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Selective inhibitors of protein arginine methyltransferase 5(PRMT5)

文档序号：1366879 发布日期：2020-08-11 浏览：30次 中文

阅读说明：本技术 蛋白质精氨酸甲基转移酶5(prmt5)的选择性抑制剂 (Selective inhibitors of protein arginine methyltransferase 5(PRMT5) ) 是由 胡安·卢恩戈 林虹 鲁帕·谢蒂 迈克尔·霍金斯 于 2018-08-09 设计创作，主要内容包括：本公开涉及式(I)化合物。还描述了包含式(I)化合物的药物组合物,以及它们的使用和制备方法。<Image he="474" wi="700" file="DDA0002444314900000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The present disclosure relates to compounds of formula (I). Also described arePharmaceutical compositions comprising compounds of formula (I), and methods for their use and preparation are described.)

1. A compound of formula I or a pharmaceutically acceptable salt or solvate thereof:

wherein

R1is-C0-C6alkyl-C1-C6Alkyl, -C0-C6alkyl-C1-C6Haloalkyl, -C1-C6alkyl-O-C1-C6Alkyl, -C1-C6alkane-S-C1-C6Alkyl, -C1-C6alkane-S-C1-C6alkane-CO2H、-C1-C6Alkyl-aryl, -C1-C6alkyl-O-aryl, -C1-C6alkyl-NH-aryl, -C1-C6alkyl-S-aryl, -C0-C6Alkyl-heteroaryl, -C1-C6alkyl-O-heteroaryl, -C1-C6alkyl-S-heteroaryl, -C1-C6alkyl-NH-heteroaryl or-C (O) NH-aryl;

R2is-C1-C6Alkyl, -C1-C6Haloalkyl, -C2-C6Alkenyl or-C2-C6An alkynyl group;

R3is H, halogen, NH2or-C1-C6An alkyl group;

R4is H, halogen, -C1-C6Alkyl, -C1-C6alkyl-O-C1-C6Alkyl, -NR6R6'、-NHCONR6R6'、-NHC(S)NR6R6'、-NH-O-R6or-NH-NR6R6'；

R5Is H, halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -C2-C6Alkenyl, -C2-C6Alkynyl or-C1-C6alkyl-OH; and is

R6And R6'Each independently is H, C1-C6Alkyl or-C1-C6alkane-OC1-C6An alkyl group;

or R6And R6' together with the atom to which it is attached form C3-C6A heterocycloalkyl ring.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1is-C1-C6alkyl-O-heteroaryl.

3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein said-C1-C6The alkyl-O-heteroaryl group is ((2-amino-3-bromoquinolin-7-yl) oxy) methyl, ((2-amino-3-chloroquinolin-7-yl) oxy) methyl, ((2-amino-3-fluoroquinolin-7-yl) oxy) methyl, ((2- ((cyclopropylmethyl) amino) quinolin-7-yl) oxy) methyl, ((2- (methylamino) quinolin-7-yl) oxy) methyl, ((2-aminoquinolin-7-yl) oxy) methyl, ((indol-6-yl) oxy) methyl, (2- (methoxyamino) quinolin-7-yl) oxy) methyl, ((quinolin-7-yl) oxy) methyl, ((3-methylimidazo [1, 2-a))]Pyridin-7-yl) oxy) methyl or ((indazol-6-yl) oxy) methyl.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1is-C1-C6alkyl-S-heteroaryl.

5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein said-C1-C6The alk-S-heteroaryl group is ((2-amino-3-bromoquinolin-7-yl) thio) methyl, ((2-amino-3-chloroquinolin-7-yl) thio) methyl, ((2-amino-3-fluoroquinolin-7-yl) thio) methyl, ((2- ((cyclopropylmethyl) amino) quinolin-7-yl) thio) methyl, ((2- (methylamino) quinolin-7-yl) thio) methyl, ((2-aminoquinolin-7-yl) thio) methyl, ((indol-6-yl) thio) methyl, or ((indazol-6-yl) thio) methyl.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1is-C1-C6alkyl-NH-heteroaryl.

7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein said-C1-C6An alk-NH-heteroaryl group is ((2-amino-3-bromoquinolin-7-yl) amino) methyl, ((2-amino-3-chloroquinolin-7-yl) amino) methyl, ((2-amino-3-fluoroquinolin-7-yl) amino) methyl, ((2- ((cyclopropylmethyl) amino) quinolin-7-yl) amino) methyl, ((2- (methylamino) quinolin-7-yl) amino) methyl, ((2-aminoquinolin-7-yl) amino) methyl, ((indol-6-yl) amino) methyl, or ((indazol-6-yl) amino) methyl.

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1is-C0-C6An alkyl-heteroaryl group.

9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein said-C0-C6The alk-heteroaryl group is 2- (2-amino-3-bromoquinolin-7-yl) ethyl, 2- (2-amino-3-chloroquinolin-7-yl) ethyl, 2- (2-amino-3-fluoroquinolin-7-yl) ethyl, 2- (2- ((cyclopropylmethyl) amino) quinolin-7-yl) ethyl, 2- (2- (methylamino) quinolin-7-yl) ethyl, 2- (2-aminoquinolin-7-yl) ethyl, (indol-6-yl) ethyl or (indazol-6-yl) ethyl.

10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1is-C1-C6alkane-S-C1-C6An alkyl group.

11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein said-C1-C6alkane-S-C1-C6Alkyl is-CH2-S-CH3。

12. The method of1 or a pharmaceutically acceptable salt thereof, wherein R1is-C1-C6alkane-S-C1-C6alkane-CO2H。

13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein said-C1-C6alkane-S-C1-C6alkane-CO2H is-CH2-S-CH2CH2CH(NH2)-CO2H。

14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1is-C1-C6alkyl-O-C1-C6An alkyl group.

15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein said-C1-C6alkyl-O-C1-C6Alkyl is-CH2-O-CH3。

16. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1is-C1-C6alkyl-O-aryl.

17. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein said-C1-C6The alkyl-O-aryl group being-CH2-O-phenyl, -CH2-O-difluorophenyl, -CH2-O-3, 4-difluorophenyl, -CH2-O-4-chlorophenyl, -CH2-O-3-chloro-4-fluorophenyl, -CH2-O-4-chloro-3-fluorophenyl, -CH2-O-dichlorophenyl, -CH2-O-3, 4-dichlorophenyl, -CH2-O-3-methyl-4-chlorophenyl, -CH2-O-3-fluoro-4-trifluoromethylphenyl, -CH2-O-3- (aminomethyl) phenyl or-CH2-O-3- (urea) phenyl.

18. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1is-C0-C6alkyl-C1-C6A haloalkyl group.

19. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein said-C0-C6alkyl-C1-C6Haloalkyl is-CH2-Cl。

20. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1is-C1-C6An alkyl-aryl group.

