com:Sub>2-4< / com:Sub> alkynyl, halo C<com:Sub>1-4< / com:Sub> alkyl, C<com:Sub>1-4< / com:Sub> alkoxy, halo C<com:Sub>1-4< / com:Sub> alkoxy, C<com:Sub>1-4< / com:Sub> alkylamino, C<com:Sub>3-6< / com:Sub> cycloalkyl, C<com:Sub>2-5< / com:Sub> heterocyclyl, C<com:Sub>6-10< / com:Sub> aryl and C<com:Sub>1-< / com:Sub> 5 heteroaryl.
[0019] In other embodiments, each R<com:Sup>1< / com:Sup> is independently H, D, F, Cl, Br, I, CN, NO<com:Sub>2< / com:Sub>, amino, hydroxy, mercapto, oxo, methyl, ethyl, propyl, butyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, propoxy, tert-butoxy, trifluoromethoxy, methylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, morpholinyl, piperazinyl, epoxypropyl, azetidinyl, phenyl, pyridyl or pyrimidinyl; wherein each of the methyl, ethyl, propyl, butyl, difluoromethyl, methoxy, ethoxy, propoxy, tert-butoxy, methylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, morpholinyl, piperazinyl, epoxypropyl, azetidinyl, phenyl, pyridyl and pyrimidinyl is unsubstituted or independently substituted with 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, CN, NO<com:Sub>2< / com:Sub>, amino, hydroxy, mercapto, oxo, methyl, ethyl, propyl, butyl, C<com:Sub>2-4< / com:Sub> alkenyl, C<com:Sub>2-4< / com:Sub> alkynyl, trifluoromethyl, methoxy, ethoxy, propoxy, trifluoromethoxy, C<com:Sub>1-3< / com:Sub> alkylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, <com:Math><semantics>C2−5<annotation encoding="application / x-tex">C_{2-5}< / annotation>< / semantics>< / com:Math> heterocyclyl, phenyl and <com:Math><semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics>< / com:Math> heteroaryl.
[0020] In some embodiments, the compound having Formula (I) of the invention has Formula (IV), Formula (IVa), Formula (IVb) or Formula (IVc), or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof, [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (IV), (IVb) [Image disponible dans le document PDF, Image available in the PDF document] or (IVc). 17
[0021] In some embodiments, R<com:Sup>4< / com:Sup> is D, F, Cl, Br, I, CN, NO<com:Sub>2< / com:Sub>, mercapto, C<com:Sub>1-4< / com:Sub> alkyl, C<com:Sub>2-4< / com:Sub> alkenyl, <com:Math><semantics>C2−4<annotation encoding="application / x-tex">C_{2-4}< / annotation>< / semantics>< / com:Math> alkynyl, halo <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>< / com:Math> cycloalkyl, <com:Math><semantics>C2−5<annotation encoding="application / x-tex">C_{2-5}< / annotation>< / semantics>< / com:Math> heterocyclyl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl, <com:Math><semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics>< / com:Math> heteroaryl, - <com:Math><semantics>NR5cR5d<annotation encoding="application / x-tex">NR^{5c}R^{5d}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(=O)NR5cR5d<annotation encoding="application / x-tex">-C(=O)NR^{5c}R^{5d}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OR9a<annotation encoding="application / x-tex">-OR^{9a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(=O)2OR9a<annotation encoding="application / x-tex">-S(=O)_2OR^{9a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(=O)2NR5cR5d<annotation encoding="application / x-tex">-S(=O)_2NR^{5c}R^{5d}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(R5e)C(=O)(CR6cR6d)hOR9a<annotation encoding="application / x-tex">-N(R^{5e})C(=O)(CR^{6c}R^{6d})_hOR^{9a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(=O)2NR5cR5d<annotation encoding="application / x-tex">-S(=O)_2NR^{5c}R^{5d}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(R5e)C(=O)(CR6cR6d)hOR9a<annotation encoding="application / x-tex">-N(R^{5e})C(=O)(CR^{6c}R^{6d})_hOR^{9a}< / annotation>< / semantics>< / com:Math>, <Formule mathématique disponible dans le document PDF, Math available in the PDF document>-S(=O)_2NR^{5 <com:Math><semantics>N(R5e)C(=O)R8a<annotation encoding="application / x-tex">N(R^{5e})C(=O)R^{8a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(R5e)C(=O)NR5cR5d<annotation encoding="application / x-tex">-N(R^{5e})C(=O)NR^{5c}R^{5d}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(R5e)S(=O)2R7a<annotation encoding="application / x-tex">-N(R^{5e})S(=O)_2R^{7a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(=O)2R7a<annotation encoding="application / x-tex">-S(=O)_2R^{7a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OS(=O)2R7a<annotation encoding="application / x-tex">-OS(=O)_2R^{7a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OS(=O)2R7a<annotation encoding="application / x-tex">-OS(=O)_2R^{7a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OS(=O)2R7a<annotation encoding="application / x-tex">-OS(=O)_2R^{7a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OS(=O)2R7a<annotation encoding="application / x-tex">-OS(=O)_2R^{7a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OS(=O)2R7a<annotation encoding="application / x-tex">-OS(=O)_2R^{7a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OS(=O)2R7a<annotation encoding="application / x-tex">-OS(=O)_2R^{7a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OS(=<annotation encoding="application / x-tex">-OS(=< / annotation>< / semantics>< / com:Math> OC(=O)OR<com:Sup>9a< / com:Sup>, -OC(=O)R<com:Sup>8a< / com:Sup> or -C(=O)R<com:Sup>8a< / com:Sup>; R<com:Sup>4< / com:Sup> is unsubstituted or substituted with 1, 2, 3 or 4 R<com:Sup>y< / com:Sup>.
[0022] In other embodiments, R<com:Sup>4< / com:Sup> is D, F, Cl, Br, I, CN, NO<com:Sub>2< / com:Sub>, mercapto, methyl, ethyl, propyl, butyl, vinyl, propenyl, allyl, ethynyl, propynyl, trifluoromethyl, difluoromethyl, 2,2-difluoroethyl, chloroethyl, 2,2,2-trifluoroethyl, 2-chloro-1-methylethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, pyrazolidinyl, oxomorpholinyl, thiomorpholinyl, 4,4-dioxothiomorpholinyl, oxazolidinyl, thiazolidinyl, 1,1- dioxoisothiazolidinyl, oxo-1,3-oxazinylalkyl, phenyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, pyrrolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, thienyl, furyl, -NR<com:Sup>5c< / com:Sup>R<com:Sup>5d< / com:Sup>, -C(=O)NR<com:Sup>5c< / com:Sup>R<com:Sup>5d< / com:Sup>, -OR<com:Sup>9a< / com:Sup>, <com:Math><semantics>−S(=O)2OR9a<annotation encoding="application / x-tex">-S(=O)_2OR^{9a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(=O)2NR5cR5d<annotation encoding="application / x-tex">-S(=O)_2NR^{5c}R^{5d}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(R5e)C(=O)(CR6cR6d)hOR9a<annotation encoding="application / x-tex">-N(R^{5e})C(=O)(CR^{6c}R^{6d})_hOR^{9a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(R5e)C(=O)R8a<annotation encoding="application / x-tex">-N(R^{5e})C(=O)R^{8a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(R5e)C(=O)R8a<annotation encoding="application / x-tex">-N(R^{5e})C(=O)R^{8a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(R5e)C(=O)R8a<annotation encoding="application / x-tex">-N(R^{5e})C(=O)R^{8a}< / annotation>< / semantics>< / com:Math> <com:Math><semantics>N(R5e)C(=O)NR5cR5d<annotation encoding="application / x-tex">N(R^{5e})C(=O)NR^{5c}R^{5d}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(R5e)S(=O)2R7a<annotation encoding="application / x-tex">-N(R^{5e})S(=O)_2R^{7a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(=O)2R7a<annotation encoding="application / x-tex">-S(=O)_2R^{7a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OS(=O)2R7a<annotation encoding="application / x-tex">-OS(=O)_2R^{7a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OC(=O)OR9a<annotation encoding="application / x-tex">-OC(=O)OR^{9a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OC(=O)R8a<annotation encoding="application / x-tex">-OC(=O)R^{8a}< / annotation>< / semantics>< / com:Math> or -C(=O)R<com:Sup>8a< / com:Sup>; R<com:Sup>4< / com:Sup> is unsubstituted or substituted with 1, 2, 3 or 4 R<com:Sup>y< / com:Sup>.
[0023] In some embodiments, each R<com:Sup>2< / com:Sup> is independently H, D, F, Cl, Br, I, CN, NO<com:Sub>2< / com:Sub>, amino, hydroxy, mercapto, C<com:Sub>1-4< / com:Sub> alkyl, C<com:Sub>2-4< / com:Sub> alkenyl, C<com:Sub>2-4< / com:Sub> alkynyl, halo C<com:Sub>1-4< / com:Sub> alkyl, halo C<com:Sub>1-4< / com:Sub> alkoxy, C<com:Sub>1-4< / com:Sub> alkylamino, hydroxy C<com:Sub>1-4< / com:Sub> alkyl, cyano C<com:Sub>1-4< / com:Sub> alkyl, amino C<com:Sub>1-4< / com:Sub> alkyl, hydroxy C<com:Sub>1-4< / com:Sub> alkoxy, amino C<com:Sub>1-4< / com:Sub> 4 alkoxy or C<com:Sub>1-4< / com:Sub> alkoxy.
[0024] In other embodiments, each R<com:Sup>2< / com:Sup> is independently H, D, F, Cl, Br, I, CN, NO<com:Sub>2< / com:Sub>, amino, hydroxy, mercapto, methyl, ethyl, propyl, butyl, trifluoromethyl, trifluoromethoxy, methylamino, dimethylamino, hydroxymethyl, hydroxyethyl, cyanomethyl, cyanoethyl, aminomethyl, aminoethyl, hydroxymethoxy, hydroxyethoxy, amino <com:Math><semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics>< / com:Math> alkoxy, methoxy, ethoxy, propoxy or butoxy.
[0025] In some embodiments, each R<com:Sup>3< / com:Sup> is independently oxo, H, D, F, Cl, Br, I, CN, NO<com:Sub>2< / com:Sub>, mercapto, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C2−4<annotation encoding="application / x-tex">C_{2-4}< / annotation>< / semantics>< / com:Math> alkenyl, <com:Math><semantics>C2−4<annotation encoding="application / x-tex">C_{2-4}< / annotation>< / semantics>< / com:Math> alkynyl, halo <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>< / com:Math> cycloalkyl, <com:Math><semantics>C2−5<annotation encoding="application / x-tex">C_{2-5}< / annotation>< / semantics>< / com:Math> heterocyclyl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl, <com:Math><semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics>< / com:Math> heteroaryl, <com:Math><semantics>−NR5aR5b<annotation encoding="application / x-tex">-NR^{5a}R^{5b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(=O)NR5aR5b<annotation encoding="application / x-tex">-C(=O)NR^{5a}R^{5b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(=O)OR9<annotation encoding="application / x-tex">-C(=O)OR^{9}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OR9<annotation encoding="application / x-tex">-OR^{9}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(=O)2OR9<annotation encoding="application / x-tex">-S(=O)_{2}OR^{9}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(=O)2NR5aR5b<annotation encoding="application / x-tex">-S(=O)_{2}NR^{5a}R^{5b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(=O)OR9<annotation encoding="application / x-tex">-C(=O)OR^{9}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OR9<annotation encoding="application / x-tex">-OR^{9}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OR9<annotation encoding="application / x-tex">-OR^{9}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OR9<annotation encoding="application / x-tex">-OR^{9}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OR9<annotation encoding="application / x-tex">-OR^{9}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OR9<annotation encoding="application / x-tex">-OR^{9}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OR9<annotation encoding="application / x-tex">-OR^{9}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−<annotation encoding="application / x-tex">-< / annotation>< / semantics>< / com:Math> <com:Math><semantics>N(R5)C(=O)(CR6aR6b)kOR9<annotation encoding="application / x-tex">N(R^5)C(=O)(CR^{6a}R^{6b})_kOR^9< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(R5)C(=O)NR5aR5b<annotation encoding="application / x-tex">-N(R^5)C(=O)NR^{5a}R^{5b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(R5)C(=O)R8<annotation encoding="application / x-tex">-N(R^5)C(=O)R^8< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(R5)S(=O)2R7<annotation encoding="application / x-tex">-N(R^5)S(=O)_2R^7< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(=O)2R7<annotation encoding="application / x-tex">-S(=O)_2R^7< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OS(=O)2R7<annotation encoding="application / x-tex">-OS(=O)_2R^7< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OC(=O)OR9<annotation encoding="application / x-tex">-OC(=O)OR^9< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OC(=O)R8<annotation encoding="application / x-tex">-OC(=O)R^8< / annotation>< / semantics>< / com:Math> or <com:Math><semantics>−C(=O)R8<annotation encoding="application / x-tex">-C(=O)R^8< / annotation>< / semantics>< / com:Math>; each <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is unsubstituted or substituted with 1, 2, 3 or 4 <com:Math><semantics>Rx<annotation encoding="application / x-tex">R^x< / annotation>< / semantics>< / com:Math>; or, any two adjacent R<com:Sup>3< / com:Sup>, together with the carbon atoms to which they are attached, form a 3- to 6-membered heterocyclic ring or heteroaromatic ring, and wherein each of 3- to 6-membered heterocyclic ring and heteroaromatic ring is unsubstituted or and independently substituted with <com:Math><semantics>1,2,3 or 4Rz<annotation encoding="application / x-tex">1, 2, 3 \text{ or } 4 R^z< / annotation>< / semantics>< / com:Math>.
[0026] In other embodiments, each R<com:Sup>3< / com:Sup> is independently oxo, H, D, F, Cl, Br, I, CN, NO<com:Sub>2< / com:Sub>, mercapto, methyl, ethyl, propyl, butyl, trifluoromethyl, 2,2-difluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, oxomorpholinyl, thiomorpholinyl, 4,4-dioxothiomorpholinyl, tetrahydrofuranyl, oxazolidinyl, thiazolidinyl, 1,1-dioxoisothiazolidinyl, oxo-1,3-oxazinyl, phenyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, pyrrolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, thienyl, furyl, <com:Math><semantics>−NR5aR5b<annotation encoding="application / x-tex">-NR^{5a}R^{5b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(=O)NR5aR5b<annotation encoding="application / x-tex">-C(=O)NR^{5a}R^{5b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(=O)OR9<annotation encoding="application / x-tex">-C(=O)OR^{9}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OR9<annotation encoding="application / x-tex">-OR^{9}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(=O)2OR9<annotation encoding="application / x-tex">-S(=O)_{2}OR^{9}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(=O)2NR5aR5b<annotation encoding="application / x-tex">-S(=O)_{2}NR^{5a}R^{5b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(R5)C(=O)OR9<annotation encoding="application / x-tex">-N(R^{5})C(=O)OR^{9}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(=O)2OR9<annotation encoding="application / x-tex">-S(=O)_{2}OR^{9}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(=O)2OR9<annotation encoding="application / x-tex">-S(=O)_{2}OR^{9}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(=O)2OR9<annotation encoding="application / x-tex">-S(=O)_{2}OR^{9}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(=O)2OR9<annotation encoding="application / x-tex">-S(=O)_{2}OR^{9}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−<annotation encoding="application / x-tex">-< / annotation>< / semantics>< / com:Math> <com:Math><semantics>N(R5)C(=O)NR5aR5b<annotation encoding="application / x-tex">N(R^5)C(=O)NR^{5a}R^{5b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(R5)C(=O)R8<annotation encoding="application / x-tex">-N(R^5)C(=O)R^8< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(R5)S(=O)2R7<annotation encoding="application / x-tex">-N(R^5)S(=O)_2R^7< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(=O)2R7<annotation encoding="application / x-tex">-S(=O)_2R^7< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OS(=O)2R7<annotation encoding="application / x-tex">-OS(=O)_2R^7< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OC(=O)OR9<annotation encoding="application / x-tex">-OC(=O)OR^9< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OC(=O)OR9<annotation encoding="application / x-tex">-OC(=O)OR^9< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OC(=O)OR9<annotation encoding="application / x-tex">-OC(=O)OR^9< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OC(=O)OR9<annotation encoding="application / x-tex">-OC(=O)OR^9< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OC(=O)OR9<annotation encoding="application / x-tex">-OC(=O)OR^9< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OC(=O)OR9<annotation encoding="application / x-tex">-OC(=O)OR^9< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OC(=O)OR9<annotation encoding="application / x-tex">-OC(=O)OR^9< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OC(=O)OR9<annotation encoding="application / x-tex">-OC(=O)OR^9< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−<annotation encoding="application / x-tex">-< / annotation>< / semantics>< / com:Math> <com:Math><semantics>OC(=O)R8<annotation encoding="application / x-tex">OC(=O)R^8< / annotation>< / semantics>< / com:Math> or <com:Math><semantics>−C(=O)R8<annotation encoding="application / x-tex">-C(=O)R^8< / annotation>< / semantics>< / com:Math>; each <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is unsubstituted or independently substituted with 1, 2, 3 or 4 <com:Math><semantics>Rx<annotation encoding="application / x-tex">R^x< / annotation>< / semantics>< / com:Math>; or, any two adjacent R<com:Sup>3< / com:Sup>, together with the carbon atoms to which they are attached, form a 3- to 6-membered heterocyclic ring or heteroaromatic ring, and wherein each of 3- to 6-membered heterocyclic ring and heteroaromatic ring is unsubstituted or independently substituted with 1, 2, <com:Math><semantics>3 or 4 Rz<annotation encoding="application / x-tex">3 \text{ or } 4 \text{ R}^z< / annotation>< / semantics>< / com:Math>.
[0027] In some embodiments, each R<com:Sup>5a< / com:Sup>, R<com:Sup>5b< / com:Sup>, R<com:Sup>5c< / com:Sup> and R<com:Sup>5d< / com:Sup> is independently H, D, C<com:Sub>1-4< / com:Sub> alkyl, C<com:Sub>2-4< / com:Sub> alkenyl, C<com:Sub>2-4< / com:Sub> alkynyl, hydroxy C<com:Sub>1-4< / com:Sub> alkyl, amino C<com:Sub>1-4< / com:Sub> alkyl, cyano C<com:Sub>1-4< / com:Sub> alkyl, halo C<com:Sub>1-4< / com:Sub> alkyl, C<com:Sub>1-4< / com:Sub> alkoxy-C<com:Sub>1-4< / com:Sub>-alkyl, C<com:Sub>1-4< / com:Sub> alkoxycarbonyl, C<com:Sub>1-4< / com:Sub> alkylcarbonyl, C<com:Sub>1-4< / com:Sub> alkylaminocarbonyl, C<com:Sub>3-6< / com:Sub> cycloalkyl, <com:Math><semantics>C2−5<annotation encoding="application / x-tex">C_{2-5}< / annotation>< / semantics>< / com:Math> heterocyclyl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl, <com:Math><semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics>< / com:Math> heteroaryl, <com:Math><semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>< / com:Math> cycloalkylcarbonyl, <com:Math><semantics>C2−5<annotation encoding="application / x-tex">C_{2-5}< / annotation>< / semantics>< / com:Math> heterocyclylcarbonyl, C<com:Sub>6-10< / com:Sub> arylcarbonyl, C<com:Sub>1-5< / com:Sub> heteroarylcarbonyl, C<com:Sub>3-6< / com:Sub> cycloalkyl-C<com:Sub>1-3< / com:Sub>-alkyl, C<com:Sub>2-5< / com:Sub> heterocyclyl-<com:Math><semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl-<com:Math><semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics>< / com:Math>-alkyl or <com:Math><semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics>< / com:Math> heteroaryl-<com:Math><semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics>< / com:Math>-alkyl; or, <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R5b<annotation encoding="application / x-tex">R^{5b}< / annotation>< / semantics>< / com:Math>, together with the N atom to which they are attached, form a 3- to 6-membered heterocyclic ring or 3- to 6- membered heteroaromatic ring; or, R5c and R5d, together with the N atom to which they are attached, form a 3- to 6-membered heterocyclic ring or 3- to 6-membered heteroaromatic ring.
[0028] In other embodiments, each R<com:Sup>5a< / com:Sup>, R<com:Sup>5b< / com:Sup>, R<com:Sup>5c< / com:Sup> and R<com:Sup>5d< / com:Sup> is independently H, D, methyl, ethyl, propyl, butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, amino C<com:Sub>1-4< / com:Sub> alkyl, cyano C<com:Sub>1-4< / com:Sub> alkyl, trifluoromethoxy, chloroethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 2-chloro- 1-methylethyl, methoxymethyl, methoxyethyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, methylcarbonyl, ethylcarbonyl, methylaminocarbonyl, ethylaminocarbonyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperidinyl, piperazinyl, phenyl, pyridinyl, pyrimidinyl, cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cyclopropyloxycarbonyl, tetrahydrofurylcarbonyl, tetrahydropyranylcarbonyl, piperidylcarbonyl, piperazinylcarbonyl, morpholinylcarbonyl, tetrahydrothiophenylcarbonyl, pyrrolidinylcarbonyl, phenylcarbonyl, pyridylcarbonyl, pyrimidinylcarbonyl, pyrrolylcarbonyl, imidazolylcarbonyl, pyrazolylcarbonyl, thienylcarbonyl, furylcarbonyl, cyclopropylmethyl, cyclobutylmethyl, tetrahydropyranylmethyl, tetrahydropyranylethyl, tetrahydrofuranylmethyl, tetrahydrofuranylethyl, phenylmethyl, phenylethyl, pyridylmethyl, pyrazolylmethyl, pyrazolylethyl, pyridylethyl or C<com:Sub>2-5< / com:Sub> heterocyclyl-C<com:Sub>1-< / com:Sub> 3-alkyl; or, R<com:Sup>5a< / com:Sup> and R<com:Sup>5b< / com:Sup>, together with the N atom to which they are attached, form an azetidine, pyrrolidine, oxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, piperazine, thiomorpholine, 1,3-oxazinane, pyrrole, pyrazole, imidazole or triazolyl; or, R<com:Sup>5c< / com:Sup> and R<com:Sup>5d< / com:Sup>, together with the N atom to which they are attached, form an azetidine, pyrrolidine, oxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, piperazine, thiomorpholine, 1,3-oxazinane, pyrrole, pyrazole, imidazole or triazolyl.
[0029] In some embodiments, each R<com:Sup>9< / com:Sup> and R<com:Sup>9a< / com:Sup> is independently H, D, C<com:Sub>1-4< / com:Sub> alkyl, C<com:Sub>2-4< / com:Sub> alkenyl, C<com:Sub>2< / com:Sub> 4 alkynyl, halo C<com:Sub>1-4< / com:Sub> alkyl, acyl, sulfonyl, C<com:Sub>3-6< / com:Sub> cycloalkyl, C<com:Sub>2-5< / com:Sub> heterocyclyl, C<com:Sub>6-10< / com:Sub> aryl, C<com:Sub>1-5< / com:Sub> heteroaryl, C<com:Sub>3-6< / com:Sub> cycloalkyl-C<com:Sub>1-3< / com:Sub>-alkyl, C<com:Sub>2-5< / com:Sub> heterocyclyl-C<com:Sub>1-3< / com:Sub>-alkyl, C<com:Sub>6-10< / com:Sub> aryl-C<com:Sub>1-3< / com:Sub>-alkyl or C<com:Sub>1-5< / com:Sub> heteroaryl-<com:Math><semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics>< / com:Math>-alkyl.
[0030] In other embodiments, each R<com:Sup>9< / com:Sup> and R<com:Sup>9a< / com:Sup> is independently H, D, methyl, ethyl, propyl, butyl, C<com:Sub>2-4< / com:Sub> alkenyl, C<com:Sub>2-4< / com:Sub> alkynyl, trifluoromethyl, chloroethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 2- chloro-1-methylethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, tetrahydrofuranyl, morpholinyl, piperidinyl, piperazinyl, phenyl, pyridyl, pyrimidinyl, cyclopropylmethyl, cyclobutylmethyl, phenylmethyl, phenylethyl, pyridylmethyl, pyridylethyl or <com:Math><semantics>C2−5<annotation encoding="application / x-tex">C_{2-5}< / annotation>< / semantics>< / com:Math> heterocyclyl-<com:Math><semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics>< / com:Math>-alkyl.
[0031] In some embodiments, each R<com:Sup>8< / com:Sup> and R<com:Sup>8a< / com:Sup> is independently H, D, amino, hydroxy, mercapto, methyl, ethyl, propyl, butyl, trifluoromethyl, chloroethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 2-chloro-1-methylethyl, methoxy, ethoxy, propoxy, trifluoromethoxy, methylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, morpholinyl, piperidinyl, piperazinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, phenyl, pyrrolyl, thienyl, furyl, pyridyl or pyrimidinyl.
[0032] In some embodiments, each R<com:Sup>x< / com:Sup> is independently oxo, H, D, F, Cl, Br, I, CN, amino, hydroxy, mercapto, methyl, ethyl, propyl, butyl, C<com:Sub>2-4< / com:Sub> alkenyl, C<com:Sub>2-4< / com:Sub> alkynyl, hydroxymethyl, hydroxyethyl, amino <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl, cyano <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl, trifluoromethyl, chloroethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 2-chloro-1-methylethyl, methoxy, ethoxy, propoxy, trifluoromethoxy, methylamino, dimethylamino, <com:Math><semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics>< / com:Math> alkylcarbonyl, <com:Math><semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics>< / com:Math> alkylcarbonyl, <com:Math><semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics>< / com:Math> alkylcarbonylamino, <com:Math><semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics>< / com:Math> <com:Math><semantics>3<annotation encoding="application / x-tex">_3< / annotation>< / semantics>< / com:Math> alkylsulfonamino, methoxyformylamino, <com:Math><semantics>C2−3<annotation encoding="application / x-tex">C_{2-3}< / annotation>< / semantics>< / com:Math> alkoxycarbonylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, <com:Math><semantics>C2−5<annotation encoding="application / x-tex">C_{2-5}< / annotation>< / semantics>< / com:Math> heterocyclyl, phenyl or <com:Math><semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics>< / com:Math> heteroaryl.
[0033] In some embodiments, each Ry is independently oxo, H, D, F, Cl, Br, I, CN, amino, hydroxy, mercapto, methyl, ethyl, propyl, butyl, C<com:Sub>2-4< / com:Sub> alkenyl, C<com:Sub>2-4< / com:Sub> alkynyl, hydroxymethyl, hydroxyethyl, amino <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl, cyano <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl, trifluoromethyl, chloroethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 2-chloro-1-methylethyl, methoxy, ethoxy, propoxy, trifluoromethoxy, methylamino, dimethylamino, <com:Math><semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics>< / com:Math> alkylcarbonyl, <com:Math><semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics>< / com:Math> alkylsulfonyl, <com:Math><semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics>< / com:Math> alkylcarbonylamino, <com:Math><semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics>< / com:Math> 3 alkylsulfonamino, methoxyformylamino, C<com:Sub>2-3< / com:Sub> alkoxycarbonylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, <com:Math><semantics>C2−5<annotation encoding="application / x-tex">C_{2-5}< / annotation>< / semantics>< / com:Math> heterocyclyl, phenyl or <com:Math><semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics>< / com:Math> heteroaryl.
[0034] In some embodiments, each R<com:Sup>5< / com:Sup> and R<com:Sup>5e< / com:Sup> is independently H, D, methyl, ethyl, propyl, butyl, hydroxy C<com:Sub>1-4< / com:Sub> alkyl, amino C<com:Sub>1-4< / com:Sub> alkyl, cyano C<com:Sub>1-4< / com:Sub> alkyl, halo C<com:Sub>1-4< / com:Sub> alkyl, C<com:Sub>1-4< / com:Sub> alkoxy-C<com:Sub>1-4< / com:Sub> alkyl; each R<com:Sup>6a< / com:Sup>, R<com:Sup>6b< / com:Sup>, R<com:Sup>6c< / com:Sup> and R<com:Sup>6d< / com:Sup> is independently H, D, F, Cl, Br, I, CN, amino, hydroxy, mercapto, methyl, ethyl, propyl, butyl, hydroxy <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl, amino <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl, cyano <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl or halo <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl.