21. The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein said-C1-C6The alkyl-aryl radical being-CH2-difluorophenyl, -CH2-3, 4-difluorophenyl, -CH2-4-chlorophenyl, -CH2-3-chloro-4-fluorophenyl, -CH2-4-chloro-3-fluorophenyl, -CH2-dichlorophenyl, -CH2-3, 4-dichlorophenyl, -CH2-3-methyl-4-chlorophenyl, -CH2-3-fluoro-4-trifluoromethylphenyl, benzo [ d][1,3]IIOxazol-5-ylmethyl, -CH2- (4-chloro-2- (hydroxymethyl) phenyl), -CH2- (4-chloro-2- (aminomethyl) phenyl), -CH2- (4-chloro-2- ((methylamino) methyl) phenyl), -CH2-4-trifluoromethylphenyl, -CH2-4- (trifluoromethoxy) phenyl, -CH2-4-fluoro-3-trifluoromethylphenyl, -CH2-4-isopropylphenyl, -CH (OH) -4-chlorophenyl, -CH (OH) -3, 4-dichlorophenyl, -CH (OH) -3, 4-difluorophenyl, -CH (OH) -3-fluoro-4-chlorophenyl, -CH (OH) -3-chloro-4-fluorophenyl, -CH (OH) -3-methyl-4-chlorophenyl, -CH (OH) -3-fluoro-4-trifluoromethylphenyl, -CH (OH) -benzo [ d ], (OH)][1,3]IIOxazol-5-yl, -CH (OH) - (4-chloro-2- (hydroxymethyl) phenyl), -CH (OH) - (4-chloro-2- (aminomethyl) phenyl), -CH (OH) - (4-chloro-2- ((methylamino) methyl) phenyl), -CH (OH) -4-trifluoromethylbenzeneA radical, -CH (OH) -4- (trifluoromethoxy) phenyl, -CH (OH) -4-fluoro-3-trifluoromethylphenyl, -CH (OH) -4-isopropylphenyl, -CH (F) -4-chlorophenyl, -CH (F) -3, 4-dichlorophenyl, -ch (f) -3, 4-difluorophenyl, -ch (f) -3-fluoro-4-chlorophenyl, -ch (f) -3-chloro-4-fluorophenyl, -ch (f) -3-methyl-4-chlorophenyl, -ch (f) -3-fluoro-4-trifluoromethylphenyl, -ch (f) -benzo [ d.][1,3]IIOxazol-5-yl, -CH (F) - (4-chloro-2- (hydroxymethyl) phenyl), -CH (F) - (4-chloro-2- (aminomethyl) phenyl), -CH (F) - (4-chloro-2- ((methylamino) methyl) phenyl), -CH (F) -4-trifluoromethylphenyl, -CH (F) -4- (trifluoromethoxy) phenyl, -CH (F) -4-fluoro-3-trifluoromethylphenyl, -CH (F) -4-isopropylphenyl, -CH (NH)2) -4-chlorophenyl, -CH (NH)2) -3, 4-dichlorophenyl, -CH (NH)2) -3, 4-difluorophenyl, -CH (NH)2) -3-fluoro-4-chlorophenyl, -CH (NH)2) -3-chloro-4-fluorophenyl, -CH (NH)2) -3-methyl-4-chlorophenyl, -CH (NH)2) -3-fluoro-4-trifluoromethylphenyl, -CH (NH)2) -benzo [ d ]][1,3]IIOxazol-5-yl, -CH (NH)2) - (4-chloro-2- (hydroxymethyl) phenyl), -CH (NH)2) - (4-chloro-2- (aminomethyl) phenyl), -CH (NH)2) - (4-chloro-2- ((methylamino) methyl) phenyl), -CH (NH)2) -4-trifluoromethylphenyl, -CH (NH)2) -4- (trifluoromethoxy) phenyl, -CH (NH)2) -4-fluoro-3-trifluoromethylphenyl, -CH (NH)2) -4-isopropylphenyl, -CH (Me) -4-chlorophenyl, -CH (Me) -3, 4-dichlorophenyl, -CH (Me) -3, 4-difluorophenyl, -CH (Me) -3-fluoro-4-chlorophenyl, -CH (Me) -3-chloro-4-fluorophenyl, -CH (Me) -3-methyl-4-chlorophenyl, -CH (Me) -3-fluoro-4-trifluoromethylphenyl, -CH (Me) -benzo [ d ]][1,3]IIOxazol-5-yl, -CH (Me) - (4-chloro-2- (hydroxymethyl) phenyl), -CH (Me) - (4-chloro-2- (aminomethyl) phenyl), -CH (Me) - (4-chloro-2- ((methylaminoamino)Phenyl), -CH (Me) -4-trifluoromethylphenyl, -CH (Me) -4- (trifluoromethoxy) phenyl, -CH (Me) -4-fluoro-3-trifluoromethylphenyl, -CH (Me) -4-isopropylphenyl, -C (Me) (OH) -4-chlorophenyl, -C (Me) (OH) -3, 4-dichlorophenyl, -C (Me) (OH) -3, 4-difluorophenyl, -C (Me) (OH) -3, 4-chlorophenyl, -C (Me) (OH) -3-fluoro-4-chlorophenyl, -C (Me) (OH) -3-chloro-4-fluorophenyl, -C (Me) (OH) -3-methyl-4-chlorophenyl, C (Me) (OH) -4-chlorophenyl, -C (Me) (OH) -benzo [ d ]][1,3]IIOxazol-5-yl, -C (Me) (OH) -3-fluoro-4-trifluoromethylphenyl, -C (Me) (OH) - (4-chloro-2- (hydroxymethyl) phenyl), -C (Me) (OH) - (4-chloro-2- (aminomethyl) phenyl), -C (Me) (OH) - (4-chloro-2- ((methylamino) methyl) phenyl), -C (Me) (OH) - (4-trifluoromethylphenyl), -C (Me) (OH) - (4-trifluoromethoxy) phenyl, -C (Me) (OH) - (4-fluoro-3-trifluoromethylphenyl), or-C (Me) (OH) - (4-isopropylphenyl).

22. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein said-C1-C6The alk-aryl group is-ch (oh) -3, 4-dichlorophenyl.

23. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1is-C (O) NH-aryl.

24. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein said-c (o) NH-aryl is 3- (aminomethyl) phenyl-NH-c (o) -.

25. The compound of any one of claims 1 to 24, wherein R2is-C1-C6Alkyl, preferably methyl.

26. The compound of any one of claims 1 to 24, wherein R2is-C1-C6Haloalkyl, preferably-CF3。

27. The compound of any one of claims 1 to 24, wherein R2is-C2-C6Alkenyl, preferably vinyl.

28. The compound of any one of claims 1 to 24, wherein R2is-C2-C6Alkynyl is preferably ethynyl.

29. The compound of any one of claims 1 to 28, wherein R3Is H.

30. The compound of any one of claims 1 to 29, wherein R4Is H.

31. The compound of any one of claims 1 to 29, wherein R4is-C1-C6Alkyl, preferably methyl.

32. The compound of any one of claims 1 to 29, wherein R4is-C1-C6alkyl-O-C1-C6An alkyl group.

33. The compound of any one of claims 1 to 29, wherein R4Is chlorine, fluorine, bromine or iodine.

34. The compound of any one of claims 1 to 29, wherein R4is-NR6R6'Wherein R is6And R6'Preferably both are H.

35. The compound of any one of claims 1 to 29, wherein R4is-NHCONR6R6'Wherein R is6And R6'Preferably both are-C1-C6An alkyl group.

36. The compound of any one of claims 1 to 29, wherein R4is-NHC (S) NR6R6'。

37. Any one of claims 1 to 29The compound of (1), wherein R4is-NH-O-R6Wherein R is6Is preferably-C1-C6An alkyl group.

38. The compound of any one of claims 1 to 29, wherein R4is-NH-NR6R6'Wherein R is6And R6'Preferably both are-C1-C6Alkyl or wherein R6Is preferably-C1-C6Alkyl and R6' is preferably H.

39. The compound of any one of claims 1 to 38, wherein R5Is H.

40. The compound of any one of claims 1 to 38, wherein R5Is halogen, preferably fluorine.

41. The compound of any one of claims 1 to 38, wherein R5is-C1-C6An alkyl group.

42. The compound of any one of claims 1 to 38, wherein R5is-C1-C6A haloalkyl group.

43. The compound of any one of claims 1 to 38, wherein R5is-C2-C6Alkenyl, preferably vinyl.

44. The compound of any one of claims 1 to 38, wherein R5is-C2-C6Alkynyl is preferably ethynyl.

45. The compound of any one of claims 1 to 38, wherein R5is-C1-C6alkyl-OH.

46. A pharmaceutical composition comprising a compound of any one of claims 1 to 45, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

47. A method of inhibiting a protein arginine methyltransferase 5(PRMT5) enzyme, the method comprising: contacting the PRMT5 enzyme with an effective amount of a compound of any one of claims 1 to 45, or a pharmaceutically acceptable salt thereof.

48. A method of treating a disease or disorder associated with aberrant PRMT5 activity in a subject, the method comprising administering to the subject a compound according to any one of claims 1 to 45, or a pharmaceutically acceptable salt thereof.

49. The method of claim 48, wherein the disease or disorder associated with aberrant PRMT5 activity is breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer, ovarian cancer, uterine cancer, cervical cancer, a leukemia such as Acute Myeloid Leukemia (AML), acute lymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia, myelodysplasia, myeloproliferative disorders, Acute Myeloid Leukemia (AML), Chronic Myelogenous Leukemia (CML), mastocytosis, Chronic Lymphocytic Leukemia (CLL), Multiple Myeloma (MM), myelodysplastic syndrome (MDS), epidermoid carcinoma, or a hemoglobinopathy such as thalassemia type b and Sickle Cell Disease (SCD).

50. The method of claim 48 or claim 49, wherein the compound or pharmaceutically acceptable salt thereof is administered in combination with one or more other agents.

Technical Field

The present disclosure relates to PRMT5 inhibitors and methods of use thereof.

Background

Protein arginine methylation is a common post-translational modification that regulates numerous cellular processes, including gene transcription, mRNA splicing, DNA repair, protein cellular localization, cell fate determination, and signal transduction. There are three types of methyl-arginine substances: ω NG monomethyl arginine (MMA), ω NG, NG asymmetric dimethyl arginine (ADMA) and ω NG, N' G symmetric dimethyl arginine (SDMA). The formation of methylated arginine is catalyzed by a methyltransferase of the protein arginine methyltransferase (PRMT) family. Currently, nine PRMTs are annotated in the human genome. Most of these enzymes are type I enzymes (PRMT1, PRMT-2, PRMT-3, PRMT-4, PRMT-6, PRMT-8) which are capable of monomethylating and asymmetrically dimethylating arginine with S-adenosylmethionine (SAM) as the methyl donor. PRMT-5, PRMT-7 and PRMT-9 are considered to be type II enzymes catalyzing the symmetrical dimethylation of arginine. Each PRMT species has seven motifs characteristic of beta chain methyltransferases (Katz et al, 2003), as well as additional "double E" and "THW" sequence motifs unique to the PRMT subfamily.

PRMT5 is a universal transcriptional repressor that can function with a number of transcription factors and repression complexes, including BRG1 and hBRM, Blimp1 and Snail. Once recruited to the promoter, the enzyme symmetrically dimethylates H3R8 and H4R 3. Importantly, the H4R3 site is the primary target for PRMT1 methylation (ADMA) and is generally considered to be a transcriptional activation marker. Thus, two markers, H4R3me2s (repressive; me2s for SDMA modification) and H4R3me2a (active; me2a for ADMA modification) were generated in vivo. The specificity of PRMT5 for H3R8 and H4R3 may be altered by its interaction with COPR5, and this may probably play an important role in determining the co-repressive state of PRMT 5.

Role of PRMT in cancer

Aberrant expression of PRMT has been identified in human cancers, and PRMT is considered a therapeutic target. Global analysis of histone modifications in prostate cancer showed that dimethylation of histone H4R3 was positively correlated with grade increase, and these changes could predict clinical outcome.

PRMT5 levels have been shown to be elevated in a panel of lymphoid cancer cell lines as well as in mantle cell lymphoma clinical samples. PRMT5 interacts with a variety of substrates involved in various cellular processes, including RNA processing, signal transduction, and transcriptional regulation. PRMT5 can directly modify histones H3 and H4, resulting in repression of gene expression. PRMT5 overexpression can stimulate cell growth and induce transformation by directly repressing tumor suppressor genes. Pal et al, mol.cell.biol.2003, 7475; pal et al, mol.cell.biol.2004, 9630; wang et al, mol.cell.biol.2008, 6262; chung et al, J BiolChem 2013,5534. In addition to its well-documented oncogenic role in transcription and translation, the transcription factor MYC maintains the appropriate pre-messenger RNA splicing, which is an essential step in lymphoma development. Koh et al, Nature2015, 5237558; hsu et al, Nature 2015525,384.

The discovery of cancer dependence has the potential to inform treatment strategies and identify putative drug targets. Integrating data from comprehensive genomic analysis of cancer cell lines and functional characterization from cancer cell dependence, it was recently found that loss of the enzyme methylthioadenosine phosphorylase (MTAP) confers a selective dependence on the protein arginine methyltransferase 5(PRMT5) and its binding partner WDR 77. MTAP is frequently lost due to its proximity to the commonly deleted tumor suppressor CDKN 2A. Cells with MTAP deletion have increased intracellular concentrations of methylthioadenosine (MTA, a metabolite cleaved by MTAP). Furthermore, MTA specifically inhibits PRMT5 enzyme activity. Administration of MTA or a small molecule PRMT5 inhibitor showed that the cell viability of MTAP-free cancer cell lines was preferentially impaired compared to isogenic MTAP-expressing counterparts. Taken together, these findings reveal that PRMT5 is a potential weakness among multiple cancer lineages that is enhanced by common "passenger" genomic changes.

Role of PRMT5 in hemoglobinopathies

The developmental transition from fetal to adult human globin gene subtypes, starting from birth, are predictive of the onset of hemoglobinopathies, thalassemia type b, and Sickle Cell Disease (SCD). The observation that increased expression of the adult globin gene (in the case of genetic persistence of the fetal hemoglobin [ HPFH ] mutation) significantly improved the clinical severity of thalassemia and SCD prompted the search for therapeutic strategies to reverse gamma-globin gene silencing. Central to gamma gene silencing is DNA methylation, which marks a key CpG dinucleotide flanking the gene transcription initiation site in adult myeloid erythroid cells. These markers have been shown to result from the recruitment of DNA methyltransferase DNMT3A to the gamma-promoter by the protein arginine methyltransferase PRMT 5. Zhao et al, Nat Struct Mol biol.200916, 304. PRMT 5-mediated methylation of histone H4R3 recruits DNMT3A, thereby coupling histone and DNA methylation in gene silencing.

PRMT5 induced a repressive histone marker H4R3me2s, which served as a template for direct DNMT3A binding and subsequent DNA methylation. Loss of PRMT5 binding or its enzymatic activity leads to demethylation of CpG dinucleotides and gene activation. In addition to the H4R3me2s marker and DNA methylation, binding of PRMT5 to the γ -promoter and its enzymatic activity are essential for assembly of the multiprotein complex on the γ -promoter, which induces a series of synergistic repressive epigenetic markers. Disruption of this complex results in reactivation of gamma gene expression. These studies provide a basis for the development of PRMT5 inhibitors as targeted therapies for thalassemia and SCD.

Disclosure of Invention

The present disclosure relates to compounds of formula I or a pharmaceutically acceptable salt or solvate thereof:

wherein

R1is-C0-C6alkyl-C1-C6Alkyl, -C0-C6alkyl-C1-C6Haloalkyl, -C1-C6alkyl-O-C1-C6Alkyl, -C1-C6alkane-S-C1-C6Alkyl, -C1-C6alkane-S-C1-C6alkane-CO2H、-C1-C6Alkyl-aryl, -C1-C6alkyl-O-aryl, -C1-C6alkyl-NH-aryl, -C1-C6alkyl-S-aryl, -C0-C6Alkyl-heteroaryl, -C1-C6alkyl-O-heteroaryl, -C1-C6alkyl-S-heteroaryl, -C1-C6alkyl-NH-heteroaryl or-C (O) NH-aryl;

R2is-C1-C6Alkyl, -C1-C6Haloalkyl, -C2-C6Alkenyl or-C2-C6An alkynyl group;

R3is H, halogen, NH2or-C1-C6An alkyl group;

R4is H, halogen, -C1-C6Alkyl, -C1-C6alkyl-O-C1-C6Alkyl, -NR6R6'、-NHC(O)NR6R6'、-NHC(S)NR6R6'、-NH-O-R6or-NH-NR6R6'；

R5Is H, halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -C2-C6Alkenyl, -C2-C6Alkynyl or-C1-C6alkyl-OH; and is

R6And R6'Each independently is H, C1-C6Alkyl or-C1-C6alkane-OC1-C6An alkyl group;

or R6And R6'Together with the atom to which they are attached form C3-C6A heterocycloalkyl ring.

Stereoisomers of the compounds of formula I and pharmaceutically acceptable salts and solvates thereof are also described. Methods of using the compounds of formula I, as well as pharmaceutical compositions comprising the compounds of formula I, are described.

Detailed Description

The present disclosure may be more fully understood by reference to the following description, including the definitions and examples below. Certain features of the disclosed compositions and methods described herein in the context of separate aspects may also be provided in combination in a single aspect. Alternatively, various features of the disclosed compositions and methods that are, for brevity, described in the context of a single aspect, may also be provided separately or in any subcombination.

The term "alkyl" when used alone or as part of a substituent group refers to groups having from 1 to 12 carbon atoms ("C") in the group1-C12"), preferably 1 to 6 carbon atoms (" C ")1-C6") a straight or branched chain hydrocarbon group. Examples of alkyl groups include methyl (Me, C)1Alkyl), ethyl (Et, C)2Alkyl), n-propyl (C)3Alkyl), isopropyl (C)3Alkyl), butyl (C)4Alkyl), isobutyl (C)4Alkyl), sec-butyl (C)4Alkyl), tert-butyl (C)4Alkyl), pentyl (C)5Alkyl), isopentyl (C)5Alkyl), tert-amyl (C)5Alkyl), hexyl (C)6Alkyl), isohexyl (C)6Alkyl), and the like.

The term "halogen" when used alone or as part of a substituent group refers to chlorine, fluorine, bromine or iodine.

The term "haloalkyl" when used alone or as part of a substituent group refers to an alkyl group wherein one or more hydrogen atoms have been replaced with one or more halogen atoms. Halogen atoms include chlorine, fluorine, bromine and iodine. Examples of haloalkyl groups of the present disclosure include, for example, trifluoromethyl (-CF)3) Chloromethyl (-CH)2Cl), and the like.

The term "cycloalkyl" when used alone or as part of a substituent group refers to having 3 to 10 carbon atoms ("C)3-C10"), preferably 3 to 6 carbon atoms (" C ")3-C6") a cyclic non-aromatic hydrocarbon group. Examples of cycloalkyl groups include, for example, cyclopropyl (C)3) Cyclobutyl (C)4) Cyclopropylmethyl (C)4) Cyclopentyl (C)5) Cyclohexyl (C)6) 1-methylcyclopropyl (C)4) 2-methylcyclopentyl (C)4) Adamantyl (C)10) And the like.

The term "heterocycloalkyl", when used alone or as part of a substituent group, refers to any 3 to 10 membered monocyclic or bicyclic saturated ring structure containing at least one heteroatom selected from O, N and S. The heterocycloalkyl group may be attached at any heteroatom or carbon atom of the ring, resulting in a stable structure. Examples of suitable heterocycloalkyl groups include, but are not limited to, azepanyl, aziridinyl, azetidinyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, piperazinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, oxaazepanyl, oxacyclopropaneyl, oxetanyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, and the like.

The term "alkenyl", when used alone or as part of a substituent group, refers to groups having from 2 to 12 carbon atoms ("C") in the group2-C12"), preferably 2 to 4 carbon atoms (" C)2-C4") straight or branched chainA chain group, wherein said group comprises at least one carbon-carbon double bond. Examples of alkenyl groups include vinyl (-CH ═ CH)2；C2Alkenyl), allyl (-CH)2-CH＝CH2；C3Alkenyl), propenyl (-CH ═ CHCH)3；C3Alkenyl), isopropenyl (-C (CH)3)＝CH2；C3Alkenyl), butenyl (-CH ═ CHCH)2CH3；C4Alkenyl), sec-butenyl (-C (CH)3)＝CHCH3；C4Alkenyl), isobutenyl (-CH ═ C (CH)3)2；C4Alkenyl), 2-butenyl (-CH)2CH＝CHCH3；C4Alkyl), pentenyl (-CH ═ CHCH)2CH2CH3；C5Alkenyl), and the like.