[0035] In another aspect, provided herein is a pharmaceutical composition comprising the compound disclosed herein.
[0036] In some embodiments, the pharmaceutical composition disclosed herein further comprises at least one of pharmaceutically acceptable carrier, excipient, diluent, adjuvant and vehicle.
[0037] In one aspect, provided herein is use of the compound or the pharmaceutical composition of the invention in the manufacture of a medicament for treating and / or preventing diseases, wherein the diseases comprise heart failure, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorder, nephropathy, thromboembolic disorder, male sexual dysfunction, systemic sclerosis, sickle cell anemia, achalasia of the cardia, fibrotic disorders and / or arteriosclerosis.
[0038] In another aspect, provided herein is use of the compound or the pharmaceutical composition of the invention in the manufacture a medicament as a soluble guanylate cyclase stimulator.
[0039] In one aspect, provided herein is the compound or the pharmaceutical composition of the invention for use in treating and / or preventing diseases in a patient, wherein the diseases comprise heart failure, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorder, nephropathy, thromboembolic disorder, male sexual dysfunction, systemic sclerosis, sickle cell anemia, achalasia of the cardia, fibrotic disorders and / or arteriosclerosis.
[0040] In another aspect, provided herein is the compound or the pharmaceutical composition of the invention for use in the manufacture a medicament as a soluble guanylate cyclase stimulator.
[0041] In one aspect, provided herein is a method of treating and / or preventing diseases in a patient, comprising administering to the patient a therapeutically effective amount of the compound or the pharmaceutical composition of the invention, wherein the diseases comprise heart failure, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorder, nephropathy, thromboembolic disorder, male sexual dysfunction, systemic sclerosis, sickle cell anemia, achalasia of the cardia, fibrotic disorders and / or arteriosclerosis.
[0042] In another aspect, provided herein is a method of treating and / or preventing diseases mediated by soluble guanylate cyalase in a patient comprising administering to the patient a therapeutically effective amount of the compound or the pharmaceutical composition of the invention. DETAILED DESCRIPTION OF THE INVENTION DEFINITIONS AND GENERAL TERMINOLOGY
[0043] Reference will now be made in detail to certain embodiments disclosed herein, examples of which are illustrated in the accompanying structures and formulas. The invention is intended to cover all alternatives, modifications, and equivalents that may be included within the scope disclosed herein. One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein.
[0044] It is further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.
[0045] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as is commonly understood by one skilled in the art to which this invention belongs.
[0046] As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, and the Handbook of Chemistry and Physics, 75th Ed. 1994. Additionally, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and Smith et al., "March's Advanced Organic Chemistry", John Wiley & Sons, New York: 2007.
[0047] The grammatical articles "a", "an" and "the", as used herein, are intended to include "at least one" or "one or more" unless otherwise indicated herein or clearly contradicted by the context. Thus, the articles are used herein to refer to one or more than one (i.e., at least one) of the grammatical objects of the article. By way of example, "a component" means one or more components, and thus, possibly, more than one component are contemplated and may be employed or used in an implementation of the described embodiments.
[0048] As used herein, "patient" refers to a human (including adults and children) or other animal. In one embodiment, "patient" refers to a human.
[0049] The term "comprise" is an open expression, it means comprising the contents disclosed herein, but don't exclude other contents.
[0050] "Stereoisomers" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. Stereoisomers include enantiomer, diastereomers, conformer (rotamer), geometric (cis / trans) isomer, atropisomer, etc.
[0051] "Enantiomers" refers to two stereoisomers of a compound which are non-superimposable mirror images of one another.
[0052] "Diastereomer" refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g., melting points, boling points, spectral properties or biological activities. Mixture of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography such as HPLC.
[0053] Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.
[0054] Any asymmetric atom (e.g., carbon or the like) of the compound(s) disclosed herein can be present in racemic or enantiomerically enriched, for example the <com:Math><semantics>(R)<annotation encoding="application / x-tex">(R)< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>(S)<annotation encoding="application / x-tex">(S)< / annotation>< / semantics>< / com:Math>- or <com:Math><semantics>(R,S)<annotation encoding="application / x-tex">(R,S)< / annotation>< / semantics>< / com:Math>- configuration. In certain embodiments, each asymmetric atom has at least 50 % enantiomeric excess, at least 60 % enantiomeric excess, at least 70 % enantiomeric excess, at least 80 % enantiomeric excess, at least 90 % enantiomeric excess, at least 95 % enantiomeric excess, or at least 99 % enantiomeric excess in the <com:Math><semantics>(R)<annotation encoding="application / x-tex">(R)< / annotation>< / semantics>< / com:Math>- or <com:Math><semantics>(S)<annotation encoding="application / x-tex">(S)< / annotation>< / semantics>< / com:Math>- configuration.
[0055] Any resulting mixtures of stereoisomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric isomers, enantiomers, diastereomers, for example, by chromatography and / or fractional crystallization.
[0056] The term "tautomer" or "tautomeric form" refers to structural isomers of different energies which are interconvertible via a low energy barrier. Where tautomerization is possible (e.g., in solution), a chemical equilibrium of tautomers can be reached. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by reorganization of some of the bonding electrons. A specific example of keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerization is phenol-keto tautomerization. The specific example of phenol-keto tautomerisms is pyridin-4-ol and pyridin-<com:Math><semantics>4(1H)<annotation encoding="application / x-tex">4(1H)< / annotation>< / semantics>< / com:Math>-one tautomerism. Unless otherwise stated, all tautomeric forms of the compounds disclosed herein are within the scope of the invention.
[0057] As described herein, compounds disclosed herein may optionally be substituted with one or more substituents, such as are illustrated by Formula above, or as exemplified by particular classes, subclasses, and species of the invention.
[0058] It will be appreciated that the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted". In general, the term "substituted" refers to the replacement of one or more hydrogen radicals in a given structure with the radical of a specified substituent. The phrase "optionally substituted" refers to that the structure or group is unsubstituted, or the structure or group is substituted with one or more specific substitutents. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group. When more than one position in a given structure can be substituted with more than one substituent selected from specified groups, the substituent may be either the same or different at each position. wherein the substitutents can be, but are not limited to, oxo (=O), H, D, cyano, nitro, halogen, hydroxy, mercapto, amino, alkyl, haloalkyl, hydroxyalkyl, cyanoalkyl, aminoalkyl, alkoxy, haloalkoxy, acyl, acyloxy, sulfonyl, sulfinyl, carboxy, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl, heteroaryloxy and the like.
[0059] Furthermore, what need to be explained is that the phrase "each...is independently", "each...and...is independently" and "each of...and...is independently" can be used interchangeably herein, unless otherwise stated, and should be broadly understood. The specific options expressed by the same symbol are independent of each other in different groups; or the specific options expressed by the same symbol are independent of each other in same groups. In the same way, the term "independently" in the description ".....independently and optionally" should be broadly understood.
[0060] The term "optional" or "optionally" refers to that a subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where the event or circumstance dese not occur. For example, "optionally substituted with 1, 2, 3 or 4 substituents independently selected from ..." includes the condition that the group is substituted with 1, or 2, or 3, or 4 substitutents, and the condition that the group is not be substituted with substituent. Futhermore, when the group is substituted with more than one substituent, these substituents are independent of each other, that is, the more than one substituent may be different from each other or may be the same.
[0061] At various places in the present specification, substituents of compounds disclosed herein are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges. For example, the term "C<com:Sub>1-< / com:Sub>C<com:Sub>6< / com:Sub> alkyl" or "C<com:Sub>1-6< / com:Sub> alkyl" is specifically intended to individually disclose methyl, ethyl, C<com:Sub>3< / com:Sub> alkyl, C<com:Sub>4< / com:Sub> alkyl, C<com:Sub>5< / com:Sub> alkyl and C<com:Sub>6< / com:Sub> alkyl; "C<com:Sub>1-4< / com:Sub> alkyl" is specifically intended to individually disclose C<com:Sub>1< / com:Sub> alkyl (i.e., methyl), C<com:Sub>2< / com:Sub> alkyl (i.e., ethyl), C<com:Sub>3< / com:Sub> alkyl (i.e., propyl, including n-propyl and i-propyl), C<com:Sub>4< / com:Sub> alkyl (i.e., butyl, including n-butyl, i-butyl, sec-butyl and t-butyl).
[0062] At various places in the present specification, linking substituents are described. Where the structure clearly requires a linking group, the Markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl" then it is understood that the "alkyl" or "aryl" represents a linking alkylene group or arylene group, respectively.
[0063] The term "alkyl" or "alkyl group" refers to a saturated linear or branched-chain monovalent hydrocarbon group of 1-20 carbon atoms, wherein the alkyl group is optionally substituted with one or more substituents described herein. In some embodiments, the alkyl group contains 1-12 carbon atoms. In other embodiments, the alkyl group contains 1-6 carbon atoms, i.e., C<com:Sub>1-6< / com:Sub> alkyl. In still other embodiments, the alkyl group contains 1-4 carbon atoms, i.e., C<com:Sub>1-4< / com:Sub>alkyl. In yet other embodiments, the alkyl group contains 1-3 carbon atoms, i.e., <com:Math><semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics>< / com:Math> alkyl. In some embodiments, the <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl of the invention can be <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl; in other embodiments, the <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl can be <com:Math><semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics>< / com:Math> alkyl.
[0064] The examples of the alkyl group include, but are not limited to, methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl, tert-butyl), n- pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1- butyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3- methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, n-heptyl, n- octyl, and the like.
[0065] In some specific structures, when an alkyl group is clearly indicated as a linking group, it should be understood that the alkyl group represents a linking alkylene group. For example, the <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl group in group "<com:Math><semantics>C3−10<annotation encoding="application / x-tex">C_{3-10}< / annotation>< / semantics>< / com:Math> cycloalkyl-<com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl" should be understood as <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkylene.
[0066] The term "alkylene" refers to a saturated divalent hydrocarbon group derived from a straight or branched chain saturated hydrocarbon by the removal of two hydrogen atoms. Unless otherwise specified, the alkylene group contains 1-12 carbon atoms. In some embodiments, the alkylene group contains 1-6 carbon atoms. In other embodiments, the alkylene group contains 1-4 carbon atoms. In still other embodiments, the alkylene group contains 1-3 carbon atoms. In yet other embodiments, the alkylene group contains 1-2 carbon atoms. Such examples include methylene (-CH<com:Sub>2< / com:Sub>-), ethylene (including -CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>- or -CH(CH<com:Sub>3< / com:Sub>)-), i-propylene (including - CH(CH<com:Sub>3< / com:Sub>)CH<com:Sub>2< / com:Sub>- or -C(CH<com:Sub>3< / com:Sub>)<com:Sub>2< / com:Sub>-), and the like. Wherein, the alkylene group may be optionally substituted with one or more substituents disclosed herein.
[0067] The term "alkenyl" refers to linear or branched-chain monovalent hydrocarbon radical of 2 to 12 carbon atoms with at least one site of a carbon-carbon, sp<com:Sup>2< / com:Sup> double bond, wherein the alkenyl radical may be optionally substituted with one or more substituents described herein, and includes radicals having "cis" and "tans" orientations, or alternatively, "E" and "Z" orientations. In some embodiments, the alkenyl contains 2 to 8 carbon atoms. In other embodiments, the alkenyl contains 2 to 6 carbon atoms. In still other embodiments, the alkenyl contains 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethylenyl (-CH=CH<com:Sub>2< / com:Sub>), allyl (-CH<com:Sub>2< / com:Sub>CH=CH<com:Sub>2< / com:Sub>), and the like.
[0068] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical of 2 to 12 carbon atoms with at least one site of a carbon-carbon, sp triple bond, wherein the alkynyl radical may be optionally substituted with one or more substituents described herein. In some embodiments, the alkynyl contains 2 to 8 carbon atoms. In other embodiments, the alkynyl contains 2 to 6 carbon atoms. In still other embodiments, the alkynyl contains 2 to 4 carbon atoms. Examples of such groups include, but are not limited to, ethynyl (-C<com:Math><semantics>≡<annotation encoding="application / x-tex">\equiv< / annotation>< / semantics>< / com:Math>CH), propargyl (-CH<com:Sub>2< / com:Sub>C<com:Math><semantics>≡<annotation encoding="application / x-tex">\equiv< / annotation>< / semantics>< / com:Math> CH), 1-propynyl (-C<com:Math><semantics>≡<annotation encoding="application / x-tex">\equiv< / annotation>< / semantics>< / com:Math>C-CH<com:Sub>3< / com:Sub>), and the like.
[0069] The term "alkoxy" refers to an alkyl group, as previously defined, attached to the parent molecular moiety via an oxygen atom. Some non-limiting examples of the alkoxy group include methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, and the like.
[0070] The terms "haloalkyl" or "haloalkoxy" refer to alkyl or alkoxy, as the case may be, substituted with one or more halogen atoms. Some non-limiting examples of such groups include trifluoromethyl, trifluoromethoxy, chloroethyl (such as 2-chloroethyl), 2,2,2-trifluoroethyl, 2,2- difluroethyl, 2-chloro-1-methylethyl, and the like.
[0071] The term "amino" refers to group-NH<com:Sub>2< / com:Sub>. The term "carboxy" refers to group -COOH.
[0072] The term "hydroxy", "cyano", "nitro", "mercapto" independently refers to group -OH, - CN, <com:Math><semantics>−NO2<annotation encoding="application / x-tex">-NO_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−SH<annotation encoding="application / x-tex">-SH< / annotation>< / semantics>< / com:Math>. The term "oxo" refers to group <com:Math><semantics>=O<annotation encoding="application / x-tex">=O< / annotation>< / semantics>< / com:Math>.
[0073] The term "alkylamino" refers to an -NH<com:Sub>2< / com:Sub> group substituted with one or two alkyl groups, wherein the alkyl group is as defined herein. Some non-limiting examples of suitable alkylamino radical include, but are not limited to, methylamino and diethylamino, and the like.
[0074] The term "hydroxyalkyl", "cyanoalkyl", "aminoalkyl" respectively refers to an alkyl substituted with one or more hydroxy (-OH), cyano(-CN) or amino (-NH<com:Sub>2< / com:Sub>), wherein the alkyl is as defined herein. In some embodiments, the "hydroxyalkyl", "cyanoalkyl", "aminoalkyl" respectively refers to "hydroxy C<com:Sub>1-6< / com:Sub> alkyl", "cyano C<com:Sub>1-6< / com:Sub> alkyl", "amino C<com:Sub>1-6< / com:Sub> alkyl", i.e., a C<com:Sub>1-6< / com:Sub> alkyl substituted with one or more hydroxy (-OH), cyano (-CN) or amino (-NH<com:Sub>2< / com:Sub>). In some embodiments, the "hydroxy <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl", "cyano <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl", "amino <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl" respectively refers to "hydroxy <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl", "cyano <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl" or "amino <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl". Such examples include, but are not limited to, hydroxymethyl, hydroxyethyl (such as 2-hydroxyethyl), aminomethyl, aminoethyl (such as 2- aminoethyl), cyanomethyl, cyanoethyl (such as 2-cyanoethyl), and the like.
[0075] The term "hydroxyalkoxy", "cyanoalkoxy", "aminoalkoxy" respectively refers to an alkoxy substituted with one or more hydroxy (-OH), cyano (-CN) or amino (-NH<com:Sub>2< / com:Sub>), wherein the alkoxy is as defined herein. Such examples include, but are not limited to, hydroxymethoxy, hydroxyethoxy, cyanomethoxy, aminomethoxy, and the like.
[0076] The term "alkoxyalkyl", "alkylaminoalkyl" respectively refers to an alkyl substituted with one or more alkoxy or alkylamino, wherein the alkyl, alkoxy and alkylamino are as defined herein. Such examples include, but are not limited to, methoxymethyl, methoxyethyl, methylaminomethyl, methylaminoethyl and the like.
[0077] The term "carbocyclyl", "carbocycle" or "carbocyclic ring" refers to a monovalent or multivalent, saturated or partially unsaturated ring having 3 to 12 carbon atoms as a monocyclic, bicyclic or tricyclic ring system, wherein the carbocyclyl group is non-aromatic, and doesn't contain any aromatic ring in the system. In some embodiments, the carbocyclyl group contains 3 to 10 ring carbon atoms, such as <com:Math><semantics>C3−10<annotation encoding="application / x-tex">C_{3-10}< / annotation>< / semantics>< / com:Math> carbocyclyl. In still other embodiments, the carbocyclyl group contains 3 to 8 ring carbon atoms, such as <com:Math><semantics>C3−8<annotation encoding="application / x-tex">C_{3-8}< / annotation>< / semantics>< / com:Math> carbocyclyl. In yet other embodiments, the carbocyclyl contains 3 to 6 ring carbon atoms, such as C<com:Sub>3-6< / com:Sub> carbocyclyl. Some examples of carbocyclyl group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. wherein the C<com:Sub>3-6< / com:Sub> carbocyclyl includes, but is not limited to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. And wherein the carbocyclyl group is optionally substituted with one or more substituents described herein.
[0078] The term "cycloalkyl" refers to a saturated ring having 3 to 12 carbon atoms as a monocyclic, bicyclic, or tricyclic ring system. In some embodiments, the cycloalkyl group contains 3 to 10 ring carbon atoms, such as <com:Math><semantics>C3−10<annotation encoding="application / x-tex">C_{3-10}< / annotation>< / semantics>< / com:Math> cycloalkyl. In other embodiments, the cycloalkyl group contains 3 to 8 ring carbon atoms, such as <com:Math><semantics>C3−8<annotation encoding="application / x-tex">C_{3-8}< / annotation>< / semantics>< / com:Math> cycloalkyl. In still other embodiments, the cycloalkyl group contains 3 to 6 ring carbon atoms, such as C<com:Sub>3-6< / com:Sub> cycloalkyl. Some examples of cycloalkyl group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc., wherein the C<com:Sub>3-6< / com:Sub> cycloalkyl includes, but is not limited to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Wherein, the cycloalkyl group may be optionally substituted with one or more substituents disclosed herein.
[0079] The term "cycloalkylalkyl" refers to a cycloalkyl group attached to the rest of the molecule through an alkyl group, wherein the cycloalkyl and alkyl are as defined herein. In the invention, the description "<com:Math><semantics>C3−10<annotation encoding="application / x-tex">C_{3-10}< / annotation>< / semantics>< / com:Math> cycloalkyl-<com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl" or "<com:Math><semantics>C3−10<annotation encoding="application / x-tex">C_{3-10}< / annotation>< / semantics>< / com:Math> cycloalkyl-<com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-alkyl", and the like, refers to that <com:Math><semantics>C3−10<annotation encoding="application / x-tex">C_{3-10}< / annotation>< / semantics>< / com:Math> cycloalkyl attaches to the rest of the molecular via <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl or <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl. The "cycloalkylalkyl" group may be optionally substituted with one or more substituents disclosed herein. Some non-limiting examples include cyclopropylmethyl, cyclopropylethyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl, and the like.
[0080] The term "heterocyclyl" or "heterocyclic ring" refers to a saturated or partially unsaturated, monocyclic, bicyclic or tricyclic ring system in which at least one ring member is selected from nitrogen, sulfur and oxygen, wherein the heterocyclyl group is non-aromatic, and doesn't contain any aromatic ring in the system. Unless otherwise specified, the heterocyclyl group may be carbon or nitrogen linked, and a -CH<com:Sub>2< / com:Sub>- group can be optionally replaced by a -C(=O)- group. In which, the sulfur can be optionally oxygenized to S-oxide and the nitrogen can be optionally oxygenized to N-oxide. And wherein the carbocyclyl group is optionally substituted with one or more substituents described herein.
[0081] In some embodiments, the heterocyclyl group may be a C<com:Sub>2-9< / com:Sub> heterocyclyl group, which refers to a heterocyclyl group containing 2 to 9 ring carbon atoms and at least one ring heteroatom selected from O, S and N. In other embodiments, the heterocyclyl group may be a C<com:Sub>2-7< / com:Sub> heterocyclyl group, which refers to a heterocyclyl group containing 2 to 7 ring carbon atoms and at least one heteroatom selected from O, S and N. In still other embodiments, the heterocyclyl group may be a <com:Math><semantics>C2−5<annotation encoding="application / x-tex">C_{2-5}< / annotation>< / semantics>< / com:Math> heterocyclyl group, which refers to a heterocyclyl group containing 2 to 5 ring carbon atoms and at least one heteroatom selected from O, S and N. Some non-limiting examples of the [Image disponible dans le document PDF, Image available in the PDF document] heterocyclyl group include: , oxiranyl, thietanyl, azetidinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, tetrahydrofuranyl, dihydrothienyl, dihydropyranyl, piperidinyl, morpholinyl, tetrahydropyrimidinyl, oxazinanyl, thiomorpholinyl and piperazinyl, etc. A -CH<com:Sub>2< / com:Sub>- group of the heterocyclyl group may be substituted with -C(=O)-, some non-limiting examples of such group include 2-oxopyrrolidinyl, 2-piperidinonyl, 3-morpholinonyl, 3-thiomorpholinonyl and oxotetrahydropyrimidinyl, etc. In some embodiments, examples of C<com:Sub>2-5< / com:Sub> heterocyclyl groups of the invention include, but are not limited to, azetidinyl, pyrrolidinyl (i.e., tetrahydropyrrolyl), pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, oxomorpholinyl, thiomorpholinyl, 4,4- dioxothiomorpholinyl, tetrahydrofuranyl, oxazolidinyl (i.e., tetrahydrooxazolyl), thiazolidinyl [Image disponible dans le document PDF, Image available in the PDF document] (i.e., tetrahydrothiazolyl), 1,1-dioxoisothiazolidinyl (such as ), oxo-1,3-oxazinanyl (such [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] ), oxazolidinyl (such as ), dihydropyridine (such as 1,2-dihydropyridine [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] , dihydropyrimidine (such as 1,6-dihydropyrimidine dihydropyrazine (such [Image disponible dans le document PDF, Image available in the PDF document] as 1,2-dihydropyrazine tetrahydropyridine, tetrahydropyrimidine or tetrahydropyrazine and the like.
[0082] The term "heterocyclylalkyl" refers to a heterocyclyl group attached to the rest of the molecule through an alkyl group, wherein the heterocyclyl and alkyl are as defined herein. In the invention, the group "<com:Math><semantics>C2−9<annotation encoding="application / x-tex">C_{2-9}< / annotation>< / semantics>< / com:Math> heterocyclyl-<com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl", and the like, refers to that <com:Math><semantics>C2−9<annotation encoding="application / x-tex">C_{2-9}< / annotation>< / semantics>< / com:Math> cycloalkyl attaches to the rest of the molecular via <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl. The heterocyclylalkyl group may be optionally substituted with one or more substituents disclosed herein. Some non-limiting examples of such group included tetrahydropyranylmethyl, tetrahydropyranylethyl, tetrahydrofuranylmethyl, tetrahydrofuranylethyl, pyrrolidinylmethyl, piperidinylmethyl, piperidinylethyl, morpholinylmethyl and morpholinylethyl, etc.
[0083] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
[0084] The term "aryl" refers to monocyclic, bicyclic and tricyclic carbocyclic ring systems having a total of six to fourteen ring members, or six to twelve ring members, or six to ten ring members, wherein at least one ring in the system is aromatic, and the aryl group has a single point or multipoint of attachment to the rest of the molecule. The term "aryl" and "aromatic ring" can be used interchangeably herein. Some non-limiting examples of the aryl group include phenyl, 2,3-dihydro-1H-indenyl, naphthalenyl and anthracenyl, etc. The aryl group may be optionally substituted with one or more substituents disclosed herein. Unless otherwise specified, the group "<com:Math><semantics>C6−14<annotation encoding="application / x-tex">C_{6-14}< / annotation>< / semantics>< / com:Math> aryl" refers to an aryl group having 6-14 ring carbon atoms.
[0085] The term "arylalkyl" or "aralkyl" refers to an aryl group attached to the rest of the molecule through an alkyl group, wherein the aryl and alkyl are as defined herein. For example, the group "<com:Math><semantics>C6−14<annotation encoding="application / x-tex">C_{6-14}< / annotation>< / semantics>< / com:Math> aryl-<com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl" refers to that <com:Math><semantics>C6−14<annotation encoding="application / x-tex">C_{6-14}< / annotation>< / semantics>< / com:Math> aryl group attaches to the rest of the molecular via <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl. The arylalkyl group may be optionally substituted with one or more substituents disclosed herein. Some non-limiting examples of such group include benzyl, phenylethyl and naphthalenylmethyl, etc.
[0086] The term "heteroaryl" refers to monocyclic, bicyclic and tricyclic carbocyclic ring systems having a total of five to twelve ring members, or five to ten ring members, or five to six ring members, wherein at least one ring in the system is aromatic, and in which at least one ring member is selected from nitrogen, oxygen and sulfur, and that has a single point or multipoint of attachment to the rest of the molecule. When -CH<com:Sub>2< / com:Sub>- group exsits in heteroaryl group, the -CH<com:Sub>2< / com:Sub>- disclosed herein is optionally replaced with <com:Math><semantics>−C(=O)<annotation encoding="application / x-tex">-C(=O)< / annotation>< / semantics>< / com:Math>. Unless specified, the heteroaryl group can be attached to the rest of the molecule (eg., the main structure in the general formula) through any reasonable site (may be C in CH, or N in NH.) The term "heteroaryl" and "heteroaromatic ring" or "heteroaromatic compound" can be used interchangeably herein. In other embodiments, the heteroaryl group may be a C<com:Sub>1-9< / com:Sub> heteroaryl group, which refers to a heteroaryl group containing 1 to 9 ring carbon atoms and at least one ring heteroatom selected from O, S and N. In other embodiments, the heteroaryl group may be a <com:Math><semantics>C1−7<annotation encoding="application / x-tex">C_{1-7}< / annotation>< / semantics>< / com:Math> heteroaryl group, which refers to a heteroaryl group containing 1 to 7 ring carbon atoms and at least one ring heteroatom selected from O, S and N. In still other embodiments, the heteroaryl group may be a <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> heteroaryl group, which refers to a heteroaryl group containing 1 to 6 ring carbon atoms and at least one ring heteroatom selected from O, S and N. In other embodiments, the heteroaryl group may be a <com:Math><semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics>< / com:Math> heteroaryl group, which refers to a heteroaryl group containing 1 to 5 ring carbon atoms and at least one ring heteroatom selected from O, S and N. In still other embodiments, the heteroaryl group may be a <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> heteroaryl group, which refers to a heteroaryl group containing 1 to 4 ring carbon atoms and at least one ring heteroatom selected from O, S and N. In yet other embodiments, the heteroaryl group may be a C<com:Sub>1-3< / com:Sub> heteroaryl group, which refers to a heteroaryl group containing 1 to 3 ring carbon atoms and at least one ring heteroatom selected from O, S and N. In some embodiments, the term "6- to 10-membered heteroaryl" refers to the heteroaryl consists of 6-10 ring atoms, wherein at least one of the ring atoms is a heteroatom selected from O, N and S. Some non-limiting examples of such group include furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, etc, and also include the following non-limiting bicyclic ring: benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl, oxoindolyl, indolinyl, imidazopyridyl, pyrazopyridyl, pyrazopyrimidinyl, quinolyl, isoquinolyl and quinazolinyl, etc. The heteroaryl group may be optionally substituted with one or more substituents disclosed herein.