The term "alkynyl" when used alone or as part of a substituent group refers to groups having from 1 to 12 carbon atoms ("C") in the group1-C12"), preferably 1 to 4 carbon atoms (" C ")2-C4") and wherein said group includes at least one carbon-carbon triple bond. Examples of alkynyl groups include ethynyl (-C ≡ CH; C2Alkynyl), propargyl (-CH)2-C≡CH；C3Alkynyl), propynyl (-C.ident.CCH)3；C3Alkynyl), butynyl (-C ≡ CCH)2CH3；C4Alkynyl), pentynyl (-C.ident.CCH)2CH2CH3；C5Alkynyl), and the like.

The term "aryl" when used alone or as part of a substituent group refers to a monocyclic or bicyclic aromatic hydrocarbon ring structure having 6 or 10 carbon atoms in the ring, wherein one or more carbon atoms in the ring are optionally replaced by a halogen atom, -C1-C3Alkyl radical, amino-substituted-C1-C3Alkyl radical, C1-C3Haloalkyl groups, amino groups (i.e. -NH)2) Or substituted with a substituted amino group. The term "aryl" when used alone or as part of a substituent group also refers to a monocyclic or bicyclic aromatic hydrocarbon ring structure having 6 or 10 carbon atoms in the ring, whichOne or more carbon atoms in the middle ring being optionally substituted by halogen atoms, -C1-C3Alkyl radical, amino-substituted-C1-C3Alkyl group, alkylamino substituted-C1-C3Alkyl radical, hydroxy-substituted-C1-C3Alkyl radical, C1-C3Haloalkyl group, -O-C1-C3Haloalkyl groups, amino groups (i.e. -NH)2) Or substituted with a substituted amino group. Halogen atoms include chlorine, fluorine, bromine and iodine. amino-substituted-C1-C3The alkyl group comprising-CH2-NH2、-CH2CH2-NH2And the like. Alkylamino substituted-C1-C3The alkyl group comprising-CH2-NHCH3And the like. C1-C3Haloalkyl groups include, for example, -CF3、-CH2CF3And the like. Substituted amino groups include, for example, -NH-C (O) -NH2. hydroxy-substituted-C1-C3The alkyl group comprising-CH2-OH and the like. The term "aryl" also includes monocyclic or bicyclic aromatic hydrocarbon ring structures having 6 or 10 carbon atoms in the ring, wherein two adjacent carbon atoms in the ring are optionally substituted such that the two adjacent carbon atoms and their respective substituents form a heterocyclic ring. Thus, aryl groups include, for example, 2, 3-dihydrobenzofuran and 1, 3-benzodioxole. Examples of aryl groups (substituted and unsubstituted) include phenyl, aminomethylphenyl, 3- (aminomethyl) phenyl, phenylurea, methylchlorophenyl, 3-methyl-4-chlorophenyl, fluorochlorophenyl, 3-fluoro-4-chlorophenyl, naphthyl, fluorophenyl, trifluoromethylphenyl, 4-trifluoromethylphenyl, fluoro-trifluoromethylphenyl, 3-fluoro-4-trifluoromethylphenyl, 4-fluoro-3-trifluoromethylphenyl, difluorophenyl, 3, 4-difluorophenyl, chlorophenyl, 4-chloro-2- (hydroxymethyl) phenyl, 2- (aminomethyl) -4-chlorophenyl, 4-chloro-2- ((methylamino) methyl) phenyl, dichlorophenyl, 3, 4-dichlorophenyl, bromophenyl, iodophenyl, chlorophenyl, fluoronaphthyl, difluoronaphthyl, chloronaphthyl, bromonaphthyl, iodonaphthyl, methylphenyl, ethylphenyl, 4-isopropylphenyl, 4- (trifluoromethoxy) phenyl, benzo [ d ] phenyl][1,3]Dioxolyl, and the like.

The term "heteroaryl" when used alone or as part of a substituent group refers to a monocyclic or bicyclic aromatic ring structure comprising carbon atoms and up to four heteroatoms selected from nitrogen, oxygen and sulfur. Heteroaryl rings may contain a total of 5, 6, 9, or 10 ring atoms. The heteroaryl moiety may be unsubstituted or one or more of the carbon atoms in the ring may be substituted with: a halogen atom; an amino group; substituted amino groups, including by-C1-C6Cycloalkyl radical, -O-C1-C3Alkyl radical or-C1-C6An amino group substituted with an alkyl group; or-C1-C3An alkyl group. Halogen atoms include chlorine, fluorine, bromine and iodine. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl,Azolyl, imidazolyl, pyrazolyl, isopyrazolylOxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furazanyl (furazanyl), indolizinyl, indolyl, indol-6-yl, isoindolinyl, indazolyl, indazol-6-yl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolizinyl, quinolinyl, aminoquinolyl, aminohaloquinolyl, quinolin-7-yl, 2-amino-3-bromoquinolin-7-yl, 2-amino-3-chloroquinolin-7-yl, 2-amino-3-fluoroquinolin-7-yl, 2- ((cyclopropylmethyl) amino) quinolin-7-yl, 2- (methylamino) quinolin-7-yl, 2- (methoxyamino) quinolin-7-yl, 2-aminoquinolin-7-yl, isoquinolyl, isothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, imidazo [1,2-a]Pyridyl, substituted imidazo [1,2-a ] s]Pyridyl, 3-methylimidazo [1,2-a ]]Pyridin-7-yl and the like.

When used herein, the carbon atom range such as C1-C6All ranges and single numbers of carbon atoms are contemplated. For example, "C1-C3"comprises C1-C3、C1-C2、C2-C3、C1、C2And C3。

The term "C1-C6An alkyl "when used alone or as part of a substituent group refers to an aliphatic linking group having 1,2, 3,4, 5, or 6 carbon atoms and includes, for example, -CH2-、-CH(CH3)-、-CH(CH3)-CH2-and-C (CH)3)2-. The term "-C0Alkyl- "means a bond. In some aspects, C1-C6The alkane may be substituted by one or more-OH, -NH2Or halogen (e.g., -F, -Cl, -Br, where-F is preferred).

"pharmaceutically acceptable" means having been or may be approved by a regulatory agency of the federal or a state government or a corresponding agency in a country other than the united states, or listed in the U.S. pharmacopeia or other generally recognized pharmacopeia for use in animals, such as in humans.

"pharmaceutically acceptable salt" refers to a salt of a compound of the disclosure that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic and may be inorganic or organic acid addition salts and base addition salts. In particular, these salts include: (1) acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2.2.2] -oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, succinic acid, 1, 2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, 2-ethanesulfonic acid, Stearic acid, muconic acid, and the like; or (2) a salt formed when an acidic proton present in the parent compound is replaced with a metal ion, such as an alkali metal ion, an alkaline earth ion, or an aluminum ion; or a salt formed when coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, or the like. Salts also include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functional group, it includes salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, methanesulfonate, acetate, maleate, oxalate, and the like.

"pharmaceutically acceptable excipient" refers to a substance that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, e.g., an inert substance added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of the agent and is compatible therewith. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.

"solvate" refers to a physical association of a compound of formula I with one or more solvent molecules.

"subject" includes humans. The terms "human," "patient," and "subject" are used interchangeably herein.

In one embodiment, "treating" any disease or disorder refers to ameliorating the disease or disorder (i.e., arresting or reducing the development of the disease or at least one clinical symptom thereof). In another embodiment, "treating" refers to ameliorating at least one physical parameter that may not be discernible by the subject. In yet another embodiment, "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, "treating" or "treatment" refers to delaying the onset of the disease or disorder.

"Compounds of the present disclosure" and equivalent expressions are intended to include compounds of formula I as described herein and subgenera thereof, which expressions include stereoisomers (e.g., enantiomers, diastereomers) and structural isomers (e.g., tautomers) of the compounds of formula I as well as pharmaceutically acceptable salts, where the context permits.

As used herein, the term "isotopic variant" refers to a compound comprising a ratio of isotopes at one or more atoms comprising the compound that is greater than natural abundance. For example, an "isotopic variant" of a compound can be radiolabeled, i.e., contain one or more radioisotopes, or can be treated with a non-radioactive isotope such as deuterium (g: (b))2H or D), carbon-13 (13C) Nitrogen-15 (15N), etc. It will be appreciated that in compounds which undergo such isotopic substitution, the following atoms may be varied when present, and thus, for example, any hydrogen may be2H/D, any carbon may be13C, or any of the nitrogens may be15N, and the presence and placement of these atoms can be determined within the skill of the art.

It is also understood that compounds having the same molecular formula but differing in the nature or order of bonding of the atoms or arrangement of the atoms in space are referred to as "isomers". Isomers in which the arrangement of atoms in space is different are referred to as "stereoisomers", for example, diastereomers, enantiomers, and atropisomers. The compounds of the present disclosure may have one or more asymmetric centers; thus, these compounds can be produced as individual (R) -or (S) -stereoisomers at each asymmetric center or as mixtures thereof. Unless otherwise indicated, the description or nomenclature of a particular compound in the specification and claims is intended to include all stereoisomers and mixtures thereof in racemic or other forms. If a chiral center is present in a structure, but the specific stereochemistry of that center is not shown, the structure encompasses two enantiomers (either individually or as a mixture of enantiomers). If more than one chiral center is present in a structure, but the specific stereochemistry of said center is not shown, the structure encompasses all enantiomers and diastereomers (individually or in mixture). Methods for determining stereochemistry and separating stereoisomers are well known in the art.