[0087] The term "heteroarylalkyl" refers to a heteroaryl group attached to the rest of the molecule through an alkyl group, wherein the heteroaryl and alkyl are as defined herein. The "heteroarylalkyl" group may be optionally substituted with one or more substituents disclosed herein. Some non-limiting examples of such group included pyridylmethyl, pyrrolylethyl and quinolylmethyl, etc.
[0088] The term "x- to y-membered" (each x and y is independently any non-zero natural number, and <com:Math><semantics>y>x<annotation encoding="application / x-tex">y > x< / annotation>< / semantics>< / com:Math>) refers to the cyclic grop consists of x to y ring atoms, wherein "x- to y-" includes any natural numbers between x and y. The ring atoms here include carbon atoms and / or heteroatoms such as O, N, S, and P, etc. For example, "3- to 8-membered", "3- to 10-membered", "3- to 6- membered" or "6- to 10-membered" refers to the cyclic grop consists of 3 to 8, 3 to 10, 3 to 6 or 6 to 10 ring atoms. The ring atoms include carbon atoms and / or heteroatoms such as O, N, S, and P, etc. For another example, "6- to 10-membered heteroaryl" represents a heteroaryl group consisting of 6, 7, 8, 9 or 10 ring atoms.
[0089] The term "acyl" denotes -C(=O)-R, wherein the substituent R is attached to the rest of the molecule through a carbonyl group (<com:Math><semantics>−C(=O)<annotation encoding="application / x-tex">-C(=O)< / annotation>< / semantics>< / com:Math>-), wherein R is a substituent described herein, including but not limited to alkyl, alkoxy, hydroxy, amino, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the like. Wherein the alkyl, alkoxy, hydroxy, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl are as defined herein, and such examples include, but are not limited to, acetyl (- <com:Math><semantics>C(=O)CH3<annotation encoding="application / x-tex">C(=O)CH_3< / annotation>< / semantics>< / com:Math>), carboxy (-<com:Math><semantics>C(=O)OH<annotation encoding="application / x-tex">C(=O)OH< / annotation>< / semantics>< / com:Math>), methoxycarbonyl (-<com:Math><semantics>C(=O)OCH3<annotation encoding="application / x-tex">C(=O)OCH_3< / annotation>< / semantics>< / com:Math>), carbamoyl (-<com:Math><semantics>C(=O)NH2<annotation encoding="application / x-tex">C(=O)NH_2< / annotation>< / semantics>< / com:Math>), benzoyl, and the like. The term "sulfonyl" denotes <com:Math><semantics>−S(=O)2−R<annotation encoding="application / x-tex">-S(=O)_2-R< / annotation>< / semantics>< / com:Math>, wherein the substituent R is attached to the rest of the molecule through a sulfonyl group (<com:Math><semantics>−S(=O)2<annotation encoding="application / x-tex">-S(=O)_2< / annotation>< / semantics>< / com:Math>-), wherein R is a substituent described herein, including but not limited to alkyl, alkoxy, hydroxy, amino, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the like. Wherein the alkyl, alkoxy, hydroxy, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl are as defined herein, and such examples include, but are not limited to, sulfonic acid <com:Math><semantics>(−S(=O)2OH),<annotation encoding="application / x-tex">(-S(=O)_2OH),< / annotation>< / semantics>< / com:Math> methylsulfonyl <com:Math><semantics>(−S(=O)2CH3),<annotation encoding="application / x-tex">(-S(=O)_2CH_3),< / annotation>< / semantics>< / com:Math> methoxysulfonyl <com:Math><semantics>(−S(=O)2OCH3),<annotation encoding="application / x-tex">(-S(=O)_2OCH_3),< / annotation>< / semantics>< / com:Math> aminosulfonyl (<com:Math><semantics>−S(=O)2NH2<annotation encoding="application / x-tex">-S(=O)_2NH_2< / annotation>< / semantics>< / com:Math>), phenylsulfonyl, and the like.
[0090] The term "sulfinyl" denotes -S(=O)-R, wherein the substituent R is attached to the rest of the molecule through a sulfonyl group (-S(=O)-), wherein R is a substituent described herein, including but not limited to alkyl, alkoxy, hydroxy, amino, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the like. Wherein, alkyl, alkoxy, hydroxy, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl are as defined herein, and such examples include, but are not limited to, sulfinyl (- <com:Math><semantics>S(=O)OH<annotation encoding="application / x-tex">S(=O)OH< / annotation>< / semantics>< / com:Math>), methylsulfinyl (<com:Math><semantics>−S(=O)CH3<annotation encoding="application / x-tex">-S(=O)CH_3< / annotation>< / semantics>< / com:Math>), phenylsulfinyl, and the like.
[0091] The terms "alkylcarbonyl", "alkylsulfonyl" denote the groups -C(=O)-alkyl and -S(=O)<com:Sub>2< / com:Sub>- alkyl, respectively, wherein the alkyl group is as fefined herein. Such examples include, but are not limited to, acetyl (<com:Math><semantics>−C(=O)CH3<annotation encoding="application / x-tex">-C(=O)CH_3< / annotation>< / semantics>< / com:Math>), methylsulfonyl (<com:Math><semantics>−S(=O)2CH3<annotation encoding="application / x-tex">-S(=O)_2CH_3< / annotation>< / semantics>< / com:Math>), and the like.
[0092] The terms "alkylcabonylamino", "alkylsulfonylamino", "alkoxycarbonylamino" denote respectively the group -NH-C(=O)-alkyl, -NH-S(=O)<com:Sub>2< / com:Sub>-alkyl and -NH-C(=O)-alkoxy (i.e., -NH-C(=O)-O-alkyl), wherein the alkyl and alkoxy groups all are as defined in the invention. Such examples include, but are not limited to, methylcarbonylamino (-NH-C(=O)CH<com:Sub>3< / com:Sub>), methylsulfonylamino (-NH-S(=O)<com:Sub>2< / com:Sub>CH<com:Sub>3< / com:Sub>), methoxylcarbonylamino (-NH-C(=O)-O-CH<com:Sub>3< / com:Sub>) and the like.
[0093] The term "alkoxycarbonyl", "alkylaminocarbonyl", "cycloalkylcarbonyl", "heterocyclylcarbonyl", "arylcarbonyl", "heteroarylcarbonyl" respectively refers to group - C(=O)-alkoxy, -C(=O)-alkylamino, -C(=O)-cyclalkyl, -C(=O)-heterocyclyl, -C(=O)-aryl, -C(=O)- heteroaryl, wherein the alkoxy, alkylamino, cycloalkyl, heterocyclyl, aryl and heteroaryl are all as defined herein. Such examples include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, methylaminocarbonyl, ethylaminocarbonyl, cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cyclopropoxycarbonyl, tetrahydrofurylcarbonyl, tetrahydropyranylcarbonyl, piperidylcarbonyl, piperazinylcarbonyl, morpholinylcarbonyl, tetrahydrothienylcarbonyl, pyrrolidinylcarbonyl, phenylcarbonyl, pyridylcarbonyl, pyrimidinylcarbonyl, pyrrolylcarbonyl, imidazolylcarbonyl, pyrazolylcarbonyl, thienylcarbonyl or furylcarbonyl, and the like.
[0094] As described herein, a bond drawn from a substituent <com:Math><semantics>(R)n1<annotation encoding="application / x-tex">(R)_{n1}< / annotation>< / semantics>< / com:Math> to the center of one ring within a ring system represents substitution of n1 substituents R at any substitutable position on the rings. For example, formula a repersents substitution of substituent R<com:Sup>4< / com:Sup> at any substitutable position on the C2 ring, furthermore, C2 ring can be optionally substituted with r R<com:Sup>3< / com:Sup>. When the C2 ring is a bicyclic system, R<com:Sup>4< / com:Sup>or R<com:Sup>3< / com:Sup> may be substituted at any substitutable position on any ring. [Image disponible dans le document PDF, Image available in the PDF document]
[0095] As described in the present invention, there are two linking sites on the group "-(CR<com:Sup>a< / com:Sup>R<com:Sup>b< / com:Sup>)<com:Sub>f< / com:Sub>- O-" that can be linked to the rest of the molecule, and the connection types of the two linking sites can be interchanged. For example, when L described in the present invention is a group in Formula b, L (ie., -(CR<com:Sup>a< / com:Sup>R<com:Sup>b< / com:Sup>)<com:Sub>f< / com:Sub>-O-) may connect to the rest of the molecule (eg., indazole structure in Formula (I)) via the E-terminus or E' terminus. [Image disponible dans le document PDF, Image available in the PDF document]
[0096] As described in the present invention, the description "any adjacent two R<com:Sup>3< / com:Sup>, together with the carbon atoms to which they are attached, form a 3- to 6-membered carbocyclic ring, heterocyclic ring, aromatic ring or heteroaromatic ring" means that any adjacent two R<com:Sup>3< / com:Sup>, together with the carbon atoms to which they are attached, may form a 3- to 6-membered carbocyclic ring, a 3- to 6-membered heterocyclic ring, a 3- to 6-membered aromatic ring or a 3- to 6-membered heteroaromatic ring, wherein the carbocyclic ring, heterocyclic ring, aromatic ring and heteroaromatic ring are all as defined in the present invention. Wherein the 3- to 6-membered aromatic ring includes 6-membered aromatic ring, i.e., benzene ring; the 3- to 6-membered heteroaromatic ring includes 5- to 6-membered heteroaromatic ring; the 3- to 6-membered carbocyclic ring and 3- to 6-membered heterocyclic ring include saturated or partially unsaturated carbocyclic ring or heterocyclic ring, and wherein -CH<com:Sub>2< / com:Sub>- may be replaced by -C(=O)-; The sulfur atom in the heterocyclic ring may be optionally oxidized to a S-oxide, and the nitrogen atom may be optionally oxidized to an N-oxide. When ring C2 is aryl or heteroaryl, the 3- to 6-membered carbocyclic ring or 3- to 6-membered heterocyclic ring is an unsaturated carbocyclic or [Image disponible dans le document PDF, Image available in the PDF document] heterocyclic ring, specific examples include but are not limited to, [Image disponible dans le document PDF, Image available in the PDF document] etc. Examples of the 3- to 6-membered aromatic ring and 3- to 6-membered [Image disponible dans le document PDF, Image available in the PDF document] heteroaromatic ring include, but are not limited to, and the like. Further more, the 3- to 6-membered carbocyclic ring, heterocyclic ring, aromatic ring and heteroaryl rings are unsubstituted or optionally substituted with 1, 2, 3 or 4 R<com:Sup>z< / com:Sup> as described herein.
[0097] As described in the present invention, the description "R<com:Sup>5a< / com:Sup> and R<com:Sup>5b< / com:Sup>, together with the N atom to which they are attached, form a 3- to 6-membered heterocyclic ring or heteroaromatic ring; or, R<com:Sup>5c< / com:Sup> and R<com:Sup>5d< / com:Sup>, together with the N atom to which they are attached, form a 3- to 6-membered heterocyclic ring or heteroaromatic ring" means that R<com:Sup>5a< / com:Sup> and R<com:Sup>5b< / com:Sup>, together with the N atom to which they are attached, or, R<com:Sup>5c< / com:Sup> and R<com:Sup>5d< / com:Sup>, together with the N atom to which they are attached, may form a 3- to 6-membered heterocyclic ring or 3- to 6-membered heteroaromatic ring, wherein the heterocyclic ring and heteroaromatic ring are all as defined in the present invention. Wherein the 3- to 6-membered heteroaromatic ring includes 5- to 6-membered heteroaromatic ring; the 3- to 6- membered heterocyclic ring or 3- to 6-membered heteroaromatic ring includes but not limited to [Image disponible dans le document PDF, Image available in the PDF document] oxazolidine (i.e., the following cyclic groups: azetidine, pyrrolidine [Image disponible dans le document PDF, Image available in the PDF document] , isothiazolidine (i.e., <com:Math><semantics>↘ξ<annotation encoding="application / x-tex">\stackrel{\xi}{\searrow}< / annotation>< / semantics>< / com:Math> ), piperidine [Image disponible dans le document PDF, Image available in the PDF document] thiazolidine , morpholine [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] , piperazine (i.e, <com:Math><semantics>⌣ξ<annotation encoding="application / x-tex">\stackrel{\xi}{\smile}< / annotation>< / semantics>< / com:Math>NH ), thiomorpholine (i.e, , 1,3-oxazinidine [Image disponible dans le document PDF, Image available in the PDF document] pyrrole (i.e, <com:Math><semantics>ξN<annotation encoding="application / x-tex">\frac{\xi}{N}< / annotation>< / semantics>< / com:Math>) [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] , imidazole , <com:Math><semantics>ξN↘NN<annotation encoding="application / x-tex">\xi_N \stackrel{N}{\searrow} N< / annotation>< / semantics>< / com:Math>), tetrazole (including but not limited to [Image disponible dans le document PDF, Image available in the PDF document] triazole (including but not limited to [Image disponible dans le document PDF, Image available in the PDF document] dihydropyridine (i.e, 1,2-dihydropyridine dihydropyrimidine (e.g., 1,6- [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] dihydropyrimidine dihydropyrazine (e.g., 1,2-dihydropyrazine ), tetrahydropyridine, tetrahydropyrimidine or tetrahydropyrazine, and the like. Furthermore, wherein the -CH<com:Sub>2< / com:Sub>- in "3- to 6-membered heterocyclic ring" may be replaced by -C(<com:Math><semantics>=<annotation encoding="application / x-tex">=< / annotation>< / semantics>< / com:Math>O)-; the sulfur atom in the heterocyclic ring may be optionally oxidized to a S-oxide, and the nitrogen atom may be optionally oxidized to an N-oxide. Such examples include, but are not limited to, [Image disponible dans le document PDF, Image available in the PDF document] dioxoisothiazolidine (i.e., and the like.
[0098] The term "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction, such as gastric upset, dizziness and the like, when administered to a human. Preferably, as used herein, the term "pharmaceutically acceptable" means molecular entities and compositions approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
[0099] The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the compound is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water or aqueous solution solutions (such as saline solution, glucose solution, glycerol solution) are preferably employed as carriers, particularly for injectable solutions. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E. W. Martin.
[00100] The term "sGC stimulator" refers to a compound or agent that has a stimulatory effect on soluble guanylate cyclase (sGC). In some embodiments, "stimulator" and "agonist" may be used interchangeably.
[00101] The term "prodrug" refers to a compound that is transformed in vivo into a compound of the invention (i.e., the compound represented by Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (II), Formula (IIa), Formula (IIb), Formula (IIc), Formula (IId), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (IVc), Formula (Va), Formula (Vb), Formula (Vc) or Formula (Vd)). Such a transformation can be affected, for example, by hydrolysis of the prodrug form in blood or enzymatic transformation to the parent form in blood or tissue. Prodrugs of the compounds disclosed herein may be, for example, esters. Some common esters which have been utilized as prodrugs are phenyl esters, aliphatic (<com:Math><semantics>C1−24<annotation encoding="application / x-tex">C_{1-24}< / annotation>< / semantics>< / com:Math>) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound disclosed herein that contains a hydroxy group may be acylated at this position in its prodrug form. Other prodrug forms include phosphates, such as, those phosphate compounds derived from the phosphonation of a hydroxy group on the parent compound. A thorough discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al., Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and S. J. Hecker et al., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.
[00102] A "metabolite" is a product produced through metabolism in the body of a specified compound or salt thereof. The metabolites of a compound may be identified using routine techniques known in the art and their activities determined using tests such as those described herein. Such products may result for example from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzyme cleavage, and the like, of the administered compound. Accordingly, the invention includes metabolites of compounds disclosed herein, including metabolites produced by contacting a compound disclosed herein with a mammal for a sufficient time period.
[00103] A "pharmaceutically acceptable salts" refers to organic or inorganic salts of a compound disclosed herein. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Some non-limiting examples of pharmaceutically acceptable and nontoxic salts formed from acid include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate; organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate; or obtained by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3- phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and <com:Math><semantics>N+(C1−4 alkyl)4<annotation encoding="application / x-tex">N^+(C_{1-4} \text{ alkyl})_4< / annotation>< / semantics>< / com:Math> salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil soluble or dispersable products may be obtained by such quaternization. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, <com:Math><semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics>< / com:Math> sulfonate or aryl sulfonate.
[00104] The term "solvate" refers to an association or complex of one or more solvent molecules and a compound disclosed herein. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid and ethanolamine. The term "hydrate" refers to the complex where the solvent molecule is water.
[00105] An "ester" refers to an in vivo hydrolysable ester of a compound of the invention containing hydroxy or carboxyl group. For example, a pharmaceutically acceptable ester is which is hydrolysed in the human or animal body to produce the parent alcohol or acid. The compounds of the present invention (i.e., the compound represented by Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (II), Formula (IIa), Formula (IIb), Formula (IIc), Formula (IId), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (IVc), Formula (Va), Formula (Vb), Formula (Vc) or Formula (Vd)) contain a carboxy group and can form in vivo hydrolysable esters with suitable groups. Such groups include, but are not limited to, alkyl, arylalkyl and the like.
[00106] An "N-oxide" refers to one or more than one nitrogen atoms oxidised to form an N- oxide, where a compound contains several amine functions. Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle. N-oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g., a peroxycarboxylic acid) (See, Advanced Organic Chemistiy, by Jerry March, 4th Edition, Wiley Interscience, pages). More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with <com:Math><semantics>m<annotation encoding="application / x-tex">m< / annotation>< / semantics>< / com:Math>-chloroperoxybenzoic acid (MCPBA), for example, in an inert solvent such as dichloromethane.
[00107] As used in the present invention, "the compound of the invention", "the compound of the present invention", "the compound described in the present invention", "a compound described in the present invention" or the like are all referred to the compound represented by any one of the general Formula described in the present invention, i.e., the compound represented by Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (II), Formula (IIa), Formula (IIb), Formula (IIc), Formula (IId), Formula (III), Formula (IV), Formula (IVa), Formula (IVb), Formula (IVc), Formula (Va), Formula (Vb), Formula (Vc) or Formula (Vd).
[00108] As used herein, the term "treat", "treating" or "treatment" of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment "treat", "treating" or "treatment" refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient. In yet another embodiment, "treat", "treating" or "treatment" refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In yet another embodiment, "treat", "treating" or "treatment" refers to preventing or delaying the onset or development or progression of the disease or disorder.
[00109] Any formula given herein is also intended to represent isotopically unenriched forms as well as isotopically enriched forms of the compounds. Any formula given herein is also intended to represent isotopically unenriched forms as well as isotopically enriched forms of the compounds. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as <com:Sup>2< / com:Sup>H, <com:Sup>3< / com:Sup>H, <com:Sup>11< / com:Sup>C, <com:Sup>13< / com:Sup>C, <com:Sup>14< / com:Sup>C, <com:Sup>15< / com:Sup>N, <com:Sup>17< / com:Sup>O, <com:Sup>18< / com:Sup>O, <com:Sup>18< / com:Sup>F, <com:Sup>31< / com:Sup>P, <com:Sup>32< / com:Sup>P, <com:Sup>35< / com:Sup>S, <com:Sup>36< / com:Sup>Cl and <com:Sup>125< / com:Sup>I respectively.
[00110] In another aspect, the compounds of the invention include isotopically enriched compounds as defined herein, for example those into which radioactive isotopes, such as <com:Sup>3< / com:Sup>H, <com:Sup>14< / com:Sup>C and <com:Sup>18< / com:Sup>F, or those into which non-radioactive isotopes, such as <com:Sup>2< / com:Sup>H and <com:Sup>13< / com:Sup>C are present. Such isotopically enriched compounds are useful in metabolic studies (with <com:Sup>14< / com:Sup>C), reaction kinetic studies (with, for example <com:Sup>2< / com:Sup>H or <com:Sup>3< / com:Sup>H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an <com:Sup>18< / com:Sup>F- enriched compound may be particularly desirable for PET or SPECT studies. Isotopically-enriched compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.
[00111] Further, substitution with heavier isotopes, particularly deuterium (i.e., <com:Sup>2< / com:Sup>H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index. It is should be understood that deuterium in this context is regarded as a substituent of a compound of the invention. The concentration of such a heavier isotope, specifically deuterium, may be defined by the isotopic enrichment factor. The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent in a compound of this invention is denoted deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g., <com:Math><semantics>D2O<annotation encoding="application / x-tex">D_2O< / annotation>< / semantics>< / com:Math>, acetone-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>.
[00112] Unless otherwise stated, all tautomeric forms of the compounds disclosed herein are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
[00113] As used herein, the abbreviations for any protective groups, amino acids and other compounds are, unless otherwise indicated, in accord with their common usage, recognized abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature (See, Biochem. 1972, 11: 942-944). DESCRIPTION OF COMPOUNDS OF THE INVENTION
[00114] The present invention provides a novel fluorine-substituted indazole compounds as sGC stimulators and pharmaceutical compositions thereof, and the use of the compounds or the pharmaceutical compositions in the manufacture of a medicament, wherein the medicament is used for the treatment and / or prevention of sGC-mediated diseases such as heart failure, sclerosis, systemic sclerosis, sickle cell anemia, achalasia of cardia, pulmonary fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis, pulmonary hypertension and the like.
[00115] In one aspect, provided herein is a compound having Formula (I) or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a ester, a pharmaceutically acceptable salt or a prodrug thereof, [Image disponible dans le document PDF, Image available in the PDF document] (I), wherein, C1 is aryl, heteroaryl, carbocyclyl or heterocyclyl; C2 is aryl, heteroaryl, carbocyclyl or heterocyclyl; and each L, R<com:Sup>1< / com:Sup>, R<com:Sup>2< / com:Sup>, R<com:Sup>3< / com:Sup>, R<com:Sup>4< / com:Sup>, m, n and r is as defined herein.
[00116] In some embodiments, provided herein is a compound having Formula (Ia), Formula (Ib) or Formula (Ic), or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof, [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (Ia), (Ib) or [Image disponible dans le document PDF, Image available in the PDF document] (Ic), wherein each L, C1, C2, R<com:Sup>1< / com:Sup>, R<com:Sup>2< / com:Sup>, R<com:Sup>3< / com:Sup>, R<com:Sup>4< / com:Sup>, m, n and r is as defined herein.
[00117] In some embodiments, L is <com:Math><semantics>−(CRaRb)t−<annotation encoding="application / x-tex">-(CR^aR^b)_{t-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−(CRaRb)f−O−<annotation encoding="application / x-tex">-(CR^aR^b)_{f-}O_{-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−(CRaRb)f−S−<annotation encoding="application / x-tex">-(CR^aR^b)_{f-}S_{-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−(CRaRb)f−S−<annotation encoding="application / x-tex">-(CR^aR^b)_{f-}S_{-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−(CRaRb)f−S−<annotation encoding="application / x-tex">-(CR^aR^b)_{f-}S_{-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−(CRaRb)f−S−<annotation encoding="application / x-tex">-(CR^aR^b)_{f-}S_{-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−(CRaRb)f−S−<annotation encoding="application / x-tex">-(CR^aR^b)_{f-}S_{-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−(CRaRb)f−S−<annotation encoding="application / x-tex">-(CR^aR^b)_{f-}S_{-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>(CRaRb)f−S(=O)2−,−(CRaRb)f−N(Rc)−,−(CRaRb)f−C(=O)N(Rc)−,−C(=O)N(Rc)−(CRaRb)f−<annotation encoding="application / x-tex">(CR^aR^b)_{f^-}S(=O)_{2^-}, -(CR^aR^b)_{f^-}N(R^c)_{-}, -(CR^aR^b)_{f^-}C(=O)N(R^c)_{-}, -C(=O)N(R^c)_{-}(CR^aR^b)_{f^-}< / annotation>< / semantics>< / com:Math> or - <com:Math><semantics>(CRaRb)f−C(=O)−;<annotation encoding="application / x-tex">(CR^{a}R^{b})_{f}-C(=O)-;< / annotation>< / semantics>< / com:Math> t is 1, 2, 3 or 4; and each f is independently 0, 1, 2, 3 or 4.
[00118] In some embodiments, each R<com:Sup>a< / com:Sup> and R<com:Sup>b< / com:Sup> is independently H, D, F, Cl, Br, I, CN, amino, hydroxy, mercapto, C<com:Sub>1-6< / com:Sub> alkyl, C<com:Sub>2-6< / com:Sub> alkenyl, C<com:Sub>2-6< / com:Sub> alkynyl, halo C<com:Sub>1-6< / com:Sub> alkyl, C<com:Sub>1-6< / com:Sub> alkoxy, C<com:Sub>1-6< / com:Sub> alkylamino, halo C<com:Sub>1-6< / com:Sub> alkoxy, acyl, sulfonyl, C<com:Sub>3-6< / com:Sub> cycloalkyl, C<com:Sub>2-5< / com:Sub> heterocyclyl, C<com:Sub>6-10< / com:Sub> aryl or C<com:Sub>1-5< / com:Sub> heteroaryl; or, R<com:Sup>a< / com:Sup> and R<com:Sup>b< / com:Sup> together form carbonyl; or, R<com:Sup>a< / com:Sup> and R<com:Sup>b< / com:Sup>, together with the carbon atom to which they are attached, form a 3- to 8-membered carbocyclic ring or 3- to 8-membered heterocyclic ring; each <com:Math><semantics>Rc<annotation encoding="application / x-tex">R^c< / annotation>< / semantics>< / com:Math> is independently H, D, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math> alkenyl, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math> alkynyl, halo <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, acyl, sufonyl, <com:Math><semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>< / com:Math> cycloalkyl, <com:Math><semantics>C2−5<annotation encoding="application / x-tex">C_{2-5}< / annotation>< / semantics>< / com:Math> heterocyclyl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl or <com:Math><semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics>< / com:Math> heteroaryl.
[00119] In some embodiments, each R<com:Sup>a< / com:Sup> and R<com:Sup>b< / com:Sup> is independently H, D, F, Cl, Br, I, CN, amino, hydroxy, mercapto, methyl, ethyl, propyl, butyl, C<com:Sub>2-4< / com:Sub> alkenyl, C<com:Sub>2-4< / com:Sub> alkynyl, halo C<com:Sub>1-4< / com:Sub> alkyl, C<com:Sub>1-4< / com:Sub> alkoxy, C<com:Sub>1-4< / com:Sub> alkylamino, halo C<com:Sub>1-4< / com:Sub> alkoxy, C<com:Sub>3-6< / com:Sub> cycloalkyl, C<com:Sub>2-5< / com:Sub> heterocyclyl, phenyl or C<com:Sub>1-5< / com:Sub> heteroaryl; or, R<com:Sup>a< / com:Sup> and R<com:Sup>b< / com:Sup> together form carbonyl; or, R<com:Sup>a< / com:Sup> and R<com:Sup>b< / com:Sup>, together with the carbon atom to which they are attached, form a 3- to 6-membered carbocyclic ring or 3- to 6-membered heterocyclic ring; and each R<com:Sup>c< / com:Sup> is independently H, D, methyl, ethyl, propyl, butyl, C<com:Sub>2-4< / com:Sub> alkenyl, C<com:Sub>2-4< / com:Sub> alkynyl, halo <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>< / com:Math> cycloalkyl, <com:Math><semantics>C2−5<annotation encoding="application / x-tex">C_{2-5}< / annotation>< / semantics>< / com:Math> heterocyclyl, phenyl or <com:Math><semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics>< / com:Math> heteroaryl.
[00120] In some embodiments, each L is independently -CH<com:Sub>2< / com:Sub>-, -CH(CH<com:Sub>3< / com:Sub>)-, -(CH<com:Sub>2< / com:Sub>)<com:Sub>2< / com:Sub>-, -(CH<com:Sub>2< / com:Sub>)<com:Sub>3< / com:Sub>-, [Image disponible dans le document PDF, Image available in the PDF document]
[00121] In some embodiments, C1 is <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl, <com:Math><semantics>C1−9<annotation encoding="application / x-tex">C_{1-9}< / annotation>< / semantics>< / com:Math> heteroaryl, <com:Math><semantics>C3−10<annotation encoding="application / x-tex">C_{3-10}< / annotation>< / semantics>< / com:Math> carbocyclyl or <com:Math><semantics>C2−9<annotation encoding="application / x-tex">C_{2-9}< / annotation>< / semantics>< / com:Math> heterocyclyl.
[00122] In some embodiments, C2 is <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl, <com:Math><semantics>C3−10<annotation encoding="application / x-tex">C_{3-10}< / annotation>< / semantics>< / com:Math> carbocyclyl, <com:Math><semantics>C2−9<annotation encoding="application / x-tex">C_{2-9}< / annotation>< / semantics>< / com:Math> heterocyclyl or 6- to 10- membered heteroaryl.
[00123] In some embodiments, C1 is <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl, <com:Math><semantics>C1−9<annotation encoding="application / x-tex">C_{1-9}< / annotation>< / semantics>< / com:Math> heteroaryl, <com:Math><semantics>C3−10<annotation encoding="application / x-tex">C_{3-10}< / annotation>< / semantics>< / com:Math> carbocyclyl or <com:Math><semantics>C2−9<annotation encoding="application / x-tex">C_{2-9}< / annotation>< / semantics>< / com:Math> heterocyclyl; and C2 is <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl, <com:Math><semantics>C3−10<annotation encoding="application / x-tex">C_{3-10}< / annotation>< / semantics>< / com:Math> carbocyclyl, <com:Math><semantics>C2−9<annotation encoding="application / x-tex">C_{2-9}< / annotation>< / semantics>< / com:Math> heterocyclyl or 6- to 10-membered heteroaryl.
[00124] In some embodiments, C1 is: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>(C1−1),<annotation encoding="application / x-tex">(C1-1),< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(C1−2),<annotation encoding="application / x-tex">(C1-2),< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(C1−3),<annotation encoding="application / x-tex">(C1-3),< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(C1−4)<annotation encoding="application / x-tex">(C1-4)< / annotation>< / semantics>< / com:Math> or <com:Math><semantics>(C1−5);<annotation encoding="application / x-tex">(C1-5);< / annotation>< / semantics>< / com:Math> each <com:Math><semantics>X1<annotation encoding="application / x-tex">X^1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>X2<annotation encoding="application / x-tex">X^2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>X3<annotation encoding="application / x-tex">X^3< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>X4<annotation encoding="application / x-tex">X^4< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>X5<annotation encoding="application / x-tex">X^5< / annotation>< / semantics>< / com:Math> is independently N or CH; each <com:Math><semantics>Y1<annotation encoding="application / x-tex">Y^1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>Y2<annotation encoding="application / x-tex">Y^2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>Y3<annotation encoding="application / x-tex">Y^3< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>Y4<annotation encoding="application / x-tex">Y^4< / annotation>< / semantics>< / com:Math> is independently CH<com:Sub>2< / com:Sub>, C(=O), NH, S, S(=O), S(=O)<com:Sub>2< / com:Sub> or O; d is 0, 1, 2, 3 or 4; wherein, is the bond through which C1 is attached to L.
[00125] In some embodiments, C1 is: [Image disponible dans le document PDF, Image available in the PDF document] 1 2 wherein each <com:Math><semantics>X1<annotation encoding="application / x-tex">X^1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>X2<annotation encoding="application / x-tex">X^2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>X3<annotation encoding="application / x-tex">X^3< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>X5<annotation encoding="application / x-tex">X^5< / annotation>< / semantics>< / com:Math> is independently N or CH; 3 Y<com:Sup>1a< / com:Sup> is CH<com:Sub>2< / com:Sub>, NH, S or O; 4 <com:Math><semantics>Y2<annotation encoding="application / x-tex">Y^2< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>C(=O)<annotation encoding="application / x-tex">C(=O)< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NH<annotation encoding="application / x-tex">NH< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>S<annotation encoding="application / x-tex">S< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>S(=O)<annotation encoding="application / x-tex">S(=O)< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>S(=O)2<annotation encoding="application / x-tex">S(=O)_2< / annotation>< / semantics>< / com:Math> or <com:Math><semantics>O<annotation encoding="application / x-tex">O< / annotation>< / semantics>< / com:Math>; 5 d is 0, 1, 2, 3 or 4; wherein, is the bond through which C1 is attached to L. 6 [Image disponible dans le document PDF, Image available in the PDF document] 16
[00127] In some embodiments, C2 is: CA 3,056,501 CPST Ref: 21924 / 00037 [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>(C2−1),<annotation encoding="application / x-tex">(C2-1),< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(C2−2),<annotation encoding="application / x-tex">(C2-2),< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(C2−3),<annotation encoding="application / x-tex">(C2-3),< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(C2−4),<annotation encoding="application / x-tex">(C2-4),< / annotation>< / semantics>< / com:Math> [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>(C2−5),<annotation encoding="application / x-tex">(C2-5),< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(C2−6),<annotation encoding="application / x-tex">(C2-6),< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(C2−7),<annotation encoding="application / x-tex">(C2-7),< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(C2−8)<annotation encoding="application / x-tex">(C2-8)< / annotation>< / semantics>< / com:Math> or [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>(C2−9);<annotation encoding="application / x-tex">(C2-9);< / annotation>< / semantics>< / com:Math> each X<com:Sup>6< / com:Sup>, X<com:Sup>7< / com:Sup>, X<com:Sup>8< / com:Sup>, X<com:Sup>9< / com:Sup>, X<com:Sup>10< / com:Sup> and X<com:Sup>11< / com:Sup> is independently N or CH; each Y<com:Sup>6< / com:Sup>, Y<com:Sup>7< / com:Sup> and Y<com:Sup>8< / com:Sup> is independently CH<com:Sub>2< / com:Sub>, C(=O), NH, S, S(=O), S(=O)<com:Sub>2< / com:Sub> or O; each Y<com:Sup>5< / com:Sup> is independently CH<com:Sub>2< / com:Sub>, NH, S or O; e is 0, 1, 2, 3 or 4; wherein, \( \frac{1}{2} \) is the bond through which C2 is attached to indazole. [Image disponible dans le document PDF, Image available in the PDF document] which C2 is attached to indazole. 1
[00129] In some embodiments, C2 is: [Image disponible dans le document PDF, Image available in the PDF document] 2 3 wherein each <com:Math><semantics>X6<annotation encoding="application / x-tex">X^6< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>X7<annotation encoding="application / x-tex">X^7< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>X8<annotation encoding="application / x-tex">X^8< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>X9<annotation encoding="application / x-tex">X^9< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>X10<annotation encoding="application / x-tex">X^{10}< / annotation>< / semantics>< / com:Math> is independently N or CH; 4 <com:Math><semantics>Y9<annotation encoding="application / x-tex">Y^9< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NH<annotation encoding="application / x-tex">NH< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>O<annotation encoding="application / x-tex">O< / annotation>< / semantics>< / com:Math> or <com:Math><semantics>S<annotation encoding="application / x-tex">S< / annotation>< / semantics>< / com:Math>; [Image disponible dans le document PDF, Image available in the PDF document] 5 wherein, is the bond through which C2 is attached to indazole. [Image disponible dans le document PDF, Image available in the PDF document] 6 7 8 9 is the bond through which C2 is attached to indazole. 10 11
[00131] In some embodiments, the compound of the invention has Formula (II), or a 12 stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, an 13 ester, a pharmaceutically acceptable salt or a prodrug thereof, [Image disponible dans le document PDF, Image available in the PDF document] (II), wherein each R<com:Sup>1< / com:Sup>, R<com:Sup>2< / com:Sup>, R<com:Sup>3< / com:Sup>, R<com:Sup>4< / com:Sup>, R<com:Sup>a< / com:Sup>, R<com:Sup>b< / com:Sup>, m, n, r, X<com:Sup>1< / com:Sup>, X<com:Sup>2< / com:Sup>, X<com:Sup>3< / com:Sup>, X<com:Sup>4< / com:Sup>, X<com:Sup>5< / com:Sup>, X<com:Sup>6< / com:Sup> and X<com:Sup>7< / com:Sup> is as defined herein.
[00132] In some embodiments, the compound of the invention has Formula (IIa), Formula (IIb) or Formula (IIc), or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a 1 solvate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof, [Image disponible dans le document PDF, Image available in the PDF document] 2 (IIb) [Image disponible dans le document PDF, Image available in the PDF document] or (IIc), wherein each <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math>, m, n, r, <com:Math><semantics>X1<annotation encoding="application / x-tex">X^1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>X2<annotation encoding="application / x-tex">X^2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>X3<annotation encoding="application / x-tex">X^3< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>X4<annotation encoding="application / x-tex">X^4< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>X5<annotation encoding="application / x-tex">X^5< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>X6<annotation encoding="application / x-tex">X^6< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>X7<annotation encoding="application / x-tex">X^7< / annotation>< / semantics>< / com:Math> is as defined herein.
[00133] In some embodiments, the compound of the invention has Formula (IId), or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a ester, a pharmaceutically acceptable salt or a prodrug thereof, [Image disponible dans le document PDF, Image available in the PDF document] (IId), wherein m1 is 0, 1 or 2; and each <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math>, n, r, <com:Math><semantics>X1<annotation encoding="application / x-tex">X^1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>X2<annotation encoding="application / x-tex">X^2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>X3<annotation encoding="application / x-tex">X^3< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>X4<annotation encoding="application / x-tex">X^4< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>X5<annotation encoding="application / x-tex">X^5< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>X6<annotation encoding="application / x-tex">X^6< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>X7<annotation encoding="application / x-tex">X^7< / annotation>< / semantics>< / com:Math> is as defined herein. In some embodiments, R<com:Sup>4< / com:Sup> is D, F, Cl, Br, I, CN, NO<com:Sub>2< / com:Sub>, mercapto, C<com:Sub>1-6< / com:Sub> alkyl, C<com:Sub>2-6< / com:Sub> alkenyl, C<com:Sub>2-6< / com:Sub> alkynyl, halo <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>−(CR6cR6d)g−C3−6<annotation encoding="application / x-tex">-(CR^{6c}R^{6d})_g-C_{3-6}< / annotation>< / semantics>< / com:Math> cycloalkyl, <com:Math><semantics>−(CR6cR6d)g−C2−5<annotation encoding="application / x-tex">-(CR^{6c}R^{6d})_g-C_{2-5}< / annotation>< / semantics>< / com:Math> heterocyclyl, <com:Math><semantics>−(CR6cR6d)g−C3−6<annotation encoding="application / x-tex">-(CR^{6c}R^{6d})_g-C_{3-6}< / annotation>< / semantics>< / com:Math> <com:Math><semantics>C6-10 aryl, -(CR6cR6d)g−C1-5 heteroaryl, -(CR6cR6d)gNR5cR5d,−(CR6cR6d)gC(=O)(CR6cR6d)hNR5cR5d,<annotation encoding="application / x-tex">C_{6\text{-}10} \text{ aryl, -} (CR^{6c}R^{6d})_g - C_{1\text{-}5} \text{ heteroaryl, -} (CR^{6c}R^{6d})_g NR^{5c}R^{5d}, - (CR^{6c}R^{6d})_g C(=O)(CR^{6c}R^{6d})_h NR^{5c}R^{5d},< / annotation>< / semantics>< / com:Math> <com:Math><semantics>−(CR6cR6d)gC(=O)(CR6cR6d)hOR9a,−(CR6cR6d)gOR9a,−(CR6cR6d)gS(=O)2(CR6cR6d)hOR9a,−(CR6cR6d)gS(=O)2(CR6cR6d)hOR9a,−(CR6cR6d)gS(=O<annotation encoding="application / x-tex">-(CR^{6c}R^{6d})_{g}C(=O)(CR^{6c}R^{6d})_{h}OR^{9a}, -(CR^{6c}R^{6d})_{g}OR^{9a}, -(CR^{6c}R^{6d})_{g}S(=O)_{2}(CR^{6c}R^{6d})_{h}OR^{9a}, -(CR^{6c}R^{6d})_{g}S(=O)_{2}(CR^{6c}R^{6d})_{h}OR^{9a}, -(CR^{6c}R^{6d})_{g}S(=O< / annotation>< / semantics>< / com:Math> [Image disponible dans le document PDF, Image available in the PDF document] - [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] is unsubstituted or substituted with 1, 2, 3 or 4 R<com:Sup>y< / com:Sup>; wherein each R<com:Sup>6c< / com:Sup>, R<com:Sup>6d< / com:Sup>, R<com:Sup>5c< / com:Sup>, R<com:Sup>5d< / com:Sup>, R<com:Sup>5e< / com:Sup>, R<com:Sup>7a< / com:Sup>, R<com:Sup>8a< / com:Sup>, R<com:Sup>9a< / com:Sup>, R<com:Sup>y< / com:Sup>, g, h and i is as defined herein.
[00134] In some embodiments, R<com:Sup>4< / com:Sup> is D, F, Cl, Br, I, CN, NO<com:Sub>2< / com:Sub>, mercapto, C<com:Sub>1-4< / com:Sub> alkyl, C<com:Sub>2-4< / com:Sub> alkenyl, <com:Math><semantics>C2−4<annotation encoding="application / x-tex">C_{2-4}< / annotation>< / semantics>< / com:Math> alkynyl, halo <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>< / com:Math> cycloalkyl, <com:Math><semantics>C2−5<annotation encoding="application / x-tex">C_{2-5}< / annotation>< / semantics>< / com:Math> heterocyclyl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl, <com:Math><semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics>< / com:Math> heteroaryl, - <com:Math><semantics>NR5cR5d<annotation encoding="application / x-tex">NR^{5c}R^{5d}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(=O)NR5cR5d<annotation encoding="application / x-tex">-C(=O)NR^{5c}R^{5d}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OR9a<annotation encoding="application / x-tex">-OR^{9a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(=O)2OR9a<annotation encoding="application / x-tex">-S(=O)_2OR^{9a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(=O)2NR5cR5d<annotation encoding="application / x-tex">-S(=O)_2NR^{5c}R^{5d}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(R5e)C(=O)(CR6cR6d)hOR9a<annotation encoding="application / x-tex">-N(R^{5e})C(=O)(CR^{6c}R^{6d})_hOR^{9a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(=O)2NR5cR5d<annotation encoding="application / x-tex">-S(=O)_2NR^{5c}R^{5d}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(R5e)C(=O)(CR6cR6d)hOR9a<annotation encoding="application / x-tex">-N(R^{5e})C(=O)(CR^{6c}R^{6d})_hOR^{9a}< / annotation>< / semantics>< / com:Math>, <Formule mathématique disponible dans le document PDF, Math available in the PDF document>-S(=O)_2NR^{5 <com:Math><semantics>N(R5e)C(=O)R8a,−N(R5e)C(=O)NR5cR5d,−N(R5e)S(=O)2R7a,−S(=O)2R7a,−OS(=O)2R7a,−OS(=O)2R7a,−OS(=O)2R7a,−OS(=O)2R7a,−OS(=O)2R7a,−OS(=O)2R7a,−OS(=<annotation encoding="application / x-tex">N(R^{5e})C(=O)R^{8a}, \quad -N(R^{5e})C(=O)NR^{5c}R^{5d}, \quad -N(R^{5e})S(=O)_2R^{7a}, \quad -S(=O)_2R^{7a}, \quad -OS(=O)_2R^{7a}, \quad -OS(=O)_2R^{7a}, \quad -OS(=O)_2R^{7a}, \quad -OS(=O)_2R^{7a}, \quad -OS(=O)_2R^{7a}, \quad -OS(=O)_2R^{7a}, \quad -OS(=< / annotation>< / semantics>< / com:Math> <com:Math><semantics>OC(=O)OR9a<annotation encoding="application / x-tex">OC(=O)OR^{9a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OC(=O)R8a<annotation encoding="application / x-tex">-OC(=O)R^{8a}< / annotation>< / semantics>< / com:Math> or <com:Math><semantics>−C(=O)R8a<annotation encoding="application / x-tex">-C(=O)R^{8a}< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is unsubstituted or substituted with 1, 2, 3 or 4 <com:Math><semantics>Ry<annotation encoding="application / x-tex">R^y< / annotation>< / semantics>< / com:Math>; wherein each R<com:Sup>6c< / com:Sup>, R<com:Sup>6d< / com:Sup>, R<com:Sup>5c< / com:Sup>, R<com:Sup>5d< / com:Sup>, R<com:Sup>5e< / com:Sup>, R<com:Sup>7a< / com:Sup>, R<com:Sup>8a< / com:Sup>, R<com:Sup>9a< / com:Sup>, R<com:Sup>y< / com:Sup> and h is as defined herein.
[00135] In other embodiments, R<com:Sup>4< / com:Sup> is D, F, Cl, Br, I, CN, NO<com:Sub>2< / com:Sub>, mercapto, methyl, ethyl, propyl, butyl, vinyl, propenyl, allyl, ethynyl, propynyl, trifluoromethyl, difluoromethyl, 2,2-difluoroethyl, chloroethyl (including but not limited to: 2-chloroethyl), 2,2,2-trifluoroethyl, 2-chloro-1- methylethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, tetrahydrofuranyl, morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, pyrazolidinyl, oxomorpholinyl, thiomorpholinyl, 4,4-dioxothiomorpholinyl, oxazolidinyl, thiazolidinyl, 1,1-dioxoisothiazolidinyl [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] oxo-1,3-oxazinylalkyl , phenyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, pyrrolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, thienyl, furyl, -NR<com:Sup>5c< / com:Sup>R<com:Sup>5d< / com:Sup>, - <com:Math><semantics>C(=O)NR5cR5d<annotation encoding="application / x-tex">C(=O)NR^{5c}R^{5d}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OR9a<annotation encoding="application / x-tex">-OR^{9a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(=O)2OR9a<annotation encoding="application / x-tex">-S(=O)_2OR^{9a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(=O)2NR5cR5d<annotation encoding="application / x-tex">-S(=O)_2NR^{5c}R^{5d}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(R5e)C(=O)(CR6cR6d)hOR9a<annotation encoding="application / x-tex">-N(R^{5e})C(=O)(CR^{6c}R^{6d})_hOR^{9a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(=O)2NR5cR5d<annotation encoding="application / x-tex">-S(=O)_2NR^{5c}R^{5d}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(=O)2NR5cR5d<annotation encoding="application / x-tex">-S(=O)_2NR^{5c}R^{5d}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(=O)2NR5cR5d<annotation encoding="application / x-tex">-S(=O)_2NR^{5c}R^{5d}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(=O)2NR5cR5d<annotation encoding="application / x-tex">-S(=O)_2NR^{5c}R^{5d}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>N(R5e)C(=O)R8a<annotation encoding="application / x-tex">N(R^{5e})C(=O)R^{8a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(R5e)C(=O)NR5cR5d<annotation encoding="application / x-tex">-N(R^{5e})C(=O)NR^{5c}R^{5d}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(R5e)S(=O)2R7a<annotation encoding="application / x-tex">-N(R^{5e})S(=O)_2R^{7a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(=O)2R7a<annotation encoding="application / x-tex">-S(=O)_2R^{7a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OS(=O)2R7a<annotation encoding="application / x-tex">-OS(=O)_2R^{7a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OS(=O)2R7a<annotation encoding="application / x-tex">-OS(=O)_2R^{7a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OS(=O)2R7a<annotation encoding="application / x-tex">-OS(=O)_2R^{7a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OS(=O)2R7a<annotation encoding="application / x-tex">-OS(=O)_2R^{7a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OS(=O)2R7a<annotation encoding="application / x-tex">-OS(=O)_2R^{7a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OS(=O)2R7a<annotation encoding="application / x-tex">-OS(=O)_2R^{7a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OS(=<annotation encoding="application / x-tex">-OS(=< / annotation>< / semantics>< / com:Math> OC(=O)OR<com:Sup>9a< / com:Sup>, -OC(=O)R<com:Sup>8a< / com:Sup> or -C(=O)R<com:Sup>8a< / com:Sup>; R<com:Sup>4< / com:Sup> is unsubstituted or optionally substituted with 1, 2, 3 or 4 <com:Math><semantics>Ry<annotation encoding="application / x-tex">R^y< / annotation>< / semantics>< / com:Math>; wherein each R<com:Sup>6c< / com:Sup>, R<com:Sup>6d< / com:Sup>, R<com:Sup>5c< / com:Sup>, R<com:Sup>5d< / com:Sup>, R<com:Sup>5e< / com:Sup>, R<com:Sup>7a< / com:Sup>, R<com:Sup>8a< / com:Sup>, R<com:Sup>9a< / com:Sup>, R<com:Sup>y< / com:Sup> and h is as defined herein.
[00136] In some embodiments, the compound of the invention has Formula (III), or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof, [Image disponible dans le document PDF, Image available in the PDF document] (III), wherein each R<com:Sup>1< / com:Sup>, R<com:Sup>2< / com:Sup>, R<com:Sup>3< / com:Sup>, R<com:Sup>4< / com:Sup>, m, n and r is as defined herein.
[00137] In some embodiments, each R<com:Sup>1< / com:Sup> is independently H, D, F, Cl, Br, I, CN, NO<com:Sub>2< / com:Sub>, amino, hydroxy, mercapto, oxo, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math> alkenyl, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math> alkynyl, halo <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy, halo <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> 6 alkoxy, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkylamino, acyl, sulfonyl, <com:Math><semantics>−(CR10R11)u−C3−6<annotation encoding="application / x-tex">-(CR^{10}R^{11})_u-C_{3-6}< / annotation>< / semantics>< / com:Math> cycloalkyl, <com:Math><semantics>−(CR10R11)u−C2−5<annotation encoding="application / x-tex">-(CR^{10}R^{11})_u-C_{2-5}< / annotation>< / semantics>< / com:Math> heterocyclyl, <com:Math><semantics>−(CR10R11)u<annotation encoding="application / x-tex">-(CR^{10}R^{11})_u< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl or <com:Math><semantics>−(CR10R11)u<annotation encoding="application / x-tex">-(CR^{10}R^{11})_u< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics>< / com:Math> heteroaryl; wherein each of the amino, hydroxy, mercapto, C<com:Sub>1-6< / com:Sub> alkyl, C<com:Sub>2-6< / com:Sub> alkenyl, C<com:Sub>2-6< / com:Sub> alkynyl, halo C<com:Sub>1-6< / com:Sub> alkyl, C<com:Sub>1-6< / com:Sub> alkoxy, halo C<com:Sub>1-6< / com:Sub> alkoxy, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkylamino, acyl, sulfonyl, <com:Math><semantics>−(CR10R11)u−C3−6<annotation encoding="application / x-tex">-(CR^{10}R^{11})_u-C_{3-6}< / annotation>< / semantics>< / com:Math> cycloalkyl, <com:Math><semantics>−(CR10R11)u−C2−5<annotation encoding="application / x-tex">-(CR^{10}R^{11})_u-C_{2-5}< / annotation>< / semantics>< / com:Math> heterocyclyl, <com:Math><semantics>−(CR10R11)u−C6−10<annotation encoding="application / x-tex">-(CR^{10}R^{11})_u-C_{6-10}< / annotation>< / semantics>< / com:Math> aryl and <com:Math><semantics>−(CR10R11)u−C1−5<annotation encoding="application / x-tex">-(CR^{10}R^{11})_u-C_{1-5}< / annotation>< / semantics>< / com:Math> heteroaryl is unsubstututed or independently substituted with 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, CN, NO<com:Sub>2< / com:Sub>, amino, hydroxy, mercapto, oxo, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math> alkenyl, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math> alkynyl, halo <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy, halo <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkylamino, <com:Math><semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>< / com:Math> cycloalkyl, <com:Math><semantics>C2−5<annotation encoding="application / x-tex">C_{2-5}< / annotation>< / semantics>< / com:Math> heterocyclyl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl and <com:Math><semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics>< / com:Math> heteroaryl; wherein <com:Math><semantics>R10<annotation encoding="application / x-tex">R^{10}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R11<annotation encoding="application / x-tex">R^{11}< / annotation>< / semantics>< / com:Math> and u are as defined herein.
[00138] In some embodiments, each R<com:Sup>1< / com:Sup> is independently H, D, F, Cl, Br, I, CN, NO<com:Sub>2< / com:Sub>, amino, hydroxy, mercapto, C<com:Sub>1-4< / com:Sub> alkyl, C<com:Sub>2-4< / com:Sub> alkenyl, C<com:Sub>2-4< / com:Sub> alkynyl, halo C<com:Sub>1-4< / com:Sub> alkyl, C<com:Sub>1-4< / com:Sub> alkoxy, halo C<com:Sub>1-4< / com:Sub> alkoxy, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkylamino, <com:Math><semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>< / com:Math> cycloalkyl, <com:Math><semantics>C2−5<annotation encoding="application / x-tex">C_{2-5}< / annotation>< / semantics>< / com:Math> heterocyclyl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl or <com:Math><semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics>< / com:Math> heteroaryl; wherein each of the <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C2−4<annotation encoding="application / x-tex">C_{2-4}< / annotation>< / semantics>< / com:Math> alkenyl, <com:Math><semantics>C2−4<annotation encoding="application / x-tex">C_{2-4}< / annotation>< / semantics>< / com:Math> alkynyl, halo <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy, halo <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> 4 alkoxy, C<com:Sub>1-4< / com:Sub> alkylamino, C<com:Sub>3-6< / com:Sub> cycloalkyl, C<com:Sub>2-5< / com:Sub> heterocyclyl, C<com:Sub>6-10< / com:Sub> aryl and C<com:Sub>1-5< / com:Sub> heteroaryl is unsubstituted or independently substituted with 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, CN, NO<com:Sub>2< / com:Sub>, amino, hydroxy, mercapto, oxo (=O), C<com:Sub>1-4< / com:Sub> alkyl, C<com:Sub>2-4< / com:Sub> alkenyl, C<com:Sub>2-4< / com:Sub> alkynyl, halo C<com:Sub>1-4< / com:Sub> alkyl, C<com:Sub>1-4< / com:Sub> alkoxy, halo C<com:Sub>1-4< / com:Sub> alkoxy, C<com:Sub>1-4< / com:Sub> alkylamino, C<com:Sub>3-6< / com:Sub> cycloalkyl, C<com:Sub>2-5< / com:Sub> heterocyclyl, C<com:Sub>6-10< / com:Sub> aryl and <com:Math><semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics>< / com:Math> heteroaryl.
[00139] In some embodiments, each R<com:Sup>1< / com:Sup> is independently H, D, F, Cl, Br, I, CN, NO<com:Sub>2< / com:Sub>, amino, hydroxy, mercapto, methyl, ethyl, propyl, butyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, propoxy, tert-butoxy, trifluoromethoxy, methylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, morpholinyl, piperazinyl, epoxypropyl, azetidinyl, phenyl, pyridyl or pyrimidinyl;
[00140] wherein each of the methyl, ethyl, propyl, butyl, difluoromethyl, methoxy, ethoxy, propoxy, tert-butoxy, methylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, morpholinyl, piperazinyl, epoxypropyl, azetidinyl, phenyl, pyridyl and pyrimidinyl is unsubstituted or independently substituted with 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, CN, NO<com:Sub>2< / com:Sub>, amino, hydroxy, mercapto, oxo (=O), methyl, ethyl, propyl, butyl, <com:Math><semantics>C2−4<annotation encoding="application / x-tex">C_{2-4}< / annotation>< / semantics>< / com:Math> alkenyl, <com:Math><semantics>C2−4<annotation encoding="application / x-tex">C_{2-4}< / annotation>< / semantics>< / com:Math> alkynyl, trifluoromethyl, methoxy, ethoxy, propoxy, trifluoromethoxy, <com:Math><semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics>< / com:Math> alkylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C<com:Sub>2-5< / com:Sub> heterocyclyl, phenyl and C<com:Sub>1-5< / com:Sub> heteroaryl.