The present disclosure relates to compounds of formula I:

according to the disclosure, R in formula I1is-C0-C6alkyl-C1-C6Alkyl, -C0-C6alkyl-C1-C6Haloalkyl, -C1-C6alkyl-O-C1-C6Alkyl, -C1-C6alkane-S-C1-C6Alkyl, -C1-C6alkane-S-C1-C6alkane-CO2H、-C1-C6Alkyl-aryl, -C1-C6alkyl-O-aryl, -C1-C6alkyl-NH-aryl, -C1-C6alkyl-S-aryl, -C0-C6Alkyl-heteroaryl, -C1-C6alkyl-O-heteroaryl, -C1-C6alk-S-heteroaryl or-C1-C6alkyl-NH-heteroaryl. In some aspects, R1is-C0-C6alkyl-C1-C6Alkyl, -C0-C6alkyl-C1-C6Haloalkyl, -C1-C6alkyl-O-C1-C6Alkyl, -C1-C6alkane-S-C1-C6Alkyl, -C1-C6alkane-S-C1-C6alkane-CO2H、-C1-C6Alkyl-aryl, -C1-C6alkyl-O-aryl, -C1-C6alkyl-NH-aryl, -C1-C6alkyl-S-aryl, -C0-C6Alkyl-heteroaryl, -C1-C6alkyl-O-heteroaryl, -C1-C6alkyl-S-heteroaryl, -C1-C6alkyl-NH-heteroaryl or-C (O) NH-aryl.

In some aspects, R1is-C0-C6alkyl-C1-C6Alkyl radicals, e.g., -C0alkyl-C1Alkyl, -C1alkyl-C1Alkyl, -C2alkyl-C1Alkyl, -C3alkyl-C1Alkyl, -C4alkyl-C1Alkyl, -C5alkyl-C1Alkyl, -C6alkyl-C1Alkyl, -C0alkyl-C2Alkyl, -C1alkyl-C2Alkyl, -C2alkyl-C2Alkyl, -C3alkyl-C2Alkyl, -C4alkyl-C2Alkyl, -C5alkyl-C2Alkyl, -C6alkyl-C2Alkyl, -C0alkyl-C3Alkyl, -C1alkyl-C3Alkyl, -C2alkyl-C3Alkyl, -C3alkyl-C3Alkyl, -C4alkyl-C3Alkyl, -C5alkyl-C3Alkyl, -C6alkyl-C3Alkyl, -C0alkyl-C4Alkyl, -C1alkyl-C4Alkyl, -C2alkyl-C4Alkyl, -C3alkyl-C4Alkyl, -C4alkyl-C4Alkyl, -C5alkyl-C4Alkyl, -C6alkyl-C4Alkyl, -C0alkyl-C5Alkyl, -C1alkyl-C5Alkyl, -C2alkyl-C5Alkyl, -C3alkyl-C5Alkyl, -C4alkyl-C5Alkyl, -C5alkyl-C5Alkyl, -C6alkyl-C5Alkyl, -C0alkyl-C6Alkyl, -C1alkyl-C6Alkyl, -C2alkyl-C6Alkyl, -C3alkyl-C6Alkyl, -C4alkyl-C6Alkyl, -C5alkyl-C6Alkyl, -C6alkyl-C6Alkyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, -CH (OH) -C1-C6Alkyl (e.g., -CH (OH) -methyl, -CH (OH) -ethyl, -CH (OH) -propyl, -CH (OH) -isopropyl, -CH (OH) -pentyl, -CH (OH) -butyl, etc.), -CH (F) -C1-C6Alkyl, -CH (NH)2)-C1-C6Alkyl, -CH (Me) -C1-C6Alkyl, -C (Me) ((OH) -C)1-C6Alkyl groups, and the like.

In other aspects, R1is-C0-C6alkyl-C1-C6Haloalkyl radicals, e.g., -C0alkyl-C1Haloalkyl, -C1alkyl-C1Haloalkyl, -C2alkyl-C1Haloalkyl, -C3alkyl-C1Haloalkyl, -C4alkyl-C1Haloalkyl, -C5alkyl-C1Haloalkyl, -C6alkyl-C1Haloalkyl, -C0alkyl-C2Haloalkyl, -C1alkyl-C2Haloalkyl, -C2alkyl-C2Haloalkyl, -C3alkyl-C2Haloalkyl, -C4alkyl-C2Haloalkyl, -C5alkyl-C2Haloalkyl, -C6alkyl-C2Haloalkyl, -C0alkyl-C3Haloalkyl, -C1alkyl-C3Haloalkyl, -C2alkyl-C3Haloalkyl, -C3alkyl-C3Haloalkyl, -C4alkyl-C3Haloalkyl, -C5alkyl-C3Haloalkyl, -C6alkyl-C3Haloalkyl, -C0alkyl-C4Haloalkyl, -C1alkyl-C4Haloalkyl, -C2alkyl-C4Haloalkyl, -C3alkyl-C4Haloalkyl, -C4alkyl-C4Haloalkyl, -C5alkyl-C4Haloalkyl, -C6alkyl-C4Haloalkyl, -C0alkyl-C5Haloalkyl, -C1alkyl-C5Haloalkyl, -C2alkyl-C5Haloalkyl, -C3alkyl-C5Haloalkyl, -C4alkyl-C5Haloalkyl, -C5alkyl-C5Haloalkyl, -C6alkyl-C5Haloalkyl, -C0alkyl-C6Haloalkyl, -C1alkyl-C6Haloalkyl, -C2alkyl-C6Haloalkyl, -C3alkyl-C6Haloalkyl, -C4alkyl-C6Haloalkyl, -C5alkyl-C6Haloalkyl, -C6alkyl-C6Haloalkyl, fluoromethyl, fluoroethyl, fluoropropyl, fluorobutyl, fluoropentyl, chloromethyl, chloroethyl, chloropropyl, chlorobutyl, chloropentyl, bromomethyl, bromoethyl, bromopropyl, bromobutyl, bromopentyl, iodomethyl, iodoethyl, iodopropyl, iodobutyl, iodopentyl, -CH (OH) -C1-C6Haloalkyl (e.g., -CH (OH) -fluoromethyl, -CH (OH) -fluoroethyl, -CH (OH) -fluoropropyl, -CH (OH) -fluoroisopropyl, -CH (OH) -fluoropentyl, -CH (OH) -fluorobutyl), -CH (F) -C1-C6Haloalkyl, -CH (NH)2)-C1-C6Haloalkyl, -CH (Me) -C1-C6Haloalkyl, -C (Me) ((OH) -C)1-C6Haloalkyl, and the like. Thus, in some aspects, R1Is chloromethyl (i.e., -CH)2-Cl)。

In some aspects, R1is-C1-C6alkyl-O-C1-C6Alkyl radicals, e.g., -C1alkyl-O-C1Alkyl, -C2alkyl-O-C1Alkyl, -C3alkyl-O-C1Alkyl, -C4alkyl-O-C1Alkyl, -C5alkyl-O-C1Alkyl, -C6alkyl-O-C1Alkyl, -C1alkyl-O-C2Alkyl, -C2alkyl-O-C2Alkyl, -C3alkyl-O-C2Alkyl, -C4alkyl-O-C2Alkyl, -C5alkyl-O-C2Alkyl, -C6alkyl-O-C2Alkyl, -C1alkyl-O-C3Alkyl, -C2alkyl-O-C3Alkyl, -C3alkyl-O-C3Alkyl, -C4alkyl-O-C3Alkyl, -C5alkyl-O-C3Alkyl, -C6alkyl-O-C3Alkyl, -C1alkyl-O-C4Alkyl, -C2alkyl-O-C4Alkyl, -C3alkyl-O-C4Alkyl, -C4alkyl-O-C4Alkyl, -C5alkyl-O-C4Alkyl, -C6alkyl-O-C4Alkyl, -C1alkyl-O-C5Alkyl, -C2alkyl-O-C5Alkyl, -C3alkyl-O-C5Alkyl, -C4alkyl-O-C5Alkyl, -C5alkyl-O-C5Alkyl, -C6alkyl-O-C5Alkyl, -C1alkyl-O-C6Alkyl, -C2alkyl-O-C6Alkyl, -C3alkyl-O-C6Alkyl, -C4alkyl-O-C6Alkyl, -C5alkyl-O-C6Alkyl or-C6alkyl-O-C6An alkyl group. In some embodiments, R1is-CH2-O-CH3。

In some aspects, R1is-C1-C6alkane-S-C1-C6Alkyl radicals, e.g., -C1alkane-S-C1Alkyl, -C2alkane-S-C1Alkyl, -C3alkane-S-C1Alkyl, -C4alkane-S-C1Alkyl, -C5alkane-S-C1Alkyl, -C6alkane-S-C1Alkyl, -C1alkane-S-C2Alkyl, -C2alkane-S-C2Alkyl, -C3alkane-S-C2Alkyl, -C4alkane-S-C2Alkyl, -C5alkane-S-C2Alkyl, -C6alkane-S-C2Alkyl, -C1alkane-S-C3Alkyl, -C2alkane-S-C3Alkyl, -C3alkane-S-C3Alkyl, -C4alkane-S-C3Alkyl, -C5alkane-S-C3Alkyl, -C6alkane-S-C3Alkyl, -C1alkane-S-C4Alkyl, -C2alkane-S-C4Alkyl, -C3alkane-S-C4Alkyl, -C4alkane-S-C4Alkyl, -C5alkane-S-C4Alkyl, -C6alkane-S-C4Alkyl, -C1alkane-S-C5Alkyl, -C2alkane-S-C5Alkyl, -C3alkane-S-C5Alkyl, -C4alkane-S-C5Alkyl, -C5alkane-S-C5Alkyl, -C6alkane-S-C5Alkyl, -C1alkane-S-C6Alkyl, -C2alkane-S-C6Alkyl, -C3alkane-S-C6Alkyl, -C4alkane-S-C6Alkyl, -C5alkane-S-C6Alkyl or-C6alkane-S-C6An alkyl group. In some embodiments, R1is-CH2-S-CH3。