[00141] In some embodiments, the compound of the invention has Formula (IV), Formula (IVa), Formula (IVb) or Formula (IVc), or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a ester, a pharmaceutically acceptable salt or a prodrug thereof, [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (IV), (IVa), (IVb) [Image disponible dans le document PDF, Image available in the PDF document] 1 or (IVc), 2 wherein each R<com:Sup>2< / com:Sup>, R<com:Sup>3< / com:Sup>, R<com:Sup>4< / com:Sup>, m and r is as defined herein. 3
[00142] In some embodiments, the compound of the invention has Formula (Va), Formula (Vb) 4 or Formula (Vc), or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a 5 solvate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof, [Image disponible dans le document PDF, Image available in the PDF document] (Vb) [Image disponible dans le document PDF, Image available in the PDF document] or (Vc), wherein each R<com:Sup>2< / com:Sup>, R<com:Sup>3a< / com:Sup>, R<com:Sup>3b< / com:Sup>, R<com:Sup>4< / com:Sup> and m is as defined herein.
[00143] In some embodiments, the compound of the invention has Formula (Vd), or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof, [Image disponible dans le document PDF, Image available in the PDF document] (Vd), wherein R<com:Sup>3a< / com:Sup>, R<com:Sup>3b< / com:Sup> and R<com:Sup>4< / com:Sup> is as defined herein.
[00144] In some embodiments, each R<com:Sup>2< / com:Sup> is independently H, D, F, Cl, Br, I, CN, NO<com:Sub>2< / com:Sub>, amino, hydroxy, mercapto, C<com:Sub>1-6< / com:Sub> alkyl, C<com:Sub>2-6< / com:Sub> alkenyl, C<com:Sub>2-6< / com:Sub> alkynyl, halo C<com:Sub>1-6< / com:Sub> alkyl, halo C<com:Sub>1-6< / com:Sub> alkoxy, C<com:Sub>1-6< / com:Sub> alkylamino, hydroxy C<com:Sub>1-6< / com:Sub> alkyl, cyano C<com:Sub>1-6< / com:Sub> alkyl, amino C<com:Sub>1-6< / com:Sub> alkyl, hydroxy C<com:Sub>1-6< / com:Sub> alkoxy, amino C<com:Sub>1-6< / com:Sub> 6 alkoxy, acyl, sulfonyl or C<com:Sub>1-6< / com:Sub> alkoxy.
[00145] In some embodiments, each R<com:Sup>2< / com:Sup> is independently H, D, F, Cl, Br, I, CN, NO<com:Sub>2< / com:Sub>, amino, hydroxy, mercapto, C<com:Sub>1-4< / com:Sub> alkyl, C<com:Sub>2-4< / com:Sub> alkenyl, C<com:Sub>2-4< / com:Sub> alkynyl, halo C<com:Sub>1-4< / com:Sub> alkyl, halo C<com:Sub>1-4< / com:Sub> alkoxy, C<com:Sub>1-4< / com:Sub> alkylamino, hydroxy C<com:Sub>1-4< / com:Sub> alkyl, cyano C<com:Sub>1-4< / com:Sub> alkyl, amino C<com:Sub>1-4< / com:Sub> alkyl, hydroxy C<com:Sub>1-4< / com:Sub> alkoxy, amino C<com:Sub>1-4< / com:Sub> 4 alkoxy or C<com:Sub>1-4< / com:Sub> alkoxy.
[00146] In other embodiments, each R<com:Sup>2< / com:Sup> is independently H, D, F, Cl, Br, I, CN, NO<com:Sub>2< / com:Sub>, amino, hydroxy, mercapto, methyl, ethyl, propyl, butyl, trifluoromethyl, trifluoromethoxy, methylamino, dimethylamino, hydroxymethyl, hydroxyethyl, cyanomethyl, cyanoethyl, aminomethyl, aminoethyl, hydroxymethoxy, hydroxyethoxy, amino <com:Math><semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics>< / com:Math> alkoxy, methoxy, ethoxy, propoxy or butoxy.
[00147] In some embodiments, each R<com:Sup>3< / com:Sup>, R<com:Sup>3a< / com:Sup> and R<com:Sup>3b< / com:Sup> is independently oxo (=O), H, D, F, Cl, Br, I, CN, NO<com:Sub>2< / com:Sub>, mercapto, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math> alkenyl, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math> alkynyl, halo <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>−(CR6aR6b)j−C3−10<annotation encoding="application / x-tex">-(CR^{6a}R^{6b})_j-C_{3-10}< / annotation>< / semantics>< / com:Math> cycloalkyl, <com:Math><semantics>−(CR6aR6b)j−C2−10<annotation encoding="application / x-tex">-(CR^{6a}R^{6b})_{j}-C_{2-10}< / annotation>< / semantics>< / com:Math> heterocyclyl, <com:Math><semantics>−(CR6aR6b)j−C6−10<annotation encoding="application / x-tex">-(CR^{6a}R^{6b})_{j}-C_{6-10}< / annotation>< / semantics>< / com:Math> aryl, <com:Math><semantics>−(CR6aR6b)j−C1−9<annotation encoding="application / x-tex">-(CR^{6a}R^{6b})_{j}-C_{1-9}< / annotation>< / semantics>< / com:Math> heteroaryl, <com:Math><semantics>−(CR6aR6b)j−C1−9<annotation encoding="application / x-tex">-(CR^{6a}R^{6b})_{j}-C_{1-9}< / annotation>< / semantics>< / com:Math> <com:Math><semantics>N=NR5<annotation encoding="application / x-tex">N=NR^5< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N=CR6R6e<annotation encoding="application / x-tex">-N=CR^{6}R^{6e}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−(CR6aR6b)jNR5aR5b<annotation encoding="application / x-tex">-(CR^{6a}R^{6b})_{j}NR^{5a}R^{5b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−(CR6aR6b)iC(=O)(CR6aR6b)kNR5aR5b<annotation encoding="application / x-tex">-(CR^{6a}R^{6b})_{i}C(=O)(CR^{6a}R^{6b})_{k}NR^{5a}R^{5b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>(CR6aR6b)jC(=O)(CR6aR6b)kOR9,<annotation encoding="application / x-tex">(CR^{6a}R^{6b})_{j}C(=O)(CR^{6a}R^{6b})_{k}OR^{9},< / annotation>< / semantics>< / com:Math> <com:Math><semantics>−(CR6aR6b)jOR9,<annotation encoding="application / x-tex">-(CR^{6a}R^{6b})_{j}OR^{9},< / annotation>< / semantics>< / com:Math> <com:Math><semantics>−(CR6aR6b)jS(=O)2(CR6aR6b)kOR9,<annotation encoding="application / x-tex">-(CR^{6a}R^{6b})_{j}S(=O)_{2}(CR^{6a}R^{6b})_{k}OR^{9},< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(CR6aR6b)iS(=O)2(CR6aR6b)kNR5aR5b,<annotation encoding="application / x-tex">(CR^{6a}R^{6b})_{i}S(=O)_{2}(CR^{6a}R^{6b})_{k}NR^{5a}R^{5b},< / annotation>< / semantics>< / com:Math> <com:Math><semantics>−(CR6aR6b)iN(R5)(CR6aR6b)pC(=O)(CR6aR6b)kOR9,<annotation encoding="application / x-tex">-(CR^{6a}R^{6b})_{i}N(R^{5})(CR^{6a}R^{6b})_{p}C(=O)(CR^{6a}R^{6b})_{k}OR^{9},< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(CR6aR6b)iN(R5)C(=O)(CR6aR6b)kNR5aR5b,<annotation encoding="application / x-tex">(CR^{6a}R^{6b})_iN(R^5)C(=O)(CR^{6a}R^{6b})_kNR^{5a}R^{5b},< / annotation>< / semantics>< / com:Math> <com:Math><semantics>−(CR6aR6b)iN(R5)C(=O)R8<annotation encoding="application / x-tex">-(CR^{6a}R^{6b})_iN(R^5)C(=O)R^8< / annotation>< / semantics>< / com:Math>, - [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] and R<com:Sup>3b< / com:Sup> is unsubstitued or independently substituted with 1, 2, 3 or 4 R<com:Sup>x< / com:Sup>; or, any two adjacent R<com:Sup>3< / com:Sup>, together with the carbon atoms to which they are attached, form a 3- to 6-membered carbocyclic ring, heterocyclic ring, aromatic ring or heteroaromatic ring, and wherein each of 3- to 6-membered carbocyclic ring, heterocyclic ring, aromatic ring and heteroaromatic ring is unsubstituted or independently substituted with 1, 2, 3 or 4 Rz; wherein the "3- to 6- membered carbocyclic ring, heterocyclic ring, aromatic ring or heteroaromatic ring" includes 3- to 6-membered carbocyclic ring, 3- to 6-membered heterocyclic ring, 3- to 6-membered aromatic ring or 3- to 6-membered heteroaromatic ring; further, the "3- to 6-membered aromatic ring" includes 6-membered aromatic ring, and the "3- to 6-membered heteroaromatic ring" includes 5- to 6-membered heteroaromatic ring; that is, any two adjacent R<com:Sup>3< / com:Sup>, together with the carbon atoms to which they are attached, may form a 3- to 6-membered carbocyclic ring, 3- to 6-membered heterocyclic ring, 6-membered aromatic ring or 5- to 6-membered heteroaromatic ring, and wherein each of 3- to 6-membered carbocyclic ring, 3- to 6-membered heterocyclic ring, 6- membered aromatic ring and 5- to 6-membered heteroaromatic ring is unsubstituted or independently substituted with 1, 2, 3 or 4 R<com:Sup>z< / com:Sup>; wherein each R<com:Sup>6a< / com:Sup>, R<com:Sup>6b< / com:Sup>, R<com:Sup>6< / com:Sup>, R<com:Sup>6e< / com:Sup>, R<com:Sup>5< / com:Sup>, R<com:Sup>5a< / com:Sup>, R<com:Sup>5b< / com:Sup>, R<com:Sup>7< / com:Sup>, R<com:Sup>8< / com:Sup>, R<com:Sup>9< / com:Sup>, R<com:Sup>x< / com:Sup>, R<com:Sup>z< / com:Sup>, j, k and p is as defined herein.
[00148] In some embodiments, each R<com:Sup>3< / com:Sup>, R<com:Sup>3a< / com:Sup> and R<com:Sup>3b< / com:Sup> is independently oxo (=O), H, D, F, Cl, Br, I, CN, NO<com:Sub>2< / com:Sub>, mercapto, C<com:Sub>1-4< / com:Sub> alkyl, C<com:Sub>2-4< / com:Sub> alkenyl, C<com:Sub>2-4< / com:Sub> alkynyl, halo C<com:Sub>1-4< / com:Sub> alkyl, C<com:Sub>3-6< / com:Sub> cycloalkyl, C<com:Sub>2-5< / com:Sub> heterocyclyl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl, <com:Math><semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics>< / com:Math> heteroaryl, <com:Math><semantics>−NR5aR5b<annotation encoding="application / x-tex">-NR^{5a}R^{5b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(=O)NR5aR5b<annotation encoding="application / x-tex">-C(=O)NR^{5a}R^{5b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(=O)OR9<annotation encoding="application / x-tex">-C(=O)OR^{9}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OR9<annotation encoding="application / x-tex">-OR^{9}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OR9<annotation encoding="application / x-tex">-OR^{9}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OR9<annotation encoding="application / x-tex">-OR^{9}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OR9<annotation encoding="application / x-tex">-OR^{9}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OR9<annotation encoding="application / x-tex">-OR^{9}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OR9<annotation encoding="application / x-tex">-OR^{9}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OR9<annotation encoding="application / x-tex">-OR^{9}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OR9<annotation encoding="application / x-tex">-OR^{9}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OR9<annotation encoding="application / x-tex">-OR^{9}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OR9<annotation encoding="application / x-tex">-OR^{9}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>S(=O)2OR9<annotation encoding="application / x-tex">S(=O)_2OR^9< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(=O)2NR5aR5b<annotation encoding="application / x-tex">-S(=O)_2NR^{5a}R^{5b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(R5)C(=O)(CR6aR6b)kOR9<annotation encoding="application / x-tex">-N(R^5)C(=O)(CR^{6a}R^{6b})_kOR^9< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(R5)C(=O)NR5aR5b<annotation encoding="application / x-tex">-N(R^5)C(=O)NR^{5a}R^{5b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(R5)C(=O)NR5aR5b<annotation encoding="application / x-tex">-N(R^5)C(=O)NR^{5a}R^{5b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(R5)C(=O)NR5aR5b<annotation encoding="application / x-tex">-N(R^5)C(=O)NR^{5a}R^{5b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(R5)C(=O)NR5aR5b<annotation encoding="application / x-tex">-N(R^5)C(=O)NR^{5a}R^{5b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(R5)C(=O)NR5aR5b<annotation encoding="application / x-tex">-N(R^5)C(=O)NR^{5a}R^{5b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>N(R5)C(=O)R8<annotation encoding="application / x-tex">N(R^5)C(=O)R^8< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(R5)S(=O)2R7<annotation encoding="application / x-tex">-N(R^5)S(=O)_2R^7< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(=O)2R7<annotation encoding="application / x-tex">-S(=O)_2R^7< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OS(=O)2R7<annotation encoding="application / x-tex">-OS(=O)_2R^7< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OC(=O)OR9<annotation encoding="application / x-tex">-OC(=O)OR^9< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OC(=O)R8<annotation encoding="application / x-tex">-OC(=O)R^8< / annotation>< / semantics>< / com:Math> or <com:Math><semantics>−<annotation encoding="application / x-tex">-< / annotation>< / semantics>< / com:Math> C(=O)R<com:Sup>8< / com:Sup>; each R<com:Sup>3< / com:Sup>, R<com:Sup>3a< / com:Sup> and R<com:Sup>3b< / com:Sup> is unsubstituted or optionally substituted with 1, 2, 3 or 4 R<com:Sup>x< / com:Sup>; or, any two adjacent R<com:Sup>3< / com:Sup>, together with the carbon atoms to which they are attached, form a 3- to 6-membered heterocyclic ring or heteroaromatic ring, and wherein each of 3- to 6-membered heterocyclic ring and heteroaromatic ring is unsubstituted or independently substituted with 1, 2, 3 or 4 R<com:Sup>z< / com:Sup>; wherein the "3- to 6-membered heterocyclic ring or heteroaromatic ring" includes 3- to 6-membered heterocyclic ring or 3- to 6-membered heteroaromatic ring; further, the "3- to 6- membered heteroaromatic ring" includes 5- to 6-membered heteroaromatic ring; that is, any two adjacent R<com:Sup>3< / com:Sup>, together with the carbon atoms to which they are attached, may form a 3- to 6- membered heterocyclic ring or 5- to 6-membered heteroaromatic ring, and wherein each of 3- to 6-membered heterocyclic ring and 5- to 6-membered heteroaromatic ring is unsubstituted or independently substituted with 1, 2, 3 or 4 R<com:Sup>z< / com:Sup>; wherein each R<com:Sup>6a< / com:Sup>, R<com:Sup>6b< / com:Sup>, R<com:Sup>5< / com:Sup>, R<com:Sup>5a< / com:Sup>, R<com:Sup>5b< / com:Sup>, R<com:Sup>7< / com:Sup>, R<com:Sup>8< / com:Sup>, R<com:Sup>9< / com:Sup>, R<com:Sup>x< / com:Sup>, R<com:Sup>z< / com:Sup> and k is as defined herein.
[00149] In some embodiments, each R<com:Sup>3< / com:Sup>, R<com:Sup>3a< / com:Sup> and R<com:Sup>3b< / com:Sup> is independently oxo (=O), H, D, F, Cl, Br, I, CN, NO<com:Sub>2< / com:Sub>, mercapto, methyl, ethyl, propyl, butyl, trifluoromethyl, 2,2-difluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, oxomorpholinyl, thiomorpholinyl, 4,4- dioxothiomorpholinyl, tetrahydrofuranyl, oxazolidinyl, thiazolidinyl, 1,1-dioxoisothiazolidinyl [Image disponible dans le document PDF, Image available in the PDF document] phenyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, pyrrolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, thienyl, furyl, <com:Math><semantics>−NR5aR5b<annotation encoding="application / x-tex">-NR^{5a}R^{5b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(=O)NR5aR5b<annotation encoding="application / x-tex">-C(=O)NR^{5a}R^{5b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(=O)OR9<annotation encoding="application / x-tex">-C(=O)OR^{9}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OR9<annotation encoding="application / x-tex">-OR^{9}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(=O)2OR9<annotation encoding="application / x-tex">-S(=O)_{2}OR^{9}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(=O)2OR9<annotation encoding="application / x-tex">-S(=O)_{2}OR^{9}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(=O)2OR9<annotation encoding="application / x-tex">-S(=O)_{2}OR^{9}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(=O)2OR9<annotation encoding="application / x-tex">-S(=O)_{2}OR^{9}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(=O)2OR9<annotation encoding="application / x-tex">-S(=O)_{2}OR^{9}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(=O)2OR9<annotation encoding="application / x-tex">-S(=O)_{2}OR^{9}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(=<annotation encoding="application / x-tex">-S(=< / annotation>< / semantics>< / com:Math> <com:Math><semantics>S(=O)2NR5aR5b<annotation encoding="application / x-tex">S(=O)_2NR^{5a}R^{5b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(R5)C(=O)OR9<annotation encoding="application / x-tex">-N(R^5)C(=O)OR^9< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(R5)C(=O)NR5aR5b<annotation encoding="application / x-tex">-N(R^5)C(=O)NR^{5a}R^{5b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(R5)C(=O)R8<annotation encoding="application / x-tex">-N(R^5)C(=O)R^8< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(R5)S(=O)2R7<annotation encoding="application / x-tex">-N(R^5)S(=O)_2R^7< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(R5)C(=O)R8<annotation encoding="application / x-tex">-N(R^5)C(=O)R^8< / annotation>< / semantics>< / com:Math> <com:Math><semantics>S(=O)2R7<annotation encoding="application / x-tex">S(=O)_2R^7< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OS(=O)2R7<annotation encoding="application / x-tex">-OS(=O)_2R^7< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OC(=O)OR9<annotation encoding="application / x-tex">-OC(=O)OR^9< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OC(=O)R8<annotation encoding="application / x-tex">-OC(=O)R^8< / annotation>< / semantics>< / com:Math> or <com:Math><semantics>−C(=O)R8<annotation encoding="application / x-tex">-C(=O)R^8< / annotation>< / semantics>< / com:Math>; each <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R3a<annotation encoding="application / x-tex">R^{3a}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R3b<annotation encoding="application / x-tex">R^{3b}< / annotation>< / semantics>< / com:Math> is unsubstituted or independently substituted with 1, 2, 3 or 4 R<com:Sup>x< / com:Sup>; or, any two adjacent R<com:Sup>3< / com:Sup>, together with the carbon atoms to which they are attached, form a 3- to 6-membered heterocyclic ring or heteroaromatic ring, and wherein each of 3- to 6-membered heterocyclic ring and heteroaromatic ring is unsubstituted or independently substituted with 1, 2, 3 or 4 R<com:Sup>z< / com:Sup>; wherein the "3- to 6-membered heterocyclic ring or heteroaromatic ring" includes 3- to 6-membered heterocyclic ring or 3- to 6-membered heteroaromatic ring; further, the "3- to 6- membered heteroaromatic ring" includes 5- to 6-membered heteroaromatic ring; that is, any two adjacent R<com:Sup>3< / com:Sup>, together with the carbon atoms to which they are attached, may form a 3- to 6- membered heterocyclic ring or 5- to 6-membered heteroaromatic ring, and wherein each of 3- to 6-membered heterocyclic ring and 5- to 6-membered heteroaromatic ring is unsubstituted or independently substituted with 1, 2, 3 or 4 R<com:Sup>z< / com:Sup>; wherein each R<com:Sup>5< / com:Sup>, R<com:Sup>5a< / com:Sup>, R<com:Sup>5b< / com:Sup>, R<com:Sup>7< / com:Sup>, R<com:Sup>8< / com:Sup>, R<com:Sup>9< / com:Sup>, R<com:Sup>x< / com:Sup> and R<com:Sup>z< / com:Sup> is as defined herein.
[00150] In some embodiments, each R<com:Sup>5< / com:Sup> and R<com:Sup>5e< / com:Sup> is independently H, D, C<com:Sub>1-6< / com:Sub> alkyl, hydroxy C<com:Sub>1-6< / com:Sub> alkyl, amino C<com:Sub>1-6< / com:Sub> alkyl, cyano C<com:Sub>1-6< / com:Sub> alkyl, halo C<com:Sub>1-6< / com:Sub> alkyl, C<com:Sub>1-6< / com:Sub> alkoxy-C<com:Sub>1-6< / com:Sub>-alkyl, C<com:Sub>3-6< / com:Sub> cycloalkyl, C<com:Sub>2-5< / com:Sub> heterocyclyl, C<com:Sub>6-10< / com:Sub> aryl, C<com:Sub>1-5< / com:Sub> heteroaryl, C<com:Sub>3-6< / com:Sub> cycloalkyl-C<com:Sub>1-6< / com:Sub>-alkyl, C<com:Sub>2-5< / com:Sub> heterocyclyl-C<com:Sub>1-6< / com:Sub>- alkyl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl-<com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl or <com:Math><semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics>< / com:Math> heteroaryl-<com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl.
[00151] In some embodiments, each R<com:Sup>5< / com:Sup> and R<com:Sup>5e< / com:Sup> is independently H, D, C<com:Sub>1-4< / com:Sub> alkyl, hydroxy C<com:Sub>1-4< / com:Sub> alkyl, amino C<com:Sub>1-4< / com:Sub> alkyl, cyano C<com:Sub>1-4< / com:Sub> alkyl, halo C<com:Sub>1-4< / com:Sub> alkyl, C<com:Sub>1-4< / com:Sub> alkoxy-C<com:Sub>1-4< / com:Sub>-alkyl, C<com:Sub>3-4< / com:Sub> cycloalkyl, C<com:Sub>2-5< / com:Sub> heterocyclyl, C<com:Sub>6-10< / com:Sub> aryl, C<com:Sub>1-5< / com:Sub> heteroaryl, C<com:Sub>3-6< / com:Sub> cycloalkyl-C<com:Sub>1-6< / com:Sub>-alkyl, C<com:Sub>2-5< / com:Sub> heterocyclyl-C<com:Sub>1-4< / com:Sub>- alkyl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl-<com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-alkyl or <com:Math><semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics>< / com:Math> heteroaryl-<com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math>-alkyl.
[00152] In some embodiments, each R<com:Sup>5< / com:Sup> and R<com:Sup>5e< / com:Sup> is independently H, D, methyl, ethyl, propyl, butyl, hydroxy C<com:Sub>1-4< / com:Sub> alkyl, amino C<com:Sub>1-4< / com:Sub> alkyl, cyano C<com:Sub>1-4< / com:Sub> alkyl, halo C<com:Sub>1-4< / com:Sub> alkyl, C<com:Sub>1-4< / com:Sub> alkoxy-C<com:Sub>1-4< / com:Sub> alkyl.
[00153] In some embodiments, each R<com:Sup>5< / com:Sup> and R<com:Sup>5e< / com:Sup> is independently H, D, methyl, ethyl, propyl, butyl, hydroxymethyl, hydroxyethyl, aminomethyl, cyanomethyl, difluoromethyl, 2,2- difluoroethyl, methoxymethyl, cyclopropyl, cyclopropoxy, phenyl, pyridyl, pyrimidinyl, cyclopropanemethyl, piperidinylmethyl, benzyl, pyridylmethyl or pyrimidinylmethyl.
[00154] In some embodiments, each R<com:Sup>5a< / com:Sup>, R<com:Sup>5b< / com:Sup>, R<com:Sup>5c< / com:Sup> and R<com:Sup>5d< / com:Sup> is independently H, D, C<com:Sub>1-6< / com:Sub> alkyl, C<com:Sub>2-< / com:Sub> 6 alkenyl, C<com:Sub>2-6< / com:Sub> alkynyl, hydroxy C<com:Sub>1-6< / com:Sub> alkyl, amino C<com:Sub>1-6< / com:Sub> alkyl, cyano C<com:Sub>1-6< / com:Sub> alkyl, halo C<com:Sub>1-6< / com:Sub> alkyl, C<com:Sub>1-6< / com:Sub> alkoxy-<com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxycarbonyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkylcarbonyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkylaminocarbonyl, <com:Math><semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>< / com:Math> cycloalkyl, <com:Math><semantics>C2−5<annotation encoding="application / x-tex">C_{2-5}< / annotation>< / semantics>< / com:Math> heterocyclyl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl, <com:Math><semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics>< / com:Math> heteroaryl, <com:Math><semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>< / com:Math> cycloalkylcarbonyl, <com:Math><semantics>C2−5<annotation encoding="application / x-tex">C_{2-5}< / annotation>< / semantics>< / com:Math> heterocyclylcarbonyl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> arylcarbonyl, <com:Math><semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics>< / com:Math> heteroarylcarbonyl, <com:Math><semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>< / com:Math> cycloalkyl-<com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkylcarbonyl, C<com:Sub>2-5< / com:Sub> heterocyclyl-C<com:Sub>1-6< / com:Sub>-alkylcarbonyl, C<com:Sub>6-10< / com:Sub> aryl-C<com:Sub>1-6< / com:Sub>-alkylcarbonyl, C<com:Sub>1-5< / com:Sub> heteroaryl- <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkylcarbonyl, <com:Math><semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>< / com:Math> cycloalkyl-<com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C2−5<annotation encoding="application / x-tex">C_{2-5}< / annotation>< / semantics>< / com:Math> heterocyclyl-<com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl-<com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>-alkyl or C<com:Sub>1-5< / com:Sub> heteroaryl-C<com:Sub>1-6< / com:Sub>-alkyl; or, R<com:Sup>5a< / com:Sup> and R<com:Sup>5b< / com:Sup>, together with the N atom to which they are attached, form a 3- to 10-membered heterocyclic ring or 3- to 10-membered heteroaromatic ring; or, R<com:Sup>5c< / com:Sup> and R<com:Sup>5d< / com:Sup>, together with the N atom to which they are attached, form a 3- to 10-membered heterocyclic ring or 3- to 10-membered heteroaromatic ring; wherein the "3- to 10-membered heteroaromatic ring" includes 5- to 10-membered heteroaromatic ring.
[00155] In some embodiments, each R<com:Sup>5a< / com:Sup>, R<com:Sup>5b< / com:Sup>, R<com:Sup>5c< / com:Sup> and R<com:Sup>5d< / com:Sup> is independently H, D, C<com:Sub>1-4< / com:Sub> alkyl, C<com:Sub>2-< / com:Sub> 4 alkenyl, C<com:Sub>2-4< / com:Sub> alkynyl, hydroxy C<com:Sub>1-4< / com:Sub> alkyl, amino C<com:Sub>1-4< / com:Sub> alkyl, cyano C<com:Sub>1-4< / com:Sub> alkyl, halo C<com:Sub>1-4< / com:Sub> alkyl, C<com:Sub>1-4< / com:Sub> alkoxy-C<com:Sub>1-4< / com:Sub>-alkyl, C<com:Sub>1-4< / com:Sub> alkoxycarbonyl, C<com:Sub>1-4< / com:Sub> alkylcarbonyl, C<com:Sub>1-4< / com:Sub> alkylaminocarbonyl, C<com:Sub>3-6< / com:Sub> cycloalkyl, <com:Math><semantics>C2−5<annotation encoding="application / x-tex">C_{2-5}< / annotation>< / semantics>< / com:Math> heterocyclyl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl, <com:Math><semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics>< / com:Math> heteroaryl, <com:Math><semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>< / com:Math> cycloalkylcarbonyl, <com:Math><semantics>C2−5<annotation encoding="application / x-tex">C_{2-5}< / annotation>< / semantics>< / com:Math> heterocyclylcarbonyl, C<com:Sub>6-10< / com:Sub> arylcarbonyl, C<com:Sub>1-5< / com:Sub> heteroarylcarbonyl, C<com:Sub>3-6< / com:Sub> cycloalkyl-C<com:Sub>1-3< / com:Sub>-alkyl, C<com:Sub>2-5< / com:Sub> heterocyclyl-<com:Math><semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl-<com:Math><semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics>< / com:Math>-alkyl or <com:Math><semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics>< / com:Math> heteroaryl-<com:Math><semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics>< / com:Math>-alkyl; or, <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R5b<annotation encoding="application / x-tex">R^{5b}< / annotation>< / semantics>< / com:Math>, together with the N atom to which they are attached, form a 3- to 6-membered heterocyclic ring or 3- to 6- membered heteroaromatic ring; or, R<com:Sup>5c< / com:Sup> and R<com:Sup>5d< / com:Sup>, together with the N atom to which they are attached, form a 3- to 6-membered heterocyclic ring or 3- to 6-membered heteroaromatic ring; wherein the "3- to 6-membered heteroaromatic ring" includes 5- to 6-membered heteroaromatic ring.
[00156] In other embodiments, each R<com:Sup>5a< / com:Sup>, R<com:Sup>5b< / com:Sup>, R<com:Sup>5c< / com:Sup> and R<com:Sup>5d< / com:Sup> is independently H, D, methyl, ethyl, propyl, butyl, hydroxymethyl, hydroxyethyl (including 2-hydroxyethyl and 1-hydroxyethyl), hydroxypropyl, hydroxybutyl, amino <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl, cyano <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl, trifluoromethoxy, chloroethyl (including 2-chloroethyl and 1-chloroethyl), 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 2-chloro-1- methylethyl, methoxymethyl, methoxyethyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, methylcarbonyl, ethylcarbonyl, methylaminocarbonyl, ethylaminocarbonyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperidinyl, piperazinyl, phenyl, pyridinyl, pyrimidinyl, cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cyclopropyloxycarbonyl, tetrahydrofurylcarbonyl, tetrahydropyranylcarbonyl, piperidylcarbonyl, piperazinylcarbonyl, morpholinylcarbonyl, tetrahydrothiophenylcarbonyl, pyrrolidinylcarbonyl, phenylcarbonyl, pyridylcarbonyl, pyrimidinylcarbonyl, pyrrolylcarbonyl, imidazolylcarbonyl, pyrazolylcarbonyl, thienylcarbonyl, furylcarbonyl, cyclopropylmethyl, cyclobutylmethyl, tetrahydropyranylmethyl, tetrahydropyranylethyl, tetrahydrofuranylmethyl, tetrahydrofuranylethyl, phenylmethyl, phenylethyl, pyridylmethyl, pyrazolylmethyl, pyrazolylethyl, pyridylethyl or C<com:Sub>2-5< / com:Sub> heterocyclyl-C<com:Sub>1-< / com:Sub> 3-alkyl; or, R<com:Sup>5a< / com:Sup> and R<com:Sup>5b< / com:Sup>, together with the N atom to which they are attached, form an azetidine, pyrrolidine, oxazolidine, thiazolidine, isothiazolidine, oxoisothiazolidine (such as dioxoisothiazolidine), piperidine, morpholine, piperazine, thiomorpholine, 1,3-oxazinane, pyrrole, pyrazole, imidazole or triazolyl; or, R<com:Sup>5c< / com:Sup> and R<com:Sup>5d< / com:Sup>, together with the N atom to which they are attached, form azetidine, pyrrolidine, oxazolidine, thiazolidine, isothiazolidine, oxoisothiazolidine (such as dioxoisothiazolidine), piperidine, morpholine, piperazine, thiomorpholine, 1,3-oxazinane, pyrrole, pyrazole, imidazole or triazolyl.
[00157] In some embodiments, each R<com:Sup>6< / com:Sup>, R<com:Sup>6a< / com:Sup>, R<com:Sup>6b< / com:Sup>, R<com:Sup>6c< / com:Sup>, R<com:Sup>6d< / com:Sup> and R<com:Sup>6e< / com:Sup> is independently H, D, F, Cl, Br, I, CN, amino, hydroxy, mercapto, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math> alkenyl, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math> alkynyl, hydroxy <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, amino <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, cyano <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, halo <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy, halo <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkylamino, acyl, sulfonyl, C<com:Sub>3-6< / com:Sub> cycloalkyl, C<com:Sub>2-5< / com:Sub> heterocyclyl, C<com:Sub>6-10< / com:Sub> aryl or C<com:Sub>1-5< / com:Sub> heteroaryl.
[00158] In some embodiments, each R<com:Sup>6< / com:Sup>, R<com:Sup>6a< / com:Sup>, R<com:Sup>6b< / com:Sup>, R<com:Sup>6c< / com:Sup>, R<com:Sup>6d< / com:Sup> and R<com:Sup>6e< / com:Sup> is independently H, D, F, Cl, Br, I, CN, amino, hydroxy, mercapto, C<com:Sub>1-4< / com:Sub> alkyl, C<com:Sub>2-4< / com:Sub> alkenyl, C<com:Sub>2-4< / com:Sub> alkynyl, hydroxy C<com:Sub>1-4< / com:Sub> alkyl, amino <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl, cyano <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl, halo <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy, halo <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkylamino, acyl, sulfonyl, <com:Math><semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>< / com:Math> cycloalkyl, <com:Math><semantics>C2−5<annotation encoding="application / x-tex">C_{2-5}< / annotation>< / semantics>< / com:Math> heterocyclyl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl or <com:Math><semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics>< / com:Math> heteroaryl.
[00159] In some embodiments, each R<com:Sup>6< / com:Sup>, R<com:Sup>6a< / com:Sup>, R<com:Sup>6b< / com:Sup>, R<com:Sup>6c< / com:Sup>, R<com:Sup>6d< / com:Sup> and R<com:Sup>6e< / com:Sup> is independently H, D, F, Cl, Br, I, CN, amino, hydroxy, mercapto, methyl, ethyl, propyl, butyl, hydroxy C<com:Sub>1-4< / com:Sub> alkyl, amino C<com:Sub>1-4< / com:Sub> alkyl, cyano <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl or halo <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl.
[00160] In some embodiments, each R<com:Sup>6< / com:Sup>, R<com:Sup>6a< / com:Sup>, R<com:Sup>6b< / com:Sup>, R<com:Sup>6c< / com:Sup>, R<com:Sup>6d< / com:Sup> and R<com:Sup>6e< / com:Sup> is independently H, D, F, Cl, Br, I, CN, amino, hydroxy, mercapto, methyl, ethyl, hydroxymethyl, hydroxyethyl, aminomethyl, aminoethyl, cyanomethyl, cyanoethyl, trifluoromethyl, difluoromethyl, monofluromethyl, chloroethyl, methoxy, ethoxy, trifluoromethoxy or difluoromethoxy.
[00161] In some embodiments, each <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R7a<annotation encoding="application / x-tex">R^{7a}< / annotation>< / semantics>< / com:Math> is independently H, D, amino, hydroxy, mercapto, C<com:Sub>1-6< / com:Sub> alkyl, C<com:Sub>2-6< / com:Sub> alkenyl, C<com:Sub>2-6< / com:Sub> alkynyl, halo C<com:Sub>1-6< / com:Sub> alkyl, C<com:Sub>1-6< / com:Sub> alkoxy, halo C<com:Sub>1-6< / com:Sub> alkoxy, C<com:Sub>1-6< / com:Sub> alkylamino, <com:Math><semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>< / com:Math> cycloalkyl, <com:Math><semantics>C2−5<annotation encoding="application / x-tex">C_{2-5}< / annotation>< / semantics>< / com:Math> heterocyclyl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl or <com:Math><semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics>< / com:Math> heteroaryl.
[00162] In some embodiments, each <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R7a<annotation encoding="application / x-tex">R^{7a}< / annotation>< / semantics>< / com:Math> is independently H, D, amino, hydroxy, mercapto, C<com:Sub>1-4< / com:Sub> alkyl, C<com:Sub>2-4< / com:Sub> alkenyl, C<com:Sub>2-4< / com:Sub> alkynyl, halo C<com:Sub>1-4< / com:Sub> alkyl, C<com:Sub>1-4< / com:Sub> alkoxy, halo C<com:Sub>1-4< / com:Sub> alkoxy, C<com:Sub>1-4< / com:Sub> alkylamino, C<com:Sub>3-6< / com:Sub> cycloalkyl, C<com:Sub>2-5< / com:Sub> heterocyclyl, C<com:Sub>6-10< / com:Sub> aryl or C<com:Sub>1-5< / com:Sub> heteroaryl.
[00163] In some embodiments, each <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R7a<annotation encoding="application / x-tex">R^{7a}< / annotation>< / semantics>< / com:Math> is independently H, D, amino, hydroxy, mercapto, methyl, ethyl, propyl, butyl or trifluoromethyl.
[00164] In some embodiments, each R<com:Sup>8< / com:Sup> and R<com:Sup>8a< / com:Sup> is independently H, D, amino, hydroxy, mercapto, C<com:Sub>1-6< / com:Sub> alkyl, C<com:Sub>2-6< / com:Sub> alkenyl, C<com:Sub>2-6< / com:Sub> alkynyl, halo C<com:Sub>1-6< / com:Sub> alkyl, C<com:Sub>1-6< / com:Sub> alkoxy, halo C<com:Sub>1-6< / com:Sub> alkoxy, C<com:Sub>1-6< / com:Sub> alkylamino, <com:Math><semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>< / com:Math> cycloalkyl, <com:Math><semantics>C2−5<annotation encoding="application / x-tex">C_{2-5}< / annotation>< / semantics>< / com:Math> heterocyclyl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl or <com:Math><semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics>< / com:Math> heteroaryl.
[00165] In some embodiments, each R<com:Sup>8< / com:Sup> and R<com:Sup>8a< / com:Sup> is independently H, D, amino, hydroxy, mercapto, C<com:Sub>1-4< / com:Sub> alkyl, C<com:Sub>2-4< / com:Sub> alkenyl, C<com:Sub>2-4< / com:Sub> alkynyl, halo C<com:Sub>1-4< / com:Sub> alkyl, C<com:Sub>1-4< / com:Sub> alkoxy, halo C<com:Sub>1-4< / com:Sub> alkoxy, C<com:Sub>1-4< / com:Sub> alkylamino, <com:Math><semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>< / com:Math> cycloalkyl, <com:Math><semantics>C2−5<annotation encoding="application / x-tex">C_{2-5}< / annotation>< / semantics>< / com:Math> heterocyclyl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl or <com:Math><semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics>< / com:Math> heteroaryl.
[00166] In some embodiments, each R<com:Sup>8< / com:Sup> and R<com:Sup>8a< / com:Sup> is independently H, D, amino, hydroxy, mercapto, methyl, ethyl, propyl, butyl, trifluoromethyl, chloroethyl, 2,2,2-trifluoroethyl, 2,2- difluoroethyl, 2-chloro-1-methylethyl, methoxy, ethoxy, propoxy, trifluoromethoxy, methylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, morpholinyl, piperidinyl, piperazinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, phenyl, pyrrolyl, thienyl, furyl, pyridyl or pyrimidinyl.
[00167] In some embodiments, each <com:Math><semantics>R9<annotation encoding="application / x-tex">R^9< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R9a<annotation encoding="application / x-tex">R^{9a}< / annotation>< / semantics>< / com:Math> is independently H, D, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math> alkenyl, C<com:Sub>2-6< / com:Sub> alkynyl, halo C<com:Sub>1-6< / com:Sub> alkyl, acyl, sulfonyl, C<com:Sub>3-6< / com:Sub> cycloalkyl, C<com:Sub>2-5< / com:Sub> heterocyclyl, C<com:Sub>6-10< / com:Sub> aryl, C<com:Sub>1-5< / com:Sub> heteroaryl, C<com:Sub>3-6< / com:Sub> cycloalkyl-C<com:Sub>1-6< / com:Sub>-alkyl, C<com:Sub>2-5< / com:Sub> heterocyclyl-C<com:Sub>1-6< / com:Sub>-alkyl, C<com:Sub>6-10< / com:Sub> aryl-C<com:Sub>1-6< / com:Sub>-alkyl or C<com:Sub>1-5< / com:Sub> heteroaryl-<com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl.
[00168] In some embodiments, each <com:Math><semantics>R9<annotation encoding="application / x-tex">R^9< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R9a<annotation encoding="application / x-tex">R^{9a}< / annotation>< / semantics>< / com:Math> is independently H, D, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C2−4<annotation encoding="application / x-tex">C_{2-4}< / annotation>< / semantics>< / com:Math> alkenyl, C<com:Sub>2-4< / com:Sub> alkynyl, halo C<com:Sub>1-4< / com:Sub> alkyl, acyl, sulfonyl, C<com:Sub>3-6< / com:Sub> cycloalkyl, C<com:Sub>2-5< / com:Sub> heterocyclyl, C<com:Sub>6-10< / com:Sub> aryl, C<com:Sub>1-5< / com:Sub> heteroaryl, C<com:Sub>3-6< / com:Sub> cycloalkyl-C<com:Sub>1-3< / com:Sub>-alkyl, C<com:Sub>2-5< / com:Sub> heterocyclyl-C<com:Sub>1-3< / com:Sub>-alkyl, C<com:Sub>6-10< / com:Sub> aryl-C<com:Sub>1-3< / com:Sub>-alkyl or C<com:Sub>1-5< / com:Sub> heteroaryl-C<com:Sub>1-3< / com:Sub>-alkyl.
[00169] In some embodiments, each R<com:Sup>9< / com:Sup> and R<com:Sup>9a< / com:Sup> is independently H, D, methyl, ethyl, propyl, butyl, <com:Math><semantics>C2−4<annotation encoding="application / x-tex">C_{2-4}< / annotation>< / semantics>< / com:Math> alkenyl, <com:Math><semantics>C2−4<annotation encoding="application / x-tex">C_{2-4}< / annotation>< / semantics>< / com:Math> alkynyl, trifluoromethyl, chloroethyl, 2,2,2-trifluoroethyl, 2,2- difluoroethyl, 2-chloro-1-methylethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, tetrahydrofuranyl, morpholinyl, piperidinyl, piperazinyl, phenyl, pyridyl, pyrimidinyl, cyclopropylmethyl, cyclobutylmethyl, phenylmethyl, phenylethyl, pyridylmethyl, pyridylethyl or C<com:Sub>2-5< / com:Sub> heterocyclyl-C<com:Sub>1-3< / com:Sub>-alkyl.
[00170] In some embodiments, each R<com:Sup>10< / com:Sup> and R<com:Sup>11< / com:Sup> is independently H, D, F, Cl, Br, I, CN, amino, hydroxy, mercapto, C<com:Sub>1-6< / com:Sub> alkyl, C<com:Sub>2-6< / com:Sub> alkenyl, C<com:Sub>2-6< / com:Sub> alkynyl, hydroxy C<com:Sub>1-6< / com:Sub> alkyl, amino C<com:Sub>1-6< / com:Sub> alkyl, cyano C<com:Sub>1-6< / com:Sub> alkyl, halo C<com:Sub>1-6< / com:Sub> alkyl, C<com:Sub>1-6< / com:Sub> alkoxy, halo C<com:Sub>1-6< / com:Sub> alkoxy, C<com:Sub>1-6< / com:Sub> alkylamino, acyl, sulfonyl, C<com:Sub>3-< / com:Sub> <com:Sub>6< / com:Sub> cycloalkyl, <com:Math><semantics>C2−5<annotation encoding="application / x-tex">C_{2-5}< / annotation>< / semantics>< / com:Math> heterocyclyl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl or <com:Math><semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics>< / com:Math> heteroaryl; or, <com:Math><semantics>R10<annotation encoding="application / x-tex">R^{10}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R11<annotation encoding="application / x-tex">R^{11}< / annotation>< / semantics>< / com:Math> together form carbonyl; or, R<com:Sup>10< / com:Sup> and R<com:Sup>11< / com:Sup>, together with the carbon atom to which they are attached, form a 3- to 8-membered carbocyclic ring or 3- to 8-membered heterocyclic ring.
[00171] In some embodiments, each R<com:Sup>x< / com:Sup> is independently oxo, H, D, F, Cl, Br, I, CN, amino, hydroxy, mercapto, C<com:Sub>1-6< / com:Sub> alkyl, C<com:Sub>2-6< / com:Sub> alkenyl, C<com:Sub>2-6< / com:Sub> alkynyl, hydroxy C<com:Sub>1-6< / com:Sub> alkyl, amino C<com:Sub>1-6< / com:Sub> alkyl, cyano C<com:Sub>1-6< / com:Sub> alkyl, halo C<com:Sub>1-6< / com:Sub> alkyl, C<com:Sub>1-6< / com:Sub> alkoxy, halo C<com:Sub>1-6< / com:Sub> alkoxy, C<com:Sub>1-6< / com:Sub> alkylamino, acyl, sulfonyl, C<com:Sub>1-6< / com:Sub> 6 alkylcarbonyl, C<com:Sub>1-6< / com:Sub> alkylsulfonyl, C<com:Sub>1-6< / com:Sub> alkylcarbonylamino, C<com:Sub>1-6< / com:Sub> alkylsulfonylamino, C<com:Sub>1-6< / com:Sub> alkoxycarbonylamino, <com:Math><semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>< / com:Math> cycloalkyl, <com:Math><semantics>C2−5<annotation encoding="application / x-tex">C_{2-5}< / annotation>< / semantics>< / com:Math> heterocyclyl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl or <com:Math><semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics>< / com:Math> heteroaryl.
[00172] In some embodiments, each R<com:Sup>x< / com:Sup> is independently oxo, H, D, F, Cl, Br, I, CN, amino, hydroxy, mercapto, C<com:Sub>1-4< / com:Sub> alkyl, C<com:Sub>2-4< / com:Sub> alkenyl, C<com:Sub>2-4< / com:Sub> alkynyl, hydroxy C<com:Sub>1-4< / com:Sub> alkyl, amino C<com:Sub>1-4< / com:Sub> alkyl, cyano C<com:Sub>1-4< / com:Sub> alkyl, halo C<com:Sub>1-4< / com:Sub> alkyl, C<com:Sub>1-4< / com:Sub> alkoxy, halo C<com:Sub>1-4< / com:Sub> alkoxy, C<com:Sub>1-4< / com:Sub> alkylamino, acyl, sulfonyl, C<com:Sub>1-4< / com:Sub> 4 alkylcarbonyl, C<com:Sub>1-4< / com:Sub> alkylsulfonyl, C<com:Sub>1-4< / com:Sub> alkylcarbonylamino, C<com:Sub>1-4< / com:Sub> alkylsulfonylamino, C<com:Sub>1-4< / com:Sub> alkoxycarbonylamino, <com:Math><semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>< / com:Math> cycloalkyl, <com:Math><semantics>C2−5<annotation encoding="application / x-tex">C_{2-5}< / annotation>< / semantics>< / com:Math> heterocyclyl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl or <com:Math><semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics>< / com:Math> heteroaryl.
[00173] In some embodiments, each R<com:Sup>x< / com:Sup> is independently oxo (=O), H, D, F, Cl, Br, I, CN, amino, hydroxy, mercapto, methyl, ethyl, propyl, butyl, C<com:Sub>2-4< / com:Sub> alkenyl, C<com:Sub>2-4< / com:Sub> alkynyl, hydroxymethyl, hydroxyethyl, amino <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl, cyano <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl, trifluoromethyl, chloroethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 2-chloro-1-methylethyl, methoxy, ethoxy, propoxy, trifluoromethoxy, methylamino, dimethylamino, C<com:Sub>1-3< / com:Sub> alkylcarbonyl, C<com:Sub>1-3< / com:Sub> alkylsulfonyl, C<com:Sub>1-3< / com:Sub> alkylcarbonylamino, C<com:Sub>1-< / com:Sub> 3 alkylsulfonamino, methoxyformylamino, <com:Math><semantics>C2−3<annotation encoding="application / x-tex">C_{2-3}< / annotation>< / semantics>< / com:Math> alkoxycarbonylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, <com:Math><semantics>C2−5<annotation encoding="application / x-tex">C_{2-5}< / annotation>< / semantics>< / com:Math> heterocyclyl, phenyl or <com:Math><semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics>< / com:Math> heteroaryl.
[00174] In some embodiments, each R<com:Sup>y< / com:Sup> is independently oxo, H, D, F, Cl, Br, I, CN, amino, hydroxy, mercapto, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math> alkenyl, <com:Math><semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics>< / com:Math> alkynyl, hydroxy <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, amino <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, cyano C<com:Sub>1-6< / com:Sub> alkyl, halo C<com:Sub>1-6< / com:Sub> alkyl, C<com:Sub>1-6< / com:Sub> alkoxy, halo C<com:Sub>1-6< / com:Sub> alkoxy, C<com:Sub>1-6< / com:Sub> alkylamino, acyl, sulfonyl, C<com:Sub>1-6< / com:Sub> 6 alkylcarbonyl, C<com:Sub>1-6< / com:Sub> alkylsulfonyl, C<com:Sub>1-6< / com:Sub> alkylcarbonylamino, C<com:Sub>1-6< / com:Sub> alkylsulfonylamino, C<com:Sub>1-6< / com:Sub> alkoxycarbonylamino, <com:Math><semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>< / com:Math> cycloalkyl, <com:Math><semantics>C2−5<annotation encoding="application / x-tex">C_{2-5}< / annotation>< / semantics>< / com:Math> heterocyclyl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl or <com:Math><semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics>< / com:Math> heteroaryl.
[00175] In some embodiments, each R<com:Sup>y< / com:Sup> is independently oxo, H, D, F, Cl, Br, I, CN, amino, hydroxy, mercapto, C<com:Sub>1-4< / com:Sub> alkyl, C<com:Sub>2-4< / com:Sub> alkenyl, C<com:Sub>2-4< / com:Sub> alkynyl, hydroxy C<com:Sub>1-4< / com:Sub> alkyl, amino C<com:Sub>1-4< / com:Sub> alkyl, cyano C<com:Sub>1-4< / com:Sub> alkyl, halo C<com:Sub>1-4< / com:Sub> alkyl, C<com:Sub>1-4< / com:Sub> alkoxy, halo C<com:Sub>1-4< / com:Sub> alkoxy, C<com:Sub>1-4< / com:Sub> alkylamino, acyl, sulfonyl, C<com:Sub>1-4< / com:Sub> 4 alkylcarbonyl, C<com:Sub>1-4< / com:Sub> alkylsulfonyl, C<com:Sub>1-4< / com:Sub> alkylcarbonylamino, C<com:Sub>1-4< / com:Sub> alkylsulfonylamino, C<com:Sub>1-4< / com:Sub> alkoxycarbonylamino, <com:Math><semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>< / com:Math> cycloalkyl, <com:Math><semantics>C2−5<annotation encoding="application / x-tex">C_{2-5}< / annotation>< / semantics>< / com:Math> heterocyclyl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl or <com:Math><semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics>< / com:Math> heteroaryl.
[00176] In some embodiments, each R<com:Sup>y< / com:Sup> is independently oxo, H, D, F, Cl, Br, I, CN, amino, hydroxy, mercapto, methyl, ethyl, propyl, butyl, C<com:Sub>2-4< / com:Sub> alkenyl, C<com:Sub>2-4< / com:Sub> alkynyl, hydroxymethyl, hydroxyethyl, amino C<com:Sub>1-4< / com:Sub> alkyl, cyano C<com:Sub>1-4< / com:Sub> alkyl, trifluoromethyl, chloroethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 2-chloro-1-methylethyl, methoxy, ethoxy, propoxy, trifluoromethoxy, methylamino, dimethylamino, <com:Math><semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics>< / com:Math> alkylcarbonyl, <com:Math><semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics>< / com:Math> alkylsulfonyl, <com:Math><semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics>< / com:Math> alkylcarbonylamino, <com:Math><semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics>< / com:Math> 3 alkylsulfonamino, methoxyformylamino, C<com:Sub>2-3< / com:Sub> alkoxycarbonylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, <com:Math><semantics>C2−5<annotation encoding="application / x-tex">C_{2-5}< / annotation>< / semantics>< / com:Math> heterocyclyl, phenyl or <com:Math><semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics>< / com:Math> heteroaryl.
[00177] In some embodiments, each R<com:Sup>z< / com:Sup> is independently oxo, H, D, F, Cl, Br, I, CN, amino, hydroxy, mercapto, C<com:Sub>1-6< / com:Sub> alkyl, C<com:Sub>2-6< / com:Sub> alkenyl, C<com:Sub>2-6< / com:Sub> alkynyl, hydroxy C<com:Sub>1-6< / com:Sub> alkyl, amino C<com:Sub>1-6< / com:Sub> alkyl, cyano C<com:Sub>1-6< / com:Sub> alkyl, halo C<com:Sub>1-6< / com:Sub> alkyl, C<com:Sub>1-6< / com:Sub> alkoxy, halo C<com:Sub>1-6< / com:Sub> alkoxy, C<com:Sub>1-6< / com:Sub> alkylamino, acyl, sulfonyl, C<com:Sub>1-6< / com:Sub> 6 alkylcarbonyl, C<com:Sub>1-6< / com:Sub> alkylsulfonyl, C<com:Sub>1-6< / com:Sub> alkylcarbonylamino, C<com:Sub>1-6< / com:Sub> alkylsulfonylamino, C<com:Sub>1-6< / com:Sub> alkoxycarbonylamino, <com:Math><semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>< / com:Math> cycloalkyl, <com:Math><semantics>C2−5<annotation encoding="application / x-tex">C_{2-5}< / annotation>< / semantics>< / com:Math> heterocyclyl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl or <com:Math><semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics>< / com:Math> heteroaryl.
[00178] In some embodiments, each R<com:Sup>z< / com:Sup> is independently oxo, H, D, F, Cl, Br, I, CN, amino, hydroxy, mercapto, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C2−4<annotation encoding="application / x-tex">C_{2-4}< / annotation>< / semantics>< / com:Math> alkenyl, <com:Math><semantics>C2−4<annotation encoding="application / x-tex">C_{2-4}< / annotation>< / semantics>< / com:Math> alkynyl, hydroxy <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl, amino <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl, cyano C<com:Sub>1-4< / com:Sub> alkyl, halo C<com:Sub>1-4< / com:Sub> alkyl, C<com:Sub>1-4< / com:Sub> alkoxy, halo C<com:Sub>1-4< / com:Sub> alkoxy, C<com:Sub>1-4< / com:Sub> alkylamino, acyl, sulfonyl, C<com:Sub>1-4< / com:Sub> 4 alkylcarbonyl, C<com:Sub>1-4< / com:Sub> alkylsulfonyl, C<com:Sub>1-4< / com:Sub> alkylcarbonylamino, C<com:Sub>1-4< / com:Sub> alkylsulfonylamino, C<com:Sub>1-4< / com:Sub> alkoxycarbonylamino, <com:Math><semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>< / com:Math> cycloalkyl, <com:Math><semantics>C2−5<annotation encoding="application / x-tex">C_{2-5}< / annotation>< / semantics>< / com:Math> heterocyclyl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl or <com:Math><semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics>< / com:Math> heteroaryl.