In some aspects, R1is-C1-C6alkane-S-C1-C6alkane-CO2H, e.g., -C1alkane-S-C1-C6alkane-CO2H、-C2alkane-S-C1-C6alkane-CO2H、-C3alkane-S-C1-C6alkane-CO2H、-C4alkane-S-C1-C6alkane-CO2H、-C5alkane-S-C1-C6alkane-CO2H、-C6alkane-S-C1-C6alkane-CO2H、-C1-C6alkane-S-C1alkane-CO2H、-C1-C6alkane-S-C2alkane-CO2H、-C1-C6alkane-S-C3alkane-CO2H、-C1-C6alkane-S-C4alkane-CO2H、-C1-C6alkane-S-C5alkane-CO2H、-C1-C6alkane-S-C6alkane-CO2H, and the like. In some embodiments, R1is-CH2-S-CH2CH2CH(NH2)-CO2H。

In some aspects, R1is-C1-C6Alkyl-aryl radicals, e.g., -C1Alkyl-aryl, -C2Alkyl-aryl, -C3Alkyl-aryl, -C4Alkyl-aryl, -C5Alkyl-aryl, -C6Alkyl-aryl, -CH2Aryl, -CH (OH) -aryl, -CH (F) -aryl, -CH (NH)2) Aryl, -CH (Me) -aryl, -C (Me) (OH) -aryl, and the like.

In which R is1is-C1-C6In some embodiments of the alk-aryl group, the-aryl group is a monocyclic or bicyclic aromatic hydrocarbon ring structure having 6 or 10 carbon atoms in the ring, wherein one or more carbon atoms in the ring are optionally substituted with a halogen atom, -C1-C3Alkyl radical, amino-substituted-C1-C3Alkyl radical, C1-C3Haloalkyl groups, amino groups (i.e. -NH)2) Or substituted with a substituted amino group.

In which R is1is-C1-C6In other embodiments of the alk-aryl group, the-aryl group is a monocyclic or bicyclic aromatic hydrocarbon ring structure having 6 or 10 carbon atoms in the ring, wherein one or more carbon atoms in the ring are optionally substituted with a halogen atom, -C1-C3Alkyl radical, amino-substituted-C1-C3Alkyl group, alkylamino substituted-C1-C3Alkyl radical, hydroxy-substituted-C1-C3Alkyl radical, C1-C3Haloalkyl group, -O-C1-C3Haloalkyl groups, amino groups (i.e. -NH)2) Or substituted with a substituted amino group.

In which R is1is-C1-C6In some embodiments of the alk-aryl, said-aryl is-4-chlorophenyl, 4-chloro-2- (hydroxymethyl) phenyl, 4-chloro-2- (aminomethyl) phenyl, 4-chloro-2- ((methylamino) methyl) phenyl, -3, 4-dichlorophenyl, -3, 4-difluorophenyl, -3-fluoro-4-chlorophenyl, 3-methyl-4-chlorophenyl, 3-fluoro-4-trifluoromethylphenyl, 4- (trifluoromethoxy) phenyl, 4-fluoro-3-trifluoromethylphenyl, benzo [ d ] phenyl][1,3]IIOxazole, 4-isopropylphenyl or 3-chloro-4-fluorophenyl. Thus, in some embodiments, R1is-CH2-difluorophenyl, -CH2-3, 4-difluorophenyl, -CH2-4-chlorophenyl, -CH2- (4-chloro-2- (hydroxymethyl) phenyl), -CH2- (4-chloro-2- (aminomethyl) phenyl), -CH2- (4-chloro-2- ((methylamino) methyl) phenyl), -CH2-3-chloro-4-fluorophenyl, -CH2-4-chloro-3-fluorophenyl, -CH2-dichlorophenyl, -CH2-3, 4-dichlorophenyl, -CH2-3, 4-difluorophenyl, -CH2-3-methyl-4-chlorophenyl, -CH2-4-trifluoromethylphenyl, -CH2-4- (trifluoromethoxy) phenyl, -CH2-3-fluoro-4-trifluoromethylphenyl、-CH2-4-fluoro-3-trifluoromethylphenyl, benzo [ d][1,3]IIOxazol-5-ylmethyl, -CH2-4-isopropylphenyl, -CH (OH) -4-chlorophenyl, -CH (OH) -4-chloro-2- (hydroxymethyl) phenyl, -CH (OH) -4-chloro-2- (aminomethyl) phenyl, -CH (OH) -4-chloro-2- ((methylamino) methyl) phenyl, -CH (OH) -3, 4-dichlorophenyl, -CH (OH) -3, 4-difluorophenyl, -CH (OH) -3-fluoro-4-chlorophenyl, -CH (OH) -3-chloro-4-fluorophenyl, -CH (OH) -3-methyl-4-chlorophenyl, -CH (OH) -4-trifluoromethylphenyl, and, -CH (OH) -4- (trifluoromethoxy) phenyl, -CH (OH) -3-fluoro-4-trifluoromethylphenyl, -CH (OH) -4-fluoro-3-trifluoromethylphenyl, -CH (OH) -benzo [ d][1,3]IIOxazol-5-yl, -CH (OH) -4-isopropylphenyl, -CH (F) -4-chlorophenyl, -CH (F) -4-chloro-2- (hydroxymethyl) phenyl, -CH (F) -4-chloro-2- (aminomethyl) phenyl, -CH (F) -4-chloro-2- ((methylamino) methyl) phenyl, -CH (F) -3, 4-dichlorophenyl, -CH (F) -3, 4-difluorophenyl, -CH (F) -3-fluoro-4-chlorophenyl, -CH (F) -3-chloro-4-fluorophenyl, -CH (F) -3-methyl-4-chlorophenyl, and, -CH (F) -4-trifluoromethylphenyl, -CH (F) -4- (trifluoromethoxy) phenyl, -CH (F) -3-fluoro-4-trifluoromethylphenyl, -CH (F) -4-fluoro-3-trifluoromethylphenyl, -CH (F) -benzo [ d ]][1,3]IIOxazol-5-yl, -CH (F) -4-isopropylphenyl, -CH (NH)2) -4-chlorophenyl, -CH (NH)2) -4-chloro-2- (hydroxymethyl) phenyl, -CH (NH)2) -4-chloro-2- (aminomethyl) phenyl, -CH (NH)2) -4-chloro-2- ((methylamino) methyl) phenyl, -CH (NH)2) -3, 4-dichlorophenyl, -CH (NH)2) -3, 4-difluorophenyl, -CH (NH)2) -3-fluoro-4-chlorophenyl, -CH (NH)2) -3-chloro-4-fluorophenyl, -CH (NH)2) -3-methyl-4-chlorophenyl, -CH (NH)2) -4-trifluoromethylphenyl, -CH (NH)2) -4- (trifluoromethoxy) phenyl, -CH (NH)2) -3-fluoro-4-trifluoromethylphenyl, -CH (NH)2) -4-fluoro-3-trisFluoromethylphenyl, -CH (NH)2) -benzo [ d ]][1,3]IIOxazol-5-yl, -CH (NH)2) -4-isopropylphenyl, -CH (Me) -4-chlorophenyl, -CH (Me) -4-chloro-2- (hydroxymethyl) phenyl, -CH (Me) -4-chloro-2- (aminomethyl) phenyl, -CH (Me) -4-chloro-2- ((methylamino) methyl) phenyl, -CH (Me) -3, 4-dichlorophenyl, -CH (Me) -3, 4-difluorophenyl, -CH (Me) -3-fluoro-4-chlorophenyl, -CH (Me) -3-chloro-4-fluorophenyl, -CH (Me) -3-methyl-4-chlorophenyl, -CH (Me) -4-trifluoromethylphenyl, and, -CH (Me) -4- (trifluoromethoxy) phenyl, -CH (Me) -3-fluoro-4-trifluoromethylphenyl, -CH (Me) -4-fluoro-3-trifluoromethylphenyl, -CH (Me) -benzo [ d][1,3]IIOxazol-5-yl, -CH (Me) -4-isopropylphenyl, -C (Me) (OH) -4-chlorophenyl, -C (Me) (OH) -4-chloro-2- (hydroxymethyl) phenyl, -C (Me) (OH) -4-chloro-2- (aminomethyl) phenyl, -C (Me) (OH) -4-chloro-2- ((methylamino) methyl) phenyl, -C (Me) (OH) -3, 4-dichlorophenyl, -C (Me) (OH) -3, 4-difluorophenyl, -C (Me) (OH) -3-fluoro-4-chlorophenyl, -C (Me) (OH) -3-chloro-4-fluorophenyl, C (Me) (OH) -3-chloro-4-fluorophenyl, -C (Me) (OH) -3-methyl-4-chlorophenyl, -C (Me) (OH) -4-trifluoromethylphenyl, -C (Me) (OH) -4- (trifluoromethoxy) phenyl, -C (Me) (OH) -3-fluoro-4-trifluoromethylphenyl, -C (Me) (OH) -4-fluoro-3-trifluoromethylphenyl, -C (Me) (OH) -4-isopropylphenyl, or-C (Me) (OH) -benzo [ d ], (OH)][1,3]IIOxazol-5-yl.