[00179] In some embodiments, each R<com:Sup>z< / com:Sup> is independently oxo, H, D, F, Cl, Br, I, CN, amino, hydroxy, mercapto, methyl, ethyl, propyl, butyl, C<com:Sub>2-4< / com:Sub> alkenyl, C<com:Sub>2-4< / com:Sub> alkynyl, hydroxymethyl, hydroxyethyl, amino C<com:Sub>1-4< / com:Sub> alkyl, cyano C<com:Sub>1-4< / com:Sub> alkyl, trifluoromethyl, chloroethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 2-chloro-1-methylethyl, methoxy, ethoxy, propoxy, trifluoromethoxy, methylamino, dimethylamino, <com:Math><semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics>< / com:Math> alkylcarbonyl, <com:Math><semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics>< / com:Math> alkylsulfonyl, <com:Math><semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics>< / com:Math> alkylcarbonylamino, <com:Math><semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics>< / com:Math> 3 alkylsulfonamino, methoxyformylamino, <com:Math><semantics>C2−3<annotation encoding="application / x-tex">C_{2-3}< / annotation>< / semantics>< / com:Math> alkoxycarbonylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, <com:Math><semantics>C2−5<annotation encoding="application / x-tex">C_{2-5}< / annotation>< / semantics>< / com:Math> heterocyclyl, phenyl or <com:Math><semantics>C1−5<annotation encoding="application / x-tex">C_{1-5}< / annotation>< / semantics>< / com:Math> heteroaryl.
[00180] In some embodiments, n is 0, 1, 2, 3 or 4.
[00181] In some embodiments, m is 0, 1, 2 or 3.
[00182] In some embodiments, r is 0, 1, 2, 3, 4, 5 or 6.
[00183] In some embodiments, each u, j and g is independently 0, 1, 2, 3 or 4.
[00184] In some embodiments, each h, i, k and p is independently 0, 1, 2, 3 or 4.
[00185] In some embodiments, the compound of the invention has one of the following structures or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof, [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), 59 [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (13), (14), (15), (16), (17), (18), (19), (20), (21), [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (22), (23), (24), (25), (26), (27), . (28), (29), (30), F, [Image disponible dans le document PDF, Image available in the PDF document] F F F =N N N Ν NH<com:Sub>2< / com:Sub> <com:Math><semantics>H2N′<annotation encoding="application / x-tex">H_2N'< / annotation>< / semantics>< / com:Math> HN. <com:Math><semantics>=<annotation encoding="application / x-tex">=< / annotation>< / semantics>< / com:Math>N Ν NH<com:Sub>2< / com:Sub> : N H<com:Sub>2< / com:Sub>N - N (32), 0 O (33), N F F <com:Math><semantics>⊆N<annotation encoding="application / x-tex">\subseteq N< / annotation>< / semantics>< / com:Math> <com:Math><semantics>⊆N<annotation encoding="application / x-tex">\subseteq N< / annotation>< / semantics>< / com:Math> Ν Ν Ν N IV NH<com:Sub>2< / com:Sub> NH<com:Sub>2< / com:Sub> <com:Math><semantics>H2N<annotation encoding="application / x-tex">H_2N< / annotation>< / semantics>< / com:Math> HN- O, <com:Math><semantics>H2N′<annotation encoding="application / x-tex">H_2N'< / annotation>< / semantics>< / com:Math> 0 0 (35), 0 (36), [Image disponible dans le document PDF, Image available in the PDF document] (37), (38), [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (40), (41), ` / / [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (42), (43), (44), (45), (46), (47), (48), (49), (50), [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (51), (52), (53), (54), (55), (56), (57), (58), (59), [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (60), (61), (62), [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (63), (64), (65), [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>(66)<annotation encoding="application / x-tex">(66)< / annotation>< / semantics>< / com:Math> or (67).
[00186] In another aspect, provided herein is a pharmaceutical composition comprising any one of the compounds disclosed herein.
[00187] In some embodiments, the pharmaceutical composition disclosed herein further comprises at least one of pharmaceutically acceptable carrier, excipient, diluent, adjuvant and vehicle.
[00188] In one aspect, provided herein is use of the compound or the pharmaceutical composition of the invention in the manufacture of a medicament for treating and / or preventing diseases, wherein the diseases comprise heart failure, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorder, nephropathy, thromboembolic disorder, male sexual dysfunction, systemic sclerosis, sickle cell anemia, achalasia of the cardia, fibrotic disorder and / or arteriosclerosis.
[00189] In another aspect, provided herein is use of the compound or the pharmaceutical composition of the invention in the manufacture a medicament as a soluble guanylate cyclase stimulator.
[00190] Also provided herein is the use of a compound disclosed herein, or a pharmaceutically acceptable salts thereof, in the manufacture of a medicament for treating sGC-mediated disease, and those diseases described herein. Also provided herein is a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by any Formula of the invention in association with at least one pharmaceutically acceptable carrier, excipient, diluent, adjuvant and vehicle.
[00191] In one aspect, provided herein is a method of treating and / or preventing diseases in a patient, comprising administering to the patient a therapeutically effective amount of the compound or the pharmaceutical composition of the invention, wherein the diseases comprise heart failure, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorder, nephropathy, thromboembolic disorder, male sexual dysfunction, systemic sclerosis, sickle cell anemia, achalasia of the cardia, fibrotic disorders and / or arteriosclerosis.
[00192] In another aspect, the present invention relates to a method of stimulating and / or activating soluble guanylate cyclase, comprising contacting the organism (including in vivo or in vitro) with an effective dosage of a compound or a pharmaceutical composition of the present invention.
[00193] In one aspect, provided herein is the compound or the pharmaceutical composition of the invention for use in treating and / or preventing the diseases comprise heart failure, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorder, nephropathy, thromboembolic disorder, male sexual dysfunction, systemic sclerosis, sickle cell anemia, achalasia of the cardia, fibrotic disorder and / or arteriosclerosis.
[00194] In another aspect, the invention relates to the compound or pharmaceutical compositions for use in stimulating and / or activating soluble guanylate cyclase.
[00195] The present invention also encompasses method of treating or lessening a patient's sGC- mediated disease, or susceptibility to these conditions, comprising administering to a patient a therapeutically effective amount of a compound of the present invention.
[00196] Unless otherwise stated, all hydrates, solvates, and pharmaceutically acceptable salts of the compounds of the present invention are within the scope of the present invention.
[00197] Specifically, the salt is a pharmaceutically acceptable salt. The phrase "pharmaceutically acceptable" refers to that the substance or composition must be compatible chemically and / or toxicologically, with the other ingredients comprising a formulation, and / or the mammal being treated therewith.
[00198] The compounds disclosed herein also include salts of the compounds which are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for preparing and / or purifying compounds of the invention, and / or for separating enantiomers of compounds of the invention.
[00199] The salt of the compound in the invention may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid and salicylic acid; a pyranosidyl acid, such as glucuronic acid and galacturonic acid; an alpha-hydroxy acid, such as citric acid and tartaric acid; an amino acid, such as aspartic acid and glutamic acid; an aromatic acid, such as benzoic acid and cinnamic acid; a sulfonic acid, such as p-toluenesulfonic acid, ethanesulfonic acid, and the like.
[00200] The biological activity of the compounds of the invention can be assessed by using any conventionally known method. Suitable assay methods are well known in the art. For example, the sGC activation activity, pharmacokinetic activity, and / or liver microsomal stability, etc., of the compounds of the invention can be assayed by appropriate conventional methods. The detection method provided by the present invention is only presented as an example and does not limit the present invention. The compounds of the invention are active in at least one of the detection methods provided herein. For example, the compounds of the present invention have an activating effect on a recombinant guanylate cyclase reporter cell line. For example, the compound of the present invention can effectively activate the activity of the CHO-K1-Rat sGC monoclonal cell line, that is, the compound of the present invention has godd sGC activation activity. For another example, the compounds of the present invention have better pharmacokinetic properties in vivo, have better absorption and exposure level, and have higher bioavailability. PHARMACEUTICAL COMPOSITION OF THE COMPOUND OF THE INVENTION AND PREPARATIONS, ADMINISTRATION AND USE
[00201] According to another aspect, the features of the pharmaceutical compositions of the present invention include the fluorine-substituted indazole compounds described in the present invention, the compounds listed in the present invention, or the compounds of Examples 1-63, and pharmaceutically acceptable carriers, adjuvants, or excipients. The amount of compound in the compositions of the present invention is effective to treat or reduce the patient's sGC related disorders.
[00202] As described above, the pharmaceutically acceptable composition disclosed herein further comprises a pharmaceutically acceptable carrier, an adjuvant, or an excipient, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. As described in the following document: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams& Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York, discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium incompatible with the compounds disclosed herein, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other components of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention.
[00203] Some non-limiting examples of materials which can serve as pharmaceutically acceptable carriers include ion exchangers; aluminium; aluminum stearate; lecithin; serum proteins such as human serum albumin; buffer substances such as phosphates; glycine; sorbic acid; potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water; salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride and zinc salts; colloidal silica; magnesium trisilicate; polyvinyl pyrrolidone; polyacrylates; waxes; polyethylene-polyoxypropylene-block polymers; wool fat; sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants.
[00204] The pharmaceutical composition of the present invention can be administered directly or in a pharmaceutical composition or drug form with a suitable carrier or excipient, which is well known in the art. The therapeutic method of the invention may comprise administering an effective compound of the invention to a subject in need thereof. In some embodiments, the subject is a mammalian subject, and in some preferred embodiments, the individual is a human subject.
[00205] The effective amount of the compound, pharmaceutical composition or medicament of the present invention can be easily determined by routine experimentation. The most effective and convenient route of administration and the most suitable formulation can also be determined by routine experimentation.
[00206] Pharmaceutical dosage forms of the compounds of the invention can be provided in the form of immediate release, controlled release, sustained release or target drug delivery systems. Commonly used dosage forms include, for example, solutions and suspensions, (micro-) emulsions, ointments, gels and patches, liposomes, tablets, dragees, soft or hard shell capsules, suppositories, ovules, implants, amorphous or crystalline powders, aerosols, and lyophilized formulations. Depending on route of administration used, special devices may be required for application or administration of the drug, such as, for example, syringes and needles, inhalers, pumps, injection pens, applicators, or special flasks. Pharmaceutical dosage forms are often composed of the drug, an excipient(s), and a container / closure system. One or multiple excipients, also referred to as inactive ingredients, can be added to a compound of the invention to improve or facilitate manufacturing, stability, administration, and safety of the drug, and can provide a means to achieve a desired drug release profile. Therefore, the type of excipient(s) to be added to the drug can depend on various factors, such as, for example, the physical and chemical properties of the drug, the route of administration, and the manufacturing procedure. Pharmaceutically acceptable excipients are available in the art and include those listed in various pharmacopoeias. (See, e.g., the U.S. Pharmacopeia (USP), Japanese Pharmacopoeia (JP), European Pharmacopoeia (EP), and British pharmacopeia (BP); the U.S. Food and Drug Administration (www.fda.gov) Center for Drug Evaluation and Research (CEDR) publications, e.g., Inactive Ingredient Guide (1996); Ash and Ash, Eds. (2002) Handbook of Pharmaceutical Additives, Synapse Information Resources, Inc., Endicott N.Y.; etc.).
[00207] Pharmaceutical dosage forms of a compound of the present invention may be manufactured by any of the methods well-known in the art, such as, for example, by conventional mixing, sieving, dissolving, melting, granulating, dragee-making, tabletting, suspending, extruding, spray-drying, levigating, emulsifying, (nano / micro-) encapsulating, entrapping, or lyophilization processes. As noted above, the compositions of the present invention can include one or more physiologically acceptable inactive ingredients that facilitate processing of active molecules into preparations for pharmaceutical use.
[00208] Proper formulation is dependent upon the desired route of administration. For intravenous injection, for example, the composition may be formulated in aqueous solution, if necessary using physiologically compatible buffers, including, for example, phosphate, histidine, or citrate for adjustment of the formulation pH, and a tonicity agent, such as, for example, sodium chloride or dextrose. For transmucosal or nasal administration, semisolid, liquid formulations, or patches may be preferred, possibly containing penetration enhancers. Such penetrants are generally known in the art. For oral administration, the compounds can be formulated in liquid or solid dosage forms, and as instant or controlled / sustained release formulations. Suitable dosage forms for oral ingestion by a subject include tablets, pills, dragees, hard and soft shell capsules, liquids, gels, syrups, slurries, suspensions, and emulsions. The compounds may also be formulated in rectal compositions, such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
[00209] Solid oral dosage forms can be obtained using excipients, which may include fillers, disintegrants, binders (dry and wet), dissolution retardants, lubricants, glidants, antiadherants, cationic exchange resins, wetting agents, antioxidants, preservatives, coloring, and flavoring agents. These excipients can be of synthetic or natural source. Examples of such excipients include cellulose derivatives, citric acid, dicalcium phosphate, gelatine, magnesium carbonate, magnesium / sodium lauryl sulfate, mannitol, polyethylene glycol, polyvinyl pyrrolidone, silicates, silicium dioxide, sodium benzoate, sorbitol, starches, stearic acid or a salt thereof, sugars (i.e., dextrose, sucrose, lactose, etc.), talc, tragacanth mucilage, vegetable oils (hydrogenated), and waxes. Ethanol and water may serve as granulation aides. In certain instances, coating of tablets with, for example, a taste-masking film, a stomach acid resistant film, or a release-retarding film is desirable. Natural and synthetic polymers, in combination with colorants, sugars, and organic solvents or water, are often used to coat tablets, resulting in dragees. When a capsule is preferred over a tablet, the drug powder, suspension, or solution thereof can be delivered in a compatible hard or soft shell capsule.
[00210] In one embodiment, the compounds of the present invention can be administered topically, such as through a skin patch, a semi-solid, or a liquid formulation, for example a gel, a (micro-) emulsion, an ointment, a solution, a (nano / micro)-suspension, or a foam. The penetration of the drug into the skin and underlying tissues can be regulated, for example, using penetration enhancers; the appropriate choice and combination of lipophilic, hydrophilic, and amphiphilic excipients, including water, organic solvents, waxes, oils, synthetic and natural polymers, surfactants, emulsifiers; by pH adjustment; and use of complexing agents. Other techniques, such as iontophoresis, may be used to regulate skin penetration of a compound of the invention. Transdermal or topical administration would be preferred, for example, in situations in which local delivery with minimal systemic exposure is desired.
[00211] For administration by inhalation, or administration to the nose, the compounds for use according to the present invention are conveniently delivered in the form of a solution, suspension, emulsion, or semisolid aerosol from pressurized packs, or a nebuliser, usually with the use of a propellant, e.g., halogenated carbons derived from methane and ethane, carbon dioxide, or any other suitable gas. For topical aerosols, hydrocarbons like butane, isobutene, and pentane are useful. In the case of a pressurized aerosol, the appropriate dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatin, for use in an inhaler or insufflator, may be formulated. These typically contain a powder mix of the compound and a suitable powder base such as lactose or starch.
[00212] Compositions formulated for parenteral administration by injection are usually sterile and can be presented in unit dosage forms, e.g., in ampoules, syringes, injection pens, or in multi- dose containers, the latter usually containing a preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents, such as buffers, tonicity agents, viscosity enhancing agents, surfactants, suspending and dispersing agents, antioxidants, biocompatible polymers, chelating agents, and preservatives. Depending on the injection site, the vehicle may contain water, a synthetic or vegetable oil, and / or organic co-solvents. In certain instances, such as with a lyophilized product or a concentrate, the parenteral formulation would be reconstituted or diluted prior to administration. Depot formulations, providing controlled or sustained release of a compound of the invention, may include injectable suspensions of nano / micro particles or nano / micro or non- micronized crystals. Polymers such as poly(lactic acid), poly(glycolic acid), or copolymers thereof, can serve as controlled / sustained release matrices, in addition to others well known in the art. Other depot delivery systems may be presented in form of implants and pumps requiring incision.
[00213] Suitable carriers for intravenous injection for the compounds of the invention are well- known in the art and include water-based solutions containing a base, such as, for example, sodium hydroxide, to form an ionized compound; sucrose or sodium chloride as a tonicity agent; and a buffer, for example, a buffer that contains phosphate or histidine. co-solvents, such as, for example, polyethylene glycols, may be added. These water-based systems are effective at dissolving compounds of the invention and produce low toxicity upon systemic administration. The proportions of the components of a solution system may be varied considerably, without destroying solubility and toxicity characteristics. Furthermore, the identity of the components may be varied. For example, low-toxicity surfactants, such as polysorbates or poloxamers, may be used, as can polyethylene glycol or other co-solvents, biocompatible polymers such as polyvinyl pyrrolidone may be added, and other sugars and polyols may substitute for dextrose.
[00214] The compounds according to the invention may act systemically and / or locally. They can be administered in a suitable manner, for example by the oral, parenteral, pulmonal, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic route, or as an implant or stent. The compounds of the present invention are preferably administered orally or parenterally.
[00215] Suitable administration forms for oral administration are those which work according to the prior art, which release the compounds according to the invention rapidly and / or in a modified manner and which contain the compounds according to the invention in crystalline and / or amorphized and / or dissolved form, for example tablets (uncoated or coated tablets, for example with gastric juice-resistant or retarded-dissolution or insoluble coatings which control the release of the compound according to the invention), tablets or films / wafers which disintegrate rapidly in the oral cavity, films / lyophilizates or capsules (for example hard or soft gelatin capsules), sugar- coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
[00216] Parenteral administration can bypass an absorption step (e.g., intravenously, intraarterially, intracardially, intraspinally or intralumbally) or include an absorption (e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously or intraperitoneally). Administration forms suitable for parenteral administration include preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophilizates or sterile powders.
[00217] For the other administration routes, suitable examples are inhalable medicament forms (including powder inhalers, nebulizers), nasal drops, solutions or sprays, tablets, films / wafers or capsules for lingual, sublingual or buccal administration, suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (e.g., patches), milch, pastes, foams, sprinkling powders, implants or stents.
[00218] The therapeutically effective compound of the invention should be present in the pharmaceutical preparations detailed above in a concentration of about 0.1 to 99.5%, preferably of about 0.5 to 95% by weight of the complete mixture.
[00219] The pharmaceutical preparations detailed above may, apart from the compound of the invention also contain other active pharmaceutical ingredients.
[00220] The therapeutically effective dose can be estimated first using various methods well known in the art. Initial doses used in animal studies may be based on effective concentrations established in cell culture assays. Dosage ranges appropriate for human subjects can be determined, for example, using data obtained from animal studies and cell culture assays. In certain embodiments, the compounds of the present invention can be prepared as an agent for oral administration. In the case of oral administration, the dosage of the compound of the invention is about 0.01 to 100 mg / kg (wherein the kg represents the body weight of the subject). In some embodiments, the dosage of the medicament is from about 0.01 to 20 mg / kg (wherein the kg represents the body weight of the subject), or optionally from about 0.01 to 10 mg / kg (wherein the kg represents the body weight of the subject), or optionally from about 0.01 to 5.0 mg / kg (wherein the kg represents the body weight of the subject). In certain embodiments, the compounds of the present invention are administered parenterally, with an effective dose of about 0.001 to 1 mg / kg, preferably about 0.01 to 0.5 mg / kg (wherein the kg represents the body weight of the subject).
[00221] The dosing regimen for medicament commonly used for oral administration is three times per week, twice per week, once per week, three times daily, twice daily, or once daily. In certain embodiments, the compound of the present invention is administered as an active ingredient in a total amount of about 0.001 to about 50, preferably 0.001 to 10 mg / kg body weight per 24 hours. In order to obtain the desired result, it is optionally possible to administer in multiple single dose forms. A single dose may preferably comprise a compound of the invention in an amount of about 0.001 to about 30, especially 0.001 to 3 mg / kg body weight.
[00222] An effective amount, or a therapeutically effective amount, or dose of the medicament (e.g., compound of the invention) refers to the amount of the medicament or compound which ameliorates the disease symptoms in subject or prolongs survival of the subject. Toxicity and therapeutic efficacy of such molecules can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., by determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio of toxic to the rapeutic effects is the therapeutic index, which can be expressed as the ratio LD<com:Sub>50< / com:Sub> / ED<com:Sub>50< / com:Sub>. Agents that exhibit high therapeutic indices are preferred.
[00223] The effective amount or therapeutically effective amount is the amount of the compound or pharmaceutical composition that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or ot...
Claims
1. A compound having Formula (IV) or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, an ester, or a pharmaceutically acceptable salt thereof, [Image disponible dans le document PDF, Image available in the PDF document] (IV), wherein each R 2 is independently H, D, F, Cl, Br, I, CN, NO 2 , amino, hydroxy, mercapto, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 1-6 alkylamino, hydroxy C 1-8 6 alkyl, cyano C 1 − 6 C_{1-6} alkyl, amino C 1 − 6 C_{1-6} alkyl, hydroxy C 1 − 6 C_{1-6} alkoxy, amino C 1 − 6 C_{1-6} alkoxy, acyl, sulfonyl or C 1 − 6 C_{1-6} alkoxy; each R 3 is independently oxo, H, D, F, Cl, Br, I, CN, NO 2 , mercapto, C 1-6 alkyl, C 2-6 alkenyl, C 2 − 6 C_{2-6} alkynyl, halo C 1 − 6 C_{1-6} alkyl, − ( C R 6 a R 6 b ) j − C 3 − 10 -(CR^{6a}R^{6b})_{j}-C_{3-10} cycloalkyl, − ( C R 6 a R 6 b ) i − C 2 − 10 -(CR^{6a}R^{6b})_{i}-C_{2-10} heterocyclyl, − ( C R 6 a R 6 b ) i − C 6 − 10 -(CR^{6a}R^{6b})_{i}-C_{6-10} aryl, − ( C R 6 a R 6 b ) i − C 1 − 9 -(CR^{6a}R^{6b})_{i}-C_{1-9} heteroaryl, − ( C R 6 a R 6 b ) i N R 5 a R 5 b -(CR^{6a}R^{6b})_{i}NR^{5a}R^{5b} , − - ( C R 6 a R 6 b ) i C ( = O ) ( C R 6 a R 6 b ) k N R 5 a R 5 b , − ( C R 6 a R 6 b ) i C ( = O ) ( C R 6 a R 6 b ) k O R 9 , − ( C R 6 a R 6 b ) i O R 9 , − ( C R 6 a R 6 b ) i O R 9 , − ( C R 6 a R 6 b ) i O R 9 , − ( C R 6 a R 6 b ) i O R 9 (CR^{6a}R^{6b})_{i}C(=O)(CR^{6a}R^{6b})_{k}NR^{5a}R^{5b}, -(CR^{6a}R^{6b})_{i}C(=O)(CR^{6a}R^{6b})_{k}OR^{9}, -(CR^{6a}R^{6b})_{i}OR^{9}, -(CR^{6a}R^{6b})_{i}OR^{9}, -(CR^{6a}R^{6b})_{i}OR^{9}, -(CR^{6a}R^{6b})_{i}OR^{9} ( C R 6 a R 6 b ) i S ( = O ) 2 ( C R 6 a R 6 b ) k O R 9 (CR^{6a}R^{6b})_iS(=O)_2(CR^{6a}R^{6b})_kOR^9 − ( C R 6 a R 6 b ) i S ( = O ) 2 ( C R 6 a R 6 b ) k N R 5 a R 5 b , -(CR^{6a}R^{6b})_iS(=O)_2(CR^{6a}R^{6b})_kNR^{5a}R^{5b}, - ( C R 6 a R 6 b ) i N ( R 5 ) ( C R 6 a R 6 b ) p C ( = O ) ( C R 6 a R 6 b ) k O R 9 (CR^{6a}R^{6b})_iN(R^5)(CR^{6a}R^{6b})_pC(=O)(CR^{6a}R^{6b})_kOR^9 , − ( C R 6 a R 6 b ) i N ( R 5 ) C ( = O ) ( C R 6 a R 6 b ) k N R 5 a R 5 b -(CR^{6a}R^{6b})_iN(R^5)C(=O)(CR^{6a}R^{6b})_kNR^{5a}R^{5b} , − ( C R 6 a R 6 b ) i N ( R 5 ) C ( = O ) R 8 -(CR^{6a}R^{6b})_iN(R^5)C(=O)R^8 , − ( C R 6 a R 6 b ) i N ( R 5 ) S ( = O ) 2 R 7 -(CR^{6a}R^{6b})_iN(R^5)S(=O)_2R^7 , − ( C R 6 a R 6 b ) i S ( = O ) 2 R 7 -(CR^{6a}R^{6b})_iS(=O)_2R^7 , ( C R 6 a R 6 b ) j O S ( = O ) 2 R 7 (CR^{6a}R^{6b})_{j}OS(=O)_{2}R^{7} , − ( C R 6 a R 6 b ) j O C ( = O ) ( C R 6 a R 6 b ) k O R 9 -(CR^{6a}R^{6b})_{j}OC(=O)(CR^{6a}R^{6b})_{k}OR^{9} , − ( C R 6 a R 6 b ) j O C ( = O ) R 8 -(CR^{6a}R^{6b})_{j}OC(=O)R^{8} or − ( C R 6 a R 6 b ) j O C ( = O ) R 8 -(CR^{6a}R^{6b})_{j}OC(=O)R^{8} ( C R 6 a R 6 b ) i C ( = O ) R 8 (CR^{6a}R^{6b})_iC(=O)R^8 ; each R 3 R^3 is unsubstituted or independently substituted with 1, 2, 3 or 4 R x R^x ; R 4 is D, F, Cl, Br, I, CN, NO 2 , mercapto, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo C 1-6 alkyl, − ( C R 6 c R 6 d ) g − C 3 − 6 -(CR^{6c}R^{6d})_g-C_{3-6} cycloalkyl, − ( C R 6 c R 6 d ) g − C 2 − 5 -(CR^{6c}R^{6d})_g-C_{2-5} heterocyclyl, − ( C R 6 c R 6 d ) g − C 6 − 10 -(CR^{6c}R^{6d})_g-C_{6-10} aryl, − ( C R 6 c R 6 d ) g − C 6 − 10 -(CR^{6c}R^{6d})_g-C_{6-10} ( C R 6 c R 6 d ) g − C 1 − 5 (CR^{6c}R^{6d})_g - C_{1-5} heteroaryl, − ( C R 6 c R 6 d ) g N R 5 c R 5 d -(CR^{6c}R^{6d})_g NR^{5c}R^{5d} , − ( C R 6 c R 6 d ) g C ( = O ) ( C R 6 c R 6 d ) h N R 5 c R 5 d -(CR^{6c}R^{6d})_g C(=O)(CR^{6c}R^{6d})_h NR^{5c}R^{5d} , − ( C R 6 c R 6 d ) g C ( = O ) ( C R 6 c R 6 d ) h N R 5 c R 5 d -(CR^{6c}R^{6d})_g C(=O)(CR^{6c}R^{6d})_h NR^{5c}R^{5d} , − ( C R 6 c R 6 d ) g C ( = O ) -(CR^{6c}R^{6d})_g C(=O) ( C R 6 c R 6 d ) g C ( = O ) ( C R 6 c R 6 d ) h O R 9 a , − ( C R 6 c R 6 d ) g O R 9 a , − ( C R 6 c R 6 d ) g S ( = O ) 2 ( C R 6 c R 6 d ) h O R 9 a , − ( C R 6 c R 6 d ) g S ( = O ) 2 ( C R 6 c R 6 d ) h O R 9 a , − ( C R 6 c R 6 d ) g S ( = O ) 2 ( C R 6 c R 6 d ) h O (CR^{6c}R^{6d})_gC(=O)(CR^{6c}R^{6d})_hOR^{9a}, -(CR^{6c}R^{6d})_gOR^{9a}, -(CR^{6c}R^{6d})_gS(=O)_2(CR^{6c}R^{6d})_hOR^{9a}, -(CR^{6c}R^{6d})_gS(=O)_2(CR^{6c}R^{6d})_hOR^{9a}, -(CR^{6c}R^{6d})_gS(=O)_2(CR^{6c}R^{6d})_hO <Formule mathématique disponible dans le document PDF, Math available in the PDF document>(CR^{6c}R^{6d})_gS(=O)_2(CR^{6c}R^{6d})_hNR^{5c}R^{5d}, -(CR^{6c}R^{6d})_gN(R^{5e})(CR^{6c}R^{6d})_iC(=O)(CR^{6c}R^{6d})_hOR^{9a}, -(CR^{6c}R^{6d})_gN(R^{5e})(CR^{6c}R^{6d})_iC(=O)(CR^{6c}R^{6d})_hOR^{9a}, -(CR^{6c}R^{6d [Image disponible dans le document PDF, Image available in the PDF document] is unsubstituted or substituted with 1, 2, 3 or 4 R y ; each R 5 and R 5e is independently H, D, C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, cyano C 1 − 6 C_{1-6} alkyl, halo C 1 − 6 C_{1-6} alkyl, C 1 − 6 C_{1-6} alkoxy- C 1 − 6 C_{1-6} -alkyl, C 3 − 6 C_{3-6} cycloalkyl, C 2 − 5 C_{2-5} heterocyclyl, C 6 − 1 C_{6-1} 10 aryl, C 1 − 5 C_{1-5} heteroaryl, C 3 − 6 C_{3-6} cycloalkyl- C 1 − 6 C_{1-6} -alkyl, C 2 − 5 C_{2-5} heterocyclyl- C 1 − 6 C_{1-6} -alkyl, C 6 − 10 C_{6-10} aryl- C 1 − 6 C_{1-6} - alkyl or C 1 − 5 C_{1-5} heteroaryl- C 1 − 6 C_{1-6} -alkyl; each R 5a , R 5b , R 5c and R 5d is independently H, D, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, cyano C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy-C 1-6 -alkyl, C 1 − 6 C_{1-6} alkoxycarbonyl, C 1 − 6 C_{1-6} alkylcarbonyl, C 1 − 6 C_{1-6} alkylaminocarbonyl, C 3 − 6 C_{3-6} cycloalkyl, C 2 − 5 C_{2-5} heterocyclyl, C 6-10 aryl, C 1-5 heteroaryl, C 3-6 cycloalkylcarbonyl, C 2-5 heterocyclylcarbonyl, C 6- 10 arylcarbonyl, C 1-5 heteroarylcarbonyl, C 3-6 cycloalkyl-C 1-6 -alkyl, C 2-5 heterocyclyl-C 1-6 - alkyl, C 6 − 10 C_{6-10} aryl- C 1 − 6 C_{1-6} -alkyl or C 1 − 5 C_{1-5} heteroaryl- C 1 − 6 C_{1-6} -alkyl; or, R 5 a R^{5a} and R 5 b R^{5b} , together with the N atom to which they are attached, form a 3- to 10-membered heterocyclic ring or 3- to 10- membered heteroaromatic ring; or, R 5c and R 5d , together with the N atom to which they are attached, form a 3- to 10-membered heterocyclic ring or 3- to 10-membered heteroaromatic ring; each R 6a , R 6b , R 6c and R 6d is independently H, D, F, Cl, Br, I, CN, amino, hydroxy, mercapto, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, cyano C 1-8 6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 alkylamino, acyl, sulfonyl, C 3-6 cycloalkyl, C 2-5 heterocyclyl, C 6-10 aryl or C 1-5 heteroaryl; each R 7 R^7 and R 7 a R^{7a} is independently H, D, amino, hydroxy, mercapto, C 1 − 6 C_{1-6} alkyl, C 2 − 6 C_{2-6} alkenyl, C 2-6 alkynyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 alkylamino, C 3-6 cycloalkyl, C 2- 5 heterocyclyl, C 6 − 10 C_{6-10} aryl or C 1 − 5 C_{1-5} heteroaryl; each R 8 and R 8a is independently H, D, amino, hydroxy, mercapto, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 alkylamino, C 3-6 cycloalkyl, C 2-1 5 heterocyclyl, C 6 − 10 C_{6-10} aryl or C 1 − 5 C_{1-5} heteroaryl; each R 9 and R 9a is independently H, D, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo C 1-6 alkyl, acyl, sulfonyl, C 3-6 cycloalkyl, C 2-5 heterocyclyl, C 6-10 aryl, C 1-5 heteroaryl, C 3-6 cycloalkyl-C 1-6 -alkyl, C 2-5 heterocyclyl-C 1-6 -alkyl, C 6-10 aryl-C 1-6 -alkyl or C 1-5 heteroaryl-C 1-6 alkyl; each R x is independently oxo, H, D, F, Cl, Br, I, CN, amino, hydroxy, mercapto, C 1-6 alkyl, C 2 − 6 C_{2-6} alkenyl, C 2 − 6 C_{2-6} alkynyl, hydroxy C 1 − 6 C_{1-6} alkyl, amino C 1 − 6 C_{1-6} alkyl, cyano C 1 − 6 C_{1-6} alkyl, halo C 1 − 6 C_{1-6} alkyl, C 1 − 6 C_{1-6} alkoxy, halo C 1 − 6 C_{1-6} alkoxy, C 1 − 6 C_{1-6} alkylamino, acyl, sulfonyl, C 1 − 6 C_{1-6} alkylcarbonyl, C 1 − 6 C_{1-6} alkylsulfonyl, C 1 − 6 C_{1-6} alkylcarbonylamino, C 1 − 6 C_{1-6} alkylsulfonylamino, C 1 − 6 C_{1-6} alkoxycarbonylamino, C 3 − 6 C_{3-6} cycloalkyl, C 2 − 5 C_{2-5} heterocyclyl, C 6 − 10 C_{6-10} aryl or C 1 − 5 C_{1-5} heteroaryl; each R y is independently oxo, H, D, F, Cl, Br, I, CN, amino, hydroxy, mercapto, C 1-6 alkyl, C 2 − 6 C_{2-6} alkenyl, C 2 − 6 C_{2-6} alkynyl, hydroxy C 1 − 6 C_{1-6} alkyl, amino C 1 − 6 C_{1-6} alkyl, cyano C 1 − 6 C_{1-6} alkyl, halo C 1 − 6 C_{1-6} alkyl, C 1 − 6 C_{1-6} alkoxy, halo C 1 − 6 C_{1-6} alkoxy, C 1 − 6 C_{1-6} alkylamino, acyl, sulfonyl, C 1 − 6 C_{1-6} alkylcarbonyl, C 1 − 6 C_{1-6} alkylsulfonyl, C 1 − 6 C_{1-6} alkylcarbonylamino, C 1 − 6 C_{1-6} alkylsulfonylamino, C 1 − 6 C_{1-6} alkoxycarbonylamino, C 3 − 6 C_{3-6} cycloalkyl, C 2 − 5 C_{2-5} heterocyclyl, C 6 − 10 C_{6-10} aryl or C 1 − 5 C_{1-5} heteroaryl; each j, g, h, i, k and p is independently 0, 1, 2, 3 or 4; m is 0, 1, 2 or 3; r is 0, 1 or 2.
2. The compound according to claim 1 having Formula (IVa), Formula (IVb) or Formula (IVc), or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, an ester, or a pharmaceutically acceptable salt thereof, [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (IVa), (IVb) or [Image disponible dans le document PDF, Image available in the PDF document] (IVc).
3. The compound according to any one of claims 1 to 2, wherein R 4 is D, F, Cl, Br, I, CN, NO 2 , mercapto, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo C 1-4 alkyl, C 3-6 cycloalkyl, C 2-5 heterocyclyl, C 6 − 10 C_{6-10} aryl, C 1 − 5 C_{1-5} heteroaryl, − N R 5 c R 5 d -NR^{5c}R^{5d} , − C ( = O ) N R 5 c R 5 d -C(=O)NR^{5c}R^{5d} , − O R 9 a -OR^{9a} , − S ( = O ) 2 O R 9 a -S(=O)_2OR^{9a} , − S ( = O ) 2 O R 9 a -S(=O)_2OR^{9a} , − S ( = O ) 2 O R 9 a -S(=O)_2OR^{9a} , − S ( = O ) 2 O R 9 a -S(=O)_2OR^{9a} , − S ( = O ) 2 O R 9 a -S(=O)_2OR^{9a} , − S ( = O ) 2 O R 9 a -S(=O)_2OR^{9a} , S ( = O ) 2 N R 5 c R 5 d S(=O)_2NR^{5c}R^{5d} , − N ( R 5 e ) C ( = O ) ( C R 6 c R 6 d ) h O R 9 a -N(R^{5e})C(=O)(CR^{6c}R^{6d})_hOR^{9a} , − N ( R 5 e ) C ( = O ) R 8 a -N(R^{5e})C(=O)R^{8a} , − N ( R 5 e ) C ( = O ) N R 5 c R 5 d -N(R^{5e})C(=O)NR^{5c}R^{5d} , − N ( R 5 e ) C ( = O ) N R 5 c R 5 d -N(R^{5e})C(=O)NR^{5c}R^{5d} N ( R 5 e ) S ( = O ) 2 R 7 a N(R^{5e})S(=O)_2R^{7a} , − S ( = O ) 2 R 7 a -S(=O)_2R^{7a} , − O S ( = O ) 2 R 7 a -OS(=O)_2R^{7a} , − O C ( = O ) O R 9 a -OC(=O)OR^{9a} , − O C ( = O ) R 8 a -OC(=O)R^{8a} or − C ( = O ) R 8 a -C(=O)R^{8a} ; R 4 R^4 is unsubstituted or substituted with 1, 2, 3 or 4 R y .
4. The compound according to any one of claims 1 to 3, wherein R 4 is D, F, Cl, Br, I, CN, NO 2 , mercapto, methyl, ethyl, propyl, butyl, vinyl, propenyl, allyl, ethynyl, propynyl, trifluoromethyl, difluoromethyl, 2,2-difluoroethyl, chloroethyl, 2,2,2-trifluoroethyl, 2-chloro- 1-methylethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, pyrazolidinyl, oxomorpholinyl, thiomorpholinyl, 4,4-dioxothiomorpholinyl, oxazolidinyl, thiazolidinyl, 1,1- dioxoisothiazolidinyl, oxo-1,3-oxazinylalkyl, phenyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, pyrrolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, thienyl, furyl, -NR 5c R 5d , - C ( = O ) N R 5 c R 5 d C(=O)NR^{5c}R^{5d} , − O R 9 a -OR^{9a} , − S ( = O ) 2 O R 9 a -S(=O)_2OR^{9a} , − S ( = O ) 2 N R 5 c R 5 d -S(=O)_2NR^{5c}R^{5d} , − N ( R 5 e ) C ( = O ) ( C R 6 c R 6 d ) h O R 9 a -N(R^{5e})C(=O)(CR^{6c}R^{6d})_hOR^{9a} , − S ( = O ) 2 N R 5 c R 5 d -S(=O)_2NR^{5c}R^{5d} , − N ( R 5 e ) C ( = O ) ( C R 6 c R 6 d ) h O R 9 a -N(R^{5e})C(=O)(CR^{6c}R^{6d})_hOR^{9a} , − S ( = O ) 2 N R 5 c R 5 d -S(=O)_2NR^{5c}R^{5d} , − S ( = O ) -S(=O) N ( R 5 e ) C ( = O ) R 8 a N(R^{5e})C(=O)R^{8a} , − N ( R 5 e ) C ( = O ) N R 5 c R 5 d -N(R^{5e})C(=O)NR^{5c}R^{5d} , − N ( R 5 e ) S ( = O ) 2 R 7 a -N(R^{5e})S(=O)_2R^{7a} , − S ( = O ) 2 R 7 a -S(=O)_2R^{7a} , − O S ( = O ) 2 R 7 a -OS(=O)_2R^{7a} , − O S ( = O ) 2 R 7 a -OS(=O)_2R^{7a} , − O S ( = O ) 2 R 7 a -OS(=O)_2R^{7a} , − O S ( = O ) 2 R 7 a -OS(=O)_2R^{7a} , − O S ( = O ) 2 R 7 a -OS(=O)_2R^{7a} , − O S ( = O ) 2 R 7 a -OS(=O)_2R^{7a} , − O S ( = -OS(= O C ( = O ) O R 9 a OC(=O)OR^{9a} , − O C ( = O ) R 8 a -OC(=O)R^{8a} or − C ( = O ) R 8 a -C(=O)R^{8a} ; R 4 R^4 is unsubstituted or substituted with 1, 2, 3 or 4 R y R^y .
5. The compound according to any one of claims 1 to 4, wherein each R 2 R^2 is independently H, D, F, Cl, Br, I, CN, NO 2 , amino, hydroxy, mercapto, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo C 1-4 alkyl, halo C 1-4 alkoxy, C 1-4 alkylamino, hydroxy C 1-4 alkyl, cyano C 1-4 alkyl, amino C 1 − 4 C_{1-4} alkyl, hydroxy C 1 − 4 C_{1-4} alkoxy, amino C 1 − 4 C_{1-4} alkoxy or C 1 − 4 C_{1-4} alkoxy; each R 3 is independently oxo, H, D, F, Cl, Br, I, CN, NO 2 , mercapto, C 1-4 alkyl, C 2-4 189 CPST Doc: 1395-4936-2966.1 alkenyl, C 2-4 alkynyl, halo C 1-4 alkyl, C 3-6 cycloalkyl, C 2-5 heterocyclyl, C 6-10 aryl, C 1-5 heteroaryl, − N R 5 a R 5 b -NR^{5a}R^{5b} , − C ( = O ) N R 5 a R 5 b -C(=O)NR^{5a}R^{5b} , − C ( = O ) O R 9 -C(=O)OR^{9} , − O R 9 -OR^{9} , − S ( = O ) 2 O R 9 -S(=O)_{2}OR^{9} , − S ( = O ) 2 N R 5 a R 5 b -S(=O)_{2}NR^{5a}R^{5b} , − C ( = O ) 2 N R 5 a R 5 b -C(=O)_{2}NR^{5a}R^{5b} , − C ( = O ) 2 N R 5 a R 5 b -C(=O)_{2}NR^{5a}R^{5b} , − C ( = O ) 2 N R 5 a R 5 b -C(=O)_{2}NR^{5a}R^{5b} , − C ( = O ) 2 N R -C(=O)_{2}NR N ( R 5 ) C ( = O ) ( C R 6 a R 6 b ) k O R 9 N(R^5)C(=O)(CR^{6a}R^{6b})_kOR^9 , − N ( R 5 ) C ( = O ) N R 5 a R 5 b -N(R^5)C(=O)NR^{5a}R^{5b} , − N ( R 5 ) C ( = O ) R 8 -N(R^5)C(=O)R^8 , − N ( R 5 ) S ( = O ) 2 R 7 -N(R^5)S(=O)_2R^7 , − N ( R 5 ) C ( = O ) R 8 -N(R^5)C(=O)R^8 S ( = O ) 2 R 7 S(=O)_2R^7 , − O S ( = O ) 2 R 7 -OS(=O)_2R^7 , − O C ( = O ) O R 9 -OC(=O)OR^9 , − O C ( = O ) R 8 -OC(=O)R^8 or − C ( = O ) R 8 -C(=O)R^8 ; each R 3 R^3 is unsubstituted or substituted with 1, 2, 3 or 4 R x 4 R^x .
6. The compound of any one of claims 1 to 5, wherein each R 2 is independently H, D, F, Cl, Br, I, CN, NO 2 , amino, hydroxy, mercapto, methyl, ethyl, propyl, butyl, trifluoromethyl, trifluoromethoxy, methylamino, dimethylamino, hydroxymethyl, hydroxyethyl, cyanomethyl, cyanoethyl, aminomethyl, aminoethyl, hydroxymethoxy, hydroxyethoxy, amino C 1-3 alkoxy, methoxy, ethoxy, propoxy or butoxy; each R 3 is independently oxo, H, D, F, Cl, Br, I, CN, NO 2 , mercapto, methyl, ethyl, propyl, butyl, trifluoromethyl, 2,2-difluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, oxomorpholinyl, thiomorpholinyl, 4,4-dioxothiomorpholinyl, tetrahydrofuranyl, oxazolidinyl, thiazolidinyl, 1,1-dioxoisothiazolidinyl, oxo-1,3-oxazinyl, phenyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, pyrrolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, thienyl, furyl, -NR 5a R 5b , - C ( = O ) N R 5 a R 5 b C(=O)NR^{5a}R^{5b} , − C ( = O ) O R 9 -C(=O)OR^{9} , − O R 9 -OR^{9} , − S ( = O ) 2 O R 9 -S(=O)_{2}OR^{9} , − S ( = O ) 2 N R 5 a R 5 b -S(=O)_{2}NR^{5a}R^{5b} , − N ( R 5 ) C ( = O ) O R 9 -N(R^{5})C(=O)OR^{9} , − S ( = O ) 2 N R 5 a R 5 b -S(=O)_{2}NR^{5a}R^{5b} N ( R 5 ) C ( = O ) N R 5 a R 5 b N(R^5)C(=O)NR^{5a}R^{5b} , − N ( R 5 ) C ( = O ) R 8 -N(R^5)C(=O)R^8 , − N ( R 5 ) S ( = O ) 2 R 7 -N(R^5)S(=O)_2R^7 , − S ( = O ) 2 R 7 -S(=O)_2R^7 , − O S ( = O ) 2 R 7 -OS(=O)_2R^7 , − O S ( = O ) 2 R 7 -OS(=O)_2R^7 , − O S ( = O ) 2 R 7 -OS(=O)_2R^7 , − O S ( = O ) 2 R 7 -OS(=O)_2R^7 , − O S ( = O ) 2 R 7 -OS(=O)_2R^7 , − O S ( = O ) 2 R 7 -OS(=O)_2R^7 , − O S ( = O ) 2 R 7 -OS(=O)_2R^7 , − O S ( = O ) 2 R 7 -OS(=O)_2R^7 , − O S ( = O ) 2 -OS(=O)_2 O C ( = O ) O R 9 OC(=O)OR^9 , − O C ( = O ) R 8 -OC(=O)R^8 or − C ( = O ) R 8 -C(=O)R^8 ; each R 3 R^3 is unsubstituted or independently substituted with 1, 2, 3 or 4 R x 4 R^{x} .
7. The compound according to any one of claims 1 to 6, wherein each R 5a , R 5b , R 5c and R 5d is independently H, D, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, hydroxy C 1-4 alkyl, amino C 1- 4 alkyl, cyano C 1-4 alkyl, halo C 1-4 alkyl, C 1-4 alkoxy-C 1-4 -alkyl, C 1-4 alkoxycarbonyl, C 1-4 alkylcarbonyl, C 1-4 alkylaminocarbonyl, C 3-6 cycloalkyl, C 2-5 heterocyclyl, C 6-10 aryl, C 1-5 heteroaryl, C 3 − 6 C_{3-6} cycloalkylcarbonyl, C 2 − 5 C_{2-5} heterocyclylcarbonyl, C 6 − 10 C_{6-10} arylcarbonyl, C 1 − 5 C_{1-5} heteroarylcarbonyl, C 3-6 cycloalkyl-C 1-3 -alkyl, C 2-5 heterocyclyl-C 1-3 -alkyl, C 6-10 aryl-C 1-3 - alkyl or C 1 − 5 C_{1-5} heteroaryl- C 1 − 3 C_{1-3} -alkyl; or, R 5 a R^{5a} and R 5 b R^{5b} , together with the N atom to which they are attached, form a 3- to 6-membered heterocyclic ring or 3- to 6-membered heteroaromatic ring; 190 CPST Doc: 1395-4936-2966.1 or, R 5c and R 5d , together with the N atom to which they are attached, form a 3- to 6-membered heterocyclic ring or 3- to 6-membered heteroaromatic ring.
8. The compound according to any one of claims 1 to 7, wherein each R 5a , R 5b , R 5c and R 5d is independently H, D, methyl, ethyl, propyl, butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, amino C 1 − 4 C_{1-4} alkyl, cyano C 1 − 4 C_{1-4} alkyl, trifluoromethoxy, chloroethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 2-chloro-1-methylethyl, methoxymethyl, methoxyethyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, methylcarbonyl, ethylcarbonyl, methylaminocarbonyl, ethylaminocarbonyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperidinyl, piperazinyl, phenyl, pyridinyl, pyrimidinyl, cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cyclopropyloxycarbonyl, tetrahydrofurylcarbonyl, tetrahydropyranylcarbonyl, piperidylcarbonyl, piperazinylcarbonyl, morpholinylcarbonyl, tetrahydrothiophenylcarbonyl, pyrrolidinylcarbonyl, phenylcarbonyl, pyridylcarbonyl, pyrimidinylcarbonyl, pyrrolylcarbonyl, imidazolylcarbonyl, pyrazolylcarbonyl, thienylcarbonyl, furylcarbonyl, cyclopropylmethyl, cyclobutylmethyl, tetrahydropyranylmethyl, tetrapyranylethyl, tetrahydrofuranylmethyl, tetrahydrofuranylethyl, phenylmethyl, phenylethyl, pyridylmethyl, pyrazolylmethyl, pyrazolylethyl, pyridylethyl or C 2-5 heterocyclyl-C 1-3 -alkyl; or, R 5a and R 5b , together with the N atom to which they are attached, form an azetidine, pyrrolidine, oxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, piperazine, thiomorpholine, 1,3-oxazinane, pyrrole, pyrazole, imidazole or triazolyl; or, R 5c and R 5d , together with the N atom to which they are attached, form an azetidine, pyrrolidine, oxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, piperazine, thiomorpholine, 1,3-oxazinane, pyrrole, pyrazole, imidazole or triazolyl.
9. The compound according to any one of claims 1 to 8, wherein each R 9 R^9 and R 9 a R^{9a} is independently H, D, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo C 1-4 alkyl, acyl, sulfonyl, C 3-6 cycloalkyl, C 2 − 5 C_{2-5} heterocyclyl, C 6 − 10 C_{6-10} aryl, C 1 − 5 C_{1-5} heteroaryl, C 3 − 6 C_{3-6} cycloalkyl- C 1 − 3 C_{1-3} -alkyl, C 2 − 5 C_{2-5} heterocyclyl- C 1 − 3 C_{1-3} -alkyl, C 6 − 10 C_{6-10} aryl- C 1 − 3 C_{1-3} -alkyl or C 1 − 5 C_{1-5} heteroaryl- C 1 − 3 C_{1-3} -alkyl.
10. The compound according to any one of claims 1 to 9, wherein each R 9 and R 9a is 191 CPST Doc: 1395-4936-2966.1 independently H, D, methyl, ethyl, propyl, butyl, C 2 − 4 C_{2-4} alkenyl, C 2 − 4 C_{2-4} alkynyl, trifluoromethyl, chloroethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 2-chloro-1-methylethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, tetrahydrofuranyl, morpholinyl, piperidinyl, piperazinyl, phenyl, pyridyl, pyrimidinyl, cyclopropylmethyl, cyclobutylmethyl, phenylmethyl, phenylethyl, pyridylmethyl, pyridylethyl or C 2-5 heterocyclyl-C 1-3 -alkyl.
11. The compound according to any one of claims 1 to 10, wherein each R 8 and R 8a is independently H, D, amino, hydroxy, mercapto, methyl, ethyl, propyl, butyl, trifluoromethyl, chloroethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 2-chloro-1-methylethyl, methoxy, ethoxy, propoxy, trifluoromethoxy, methylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, morpholinyl, piperazinyl, piperazinyl, thiomorpholinyl, 1,1- dioxothiomorpholinyl, phenyl, pyrrolyl, thienyl, furyl, pyridyl or pyrimidinyl; each R 5 and R 5e is independently H, D, methyl, ethyl, propyl, butyl, hydroxy C 1-4 alkyl, amino C 1-4 alkyl, cyano C 1-4 alkyl, halo C 1-4 alkyl or C 1-4 alkoxy-C 1-4 alkyl; each R 6a , R 6b , R 6c and R 6d is independently H, D, F, Cl, Br, I, CN, amino, hydroxy, mercapto, methyl, ethyl, propyl, butyl, hydroxy C 1 − 4 C_{1-4} alkyl, amino C 1 − 4 C_{1-4} alkyl, cyano C 1 − 4 C_{1-4} alkyl, halo C 1 − 4 C_{1-4} alkyl.
12. The compound according to any one of claims 1 to 11, wherein each R x is independently oxo, H, D, F, Cl, Br, I, CN, amino, hydroxy, mercapto, methyl, ethyl, propyl, butyl, C 2-4 alkenyl, C 2-4 alkynyl, hydroxymethyl, hydroxyethyl, amino C 1-4 alkyl, cyano C 1-4 alkyl, trifluoromethyl, chloroethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 2-chloro-1- methylethyl, methoxy, ethoxy, propoxy, trifluoromethoxy, methylamino, dimethylamino, C 1-3 alkylcarbonyl, C 1 − 3 C_{1-3} alkylsulfonyl, C 1 − 3 C_{1-3} alkylcarbonylamino, C 1 − 3 C_{1-3} alkylsulfonamino, methoxyformylamino, C 2-3 alkoxycarbonylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 2-5 heterocyclyl, phenyl or C 1-5 heteroaryl; each R y is independently oxo, H, D, F, Cl, Br, I, CN, amino, hydroxy, mercapto, methyl, ethyl, propyl, butyl, C 2-4 alkenyl, C 2-4 alkynyl, hydroxymethyl, hydroxyethyl, amino C 1-4 alkyl, cyano C 1-4 alkyl, trifluoromethyl, chloroethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 2-chloro- 1-methylethyl, methoxy, ethoxy, propoxy, trifluoromethoxy, methylamino, dimethylamino, C 1- 3 alkylcarbonyl, C 1 − 3 C_{1-3} alkylsulfonyl, C 1 − 3 C_{1-3} alkylcarbonylamino, C 1 − 3 C_{1-3} alkylsulfonamino, methoxyformylamino, C 2-3 alkoxycarbonylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 2-5 heterocyclyl, phenyl or C 1-5 heteroaryl.
13. The compound according to any one of claims 1 to 12 having one of the following structures or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, an ester, or a pharmaceutically acceptable salt thereof, [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (1), (2), (3), [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (4), (5), (6), [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (7), (8), (9), 193 [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (10), (11), (12), (13), (14), (15), (16), (17), (18), [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (19), (20), (21), (22), (23), (24), (25), (26), (27), [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (28), (29), (30), (31), (32), (33), (34), (35), (36), [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] F, F [Image disponible dans le document PDF, Image available in the PDF document] N Ν N NH 2 H 2 N ′ H_2N' HÙ~ O (45), (46), ÒН (47), (48), [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (49), (50), (51), [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (52), (53), (54), [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] 56 9) (6 1 • [Image disponible dans le document PDF, Image available in the PDF document] (67).
14. A pharmaceutical composition comprising the compound of any one of claims 1 to 13; and further comprising at least one of pharmaceutically acceptable carrier, excipient, diluent, adjuvant and vehicle.
15. Use of the compound according to any one of claims 1 to 13 or the pharmaceutical composition according to claim 14 in the manufacture of a medicament for treating and / or preventing diseases, wherein the diseases are heart failure, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorder, nephropathy, thromboembolic disorder, male sexual dysfunction, systemic sclerosis, sickle cell anemia, achalasia of the cardia, fibrotic disorders and / or arteriosclerosis.
16. Use of the compound according to any one of claims 1 to 13 or the pharmaceutical composition according to claim 14 in the manufacture a medicament as a soluble guanylate cyclase stimulator.
17. The compound according to any one of claims 1 to 13 or the pharmaceutical composition according to claim 14 for use in treating and / or preventing diseases in a patient, wherein the diseases are heart failure, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorder, nephropathy, thromboembolic disorder, male sexual dysfunction, systemic sclerosis, sickle cell anemia, achalasia of the cardia, fibrotic disorder and / or arteriosclerosis.
18. A use of the compound according to any one of claims 1 to 13 or the pharmaceutical composition according to claim 14, for treating and / or preventing diseases in a patient wherein the diseases are heart failure, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorder, nephropathy, thromboembolic disorder, male sexual dysfunction, systemic sclerosis, sickle cell anemia, achalasia of the cardia, fibrotic disorders and / or arteriosclerosis.