In which R is1is-C1-C6In some embodiments of the alk-aryl, said-aryl is-4-chlorophenyl, -3, 4-dichlorophenyl, -3, 4-difluorophenyl, -3-fluoro-4-chlorophenyl, 3-methyl-4-chlorophenyl, 3-fluoro-4-trifluoromethylphenyl, benzo [ d][1,3]IIOxazole or 3-chloro-4-fluorophenyl. Thus, in some embodiments, R1is-CH2-difluoro (E)Phenyl, -CH2-3, 4-difluorophenyl, -CH2-4-chlorophenyl, -CH2-3-chloro-4-fluorophenyl, -CH2-4-chloro-3-fluorophenyl, -CH2-dichlorophenyl, -CH2-3, 4-dichlorophenyl, -CH2-3-methyl-4-chlorophenyl, -CH2-3-fluoro-4-trifluoromethylphenyl, benzo [ d][1,3]IIOxazol-5-ylmethyl, -CH (OH) -4-chlorophenyl, -CH (OH) -3, 4-dichlorophenyl, -CH (OH) -3, 4-difluorophenyl, -CH (OH) -3-fluoro-4-chlorophenyl, -CH (OH) -3-chloro-4-fluorophenyl, -CH (OH) -3-methyl-4-chlorophenyl, -CH (OH) -3-fluoro-4-trifluoromethylphenyl, -CH (OH) -benzo [ d ]][1,3]IIOxazol-5-yl, -CH (F) -4-chlorophenyl, -CH (F) -3, 4-dichlorophenyl, -CH (F) -3, 4-difluorophenyl, -CH (F) -3-fluoro-4-chlorophenyl, -CH (F) -3-chloro-4-fluorophenyl, -CH (F) -3-methyl-4-chlorophenyl, -CH (F) -3-fluoro-4-trifluoromethylphenyl, -CH (F) -benzo [ d ]][1,3]IIOxazol-5-yl, -CH (NH)2) -4-chlorophenyl, -CH (NH)2) -3, 4-dichlorophenyl, -CH (NH)2) -3, 4-difluorophenyl, -CH (NH)2) -3-fluoro-4-chlorophenyl, -CH (NH)2) -3-chloro-4-fluorophenyl, -CH (NH)2) -3-methyl-4-chlorophenyl, -CH (NH)2) -3-fluoro-4-trifluoromethylphenyl, -CH (NH)2) -benzo [ d ]][1,3]IIOxazol-5-yl, -CH (Me) -4-chlorophenyl, -CH (Me) -3, 4-dichlorophenyl, -CH (Me) -3, 4-difluorophenyl, -CH (Me) -3-fluoro-4-chlorophenyl, -CH (Me) -3-chloro-4-fluorophenyl, -CH (Me) -3-methyl-4-chlorophenyl, -CH (Me) -3-fluoro-4-trifluoromethylphenyl, -CH (Me) -benzo [ d ]][1,3]IIAzol-5-yl, -C (Me) (OH) -4-chlorophenyl, -C (Me)(OH) -3, 4-dichlorophenyl, -C (Me) (OH) -3, 4-difluorophenyl, -C (Me) (OH) -3-fluoro-4-chlorophenyl, -C (Me) (OH) -3-chloro-4-fluorophenyl, (OH) -3-methyl-4-chlorophenyl, -C (Me) (OH) -3-fluoro-4-trifluoromethylphenyl, or-C (Me) (OH) -benzo [ d-][1,3]IIOxazol-5-yl.

In which R is1is-C1-C6In other embodiments of the alk-aryl, said-aryl is-4-chlorophenyl, -3, 4-dichlorophenyl, -3, 4-difluorophenyl, -3-fluoro-4-chlorophenyl, 3-methyl-4-chlorophenyl, 3-fluoro-4-trifluoromethylphenyl, or-3-chloro-4-fluorophenyl. Thus, in some embodiments, R1is-CH2-difluorophenyl, -CH2-3, 4-difluorophenyl, -CH2-4-chlorophenyl, -CH2-3-chloro-4-fluorophenyl, -CH2-4-chloro-3-fluorophenyl, -CH2-dichlorophenyl, -CH2-3, 4-dichlorophenyl, -CH2-3-methyl-4-chlorophenyl, -CH2-3-fluoro-4-trifluoromethylphenyl, -CH (OH) -4-chlorophenyl, -CH (OH) -3, 4-dichlorophenyl, -CH (OH) -3, 4-difluorophenyl, -CH (OH) -3-fluoro-4-chlorophenyl, -CH (OH) -3-chloro-4-fluorophenyl, -CH (OH) -3-methyl-4-chlorophenyl, -CH (OH) -3-fluoro-4-trifluoromethylphenyl, -CH (F) -4-chlorophenyl, -CH (F) -3, 4-dichlorophenyl, -CH (F) -3, 4-difluorophenyl, -CH (F) -3-fluoro-4-chlorophenyl, C, -CH (F) -3-chloro-4-fluorophenyl, -CH (F) -3-methyl-4-chlorophenyl, -CH (F) -3-fluoro-4-trifluoromethylphenyl, -CH (NH)2) -4-chlorophenyl, -CH (NH)2) -3, 4-dichlorophenyl, -CH (NH)2) -3, 4-difluorophenyl, -CH (NH)2) -3-fluoro-4-chlorophenyl, -CH (NH)2) -3-chloro-4-fluorophenyl, -CH (NH)2) -3-methyl-4-chlorophenyl, -CH (NH)2) -3-fluoro-4-trifluoromethylphenyl, -CH (Me) -4-chlorophenyl, -CH (Me) -3, 4-dichlorophenyl, -CH (Me) -3, 4-difluorophenyl, -CH (Me) -3-fluoro-4-chlorophenyl, -CH (Me) -3-chloro-4-fluorophenyl, -CH (Me) -3-methyl-4-chlorophenyl, -CH (Me) -3-fluoro-4-trifluoromethylphenyl, -C (Me) (OH) -4-chlorophenyl, -C (Me) (OH) -3, 4-dichlorophenyl, -C (Me) (OH) -3, 4-difluorophenyl, -C (Me) (OH) -3-fluoro-4-chlorophenyl, -C (Me) (OH) -3-chloro-4-fluorophenyl, -C (Me)Me) (OH) -3-methyl-4-chlorophenyl or-C (Me) (OH) -3-fluoro-4-trifluoromethylphenyl.

In some aspects, R1is-C1-C6alkyl-O-aryl, e.g., -C1alkyl-O-aryl, -C2alkyl-O-aryl, -C3alkyl-O-aryl, -C4alkyl-O-aryl, -C5alkyl-O-aryl, -C6alkyl-O-aryl, -CH2-O-aryl and the like. In which R is1is-C1-C6In some embodiments of the alk-O-aryl, said-aryl is-4-chlorophenyl, -3, 4-dichlorophenyl, -3, 4-difluorophenyl, -3-fluoro-4-chlorophenyl, 3-methyl-4-chlorophenyl, 3-fluoro-4-trifluoromethylphenyl, -3-chloro-4-fluorophenyl, -phenyl, -3- (aminomethyl) phenyl, 3- (urea) phenyl, 3-methyl-4-chlorophenyl, 3-fluoro-4-chlorophenyl, -3-fluoro-4-trifluoromethylphenyl, difluorophenyl, chlorophenyl, 4-chlorophenyl, dichlorophenyl, 3, 4-dichlorophenyl, phenyl, 4-dichlorophenyl, phenyl, trifluoromethyl, or mixtures thereof, Bromophenyl, iodophenyl or chlorofluorophenyl. Thus, in some embodiments, R1is-CH2-O-phenyl, -CH2-O-difluorophenyl, -CH2-O-3, 4-difluorophenyl, -CH2-O-4-chlorophenyl, -CH2-O-3-chloro-4-fluorophenyl, -CH2-O-4-chloro-3-fluorophenyl, -CH2-O-dichlorophenyl, -CH2-O-3, 4-dichlorophenyl, -CH2-O-3-methyl-4-chlorophenyl, -CH2-O-3-fluoro-4-trifluoromethylphenyl, -CH2-O-3- (aminomethyl) phenyl, -CH2-O-3- (urea) phenyl. In which R is1is-C1-C6In some embodiments of the alk-O-aryl, said-aryl is-4-chloro-2- (hydroxymethyl) phenyl, -4-chloro-2- (aminomethyl) phenyl, -4-chloro-2- ((methylamino) methyl) phenyl, -4-trifluoromethylphenyl, -4- (trifluoromethoxy) phenyl, 4-fluoro-3-trifluoromethylphenyl, or-4-isopropylphenyl.

In some aspects, R1is-C1-C6alkyl-NH-aryl radicals, e.g., -C1alkyl-NH-aryl, -C2alkyl-NH-aryl, -C3alkyl-NH-aryl, -C4alkyl-NH-aryl, -C5alkyl-NH-aryl, -C6alkyl-NH-aryl, -CH2-NH-aryl, and the like. In which R is1is-C1-C6In some embodiments of the alk-NH-aryl, said-aryl is-4-chlorophenyl, -3, 4-dichlorophenyl, -3, 4-difluorophenyl, -3-fluoro-4-chlorophenyl, 3-methyl-4-chlorophenyl, 3-fluoro-4-trifluoromethylphenyl, -3-chloro-4-fluorophenyl, -phenyl, -3- (aminomethyl) phenyl, 3- (urea) phenyl, 3-methyl-4-chlorophenyl, 3-fluoro-4-chlorophenyl, -3-fluoro-4-trifluoromethylphenyl, difluorophenyl, chlorophenyl, 4-chlorophenyl, dichlorophenyl, 3, 4-dichlorophenyl, phenyl, 4-dichlorophenyl, phenyl, trifluoromethyl, or mixtures thereof, Bromophenyl, iodophenyl, chlorofluorophenyl. Thus, in some embodiments, R1is-CH2-NH-difluorophenyl, -CH2-NH-3, 4-difluorophenyl, -CH2-NH-4-chlorophenyl, -CH2-NH-3-chloro-4-fluorophenyl, -CH2-NH-4-chloro-3-fluorophenyl, -CH2-NH-dichlorophenyl, -CH2-NH-3, 4-dichlorophenyl, -CH2-NH-3-methyl-4-chlorophenyl, -CH2-NH-3-fluoro-4-trifluoromethylphenyl, -CH2-NH-3- (aminomethyl) phenyl, -CH2-NH-3- (urea) phenyl. In which R is1is-C1-C6In some embodiments of the alk-NH-aryl group, said-aryl group is 4-chloro-2- (hydroxymethyl) phenyl, -4-chloro-2- (aminomethyl) phenyl, -4-chloro-2- ((methylamino) methyl) phenyl, -4-trifluoromethylphenyl, -4- (trifluoromethoxy) phenyl, 4-fluoro-3-trifluoromethylphenyl, -4-isopropylphenyl.

In some aspects, R1is-C1-C6alk-S-aryl radicals, e.g., -C1alkyl-S-aryl, -C2alkyl-S-aryl, -C3alkyl-S-aryl, -C4alkyl-S-aryl, -C5alkyl-S-aryl, -C6alkyl-S-aryl, -CH2-S-aryl and the like. In which R is1is-C1-C6In some embodiments of the alk-S-aryl said-aryl is-4-chlorophenyl, -3, 4-dichlorophenyl, -3, 4-difluorophenyl, -3-fluoro-4-chlorophenyl, 3-methyl-4-chlorophenyl, 3-fluoro-4-trifluoromethylphenyl, -3-chloro-4-fluorophenyl, -phenyl, -3- (aminomethyl) phenyl, 3- (urea) phenyl, 3-methyl-4-chlorophenyl, 3-fluoro-4-chlorophenyl, -3-fluoro-4-trifluoromethylphenyl, difluorophenyl, chlorophenyl, 4-chlorophenyl, dichlorophenyl, 3, 4-di.Chlorophenyl, bromophenyl, iodophenyl, chlorophenyl. Thus, in some embodiments, R1is-CH2-S-difluorophenyl, -CH2-S-3, 4-difluorophenyl, -CH2-S-4-chlorophenyl, -CH2-S-3-chloro-4-fluorophenyl, -CH2-S-4-chloro-3-fluorophenyl, -CH2-S-dichlorophenyl, -CH2-S-3, 4-dichlorophenyl, -CH2-S-3-methyl-4-chlorophenyl, -CH2-S-3-fluoro-4-trifluoromethylphenyl, -CH2-S-3- (aminomethyl) phenyl, -CH2-S-3- (urea) phenyl. In which R is1is-C1-C6In some embodiments of the alk-S-aryl, said-aryl is-4-chloro-2- (hydroxymethyl) phenyl, -4-chloro-2- (aminomethyl) phenyl, -4-chloro-2- ((methylamino) methyl) phenyl, -4-trifluoromethylphenyl, -4- (trifluoromethoxy) phenyl, 4-fluoro-3-trifluoromethylphenyl, or-4-isopropylphenyl.

In some aspects, R1is-C0-C6Alk-heteroaryl radicals, e.g., -C0Alkyl-heteroaryl, -C1Alkyl-heteroaryl, -C2Alkyl-heteroaryl, -C3Alkyl-heteroaryl, -C4Alkyl-heteroaryl, -C5Alk-heteroaryl and-C6An alkyl-heteroaryl group. In which R is1is-C0-C6In some embodiments of the alk-heteroaryl, the heteroaryl is indolyl, indol-6-yl, indazolyl, indazol-6-yl, quinolinyl, aminoquinolinyl, aminohaloquinolinyl, 2-amino-3-bromoquinolin-7-yl, 2-amino-3-chloroquinolin-7-yl, 2-amino-3-fluoroquinolin-7-yl, 2- ((cyclopropylmethyl) amino) quinolin-7-yl, 2- (methylamino) quinolin-7-yl, or 2-aminoquinolin-7-yl. Thus, in some embodiments, R1Is 2- (2-amino-3-bromoquinolin-7-yl) ethyl (i.e., -CH)2CH2- (2-amino-3-bromoquinolin-7-yl)), 2- (2-amino-3-chloroquinolin-7-yl) ethyl, 2- (2-amino-3-fluoroquinolin-7-yl) ethyl, 2- (2- ((cyclopropylmethyl) amino) quinolin-7-yl) ethyl, 2- (2- (methylamino) quinolin-7-yl) ethyl, 2- (2-aminoquinolin-7-yl) ethyl, (indol-6-yl) ethyl, or (indazol-6-yl) ethyl. In which R is1is-C0-C6Some examples of alk-heteroarylIn an embodiment, the heteroaryl is 3-methylimidazo [1,2-a ]]Pyridin-7-yl, and R1Is (3-methylimidazo [1, 2-a)]Pyridin-7-yl) ethyl.

In some aspects, R1is-C1-C6alkyl-O-heteroaryl, e.g., -C1alkyl-O-heteroaryl, -C2alkyl-O-heteroaryl, -C3alkyl-O-heteroaryl, -C4alkyl-O-heteroaryl, -C5alkyl-O-heteroaryl and-C6alkyl-O-heteroaryl. In which R is1is-C1-C6In some embodiments of the alk-O-heteroaryl, said heteroaryl is indolyl, indol-6-yl, indazolyl, indazol-6-yl, quinolinyl, quinolin-7-yl, aminoquinolinyl, aminohaloquinolinyl, 2-amino-3-bromoquinolin-7-yl, 2-amino-3-chloroquinolin-7-yl, 2-amino-3-fluoroquinolin-7-yl, 2- ((cyclopropylmethyl) amino) quinolin-7-yl, 2- (methylamino) quinolin-7-yl, 2- (methoxyamino) quinolin-7-yl, 3-methylimidazo [1,2-a ] yl]Pyridin-7-yl or 2-aminoquinolin-7-yl. Thus, in some embodiments, R1Is ((2-amino-3-bromoquinolin-7-yl) oxy) methyl (i.e., -CH)2-O- (2-amino-3-bromoquinolin-7-yl)), ((2-amino-3-chloroquinolin-7-yl) oxy) methyl, ((2-amino-3-fluoroquinolin-7-yl) oxy) methyl, ((2- ((cyclopropylmethyl) amino) quinolin-7-yl) oxy) methyl, ((2- (methylamino) quinolin-7-yl) oxy) methyl, ((2-aminoquinolin-7-yl) oxy) methyl, ((indol-6-yl) oxy) methyl, (2- (methoxyamino) quinolin-7-yl) oxy) methyl, ((indazol-6-yl) oxy) methyl, or ((3-methylimidazo [1,2-a]Pyridin-7-yl) oxy) methyl.

In which R is1is-C1-C6In some embodiments of the alk-O-heteroaryl, the heteroaryl is indolyl, indol-6-yl, indazolyl, indazol-6-yl, quinolinyl, quinolin-7-yl, aminoquinolinyl, aminohaloquinolinyl, 2-amino-3-bromoquinolin-7-yl, 2-amino-3-chloroquinolin-7-yl, 2-amino-3-fluoroquinolin-7-yl, 2- ((cyclopropylmethyl) amino) quinolin-7-yl, 2- (methylamino) quinolin-7-yl, 2- (methoxyamino) quinolin-7-yl, or 2-aminoquinolin-7-yl. Thus, in some embodimentsIn, R1Is ((2-amino-3-bromoquinolin-7-yl) oxy) methyl (i.e., -CH)2-O- (2-amino-3-bromoquinolin-7-yl)), ((2-amino-3-chloroquinolin-7-yl) oxy) methyl, ((2-amino-3-fluoroquinolin-7-yl) oxy) methyl, ((2- ((cyclopropylmethyl) amino) quinolin-7-yl) oxy) methyl, ((2- (methylamino) quinolin-7-yl) oxy) methyl, ((2-aminoquinolin-7-yl) oxy) methyl, ((indol-6-yl) oxy) methyl, 2- (methoxyamino) quinolin-7-yl) oxy) methyl, ((quinolin-7-yl) oxy) methyl, or ((indazol-6-yl) oxy) methyl.

In which R is1is-C1-C6In other embodiments of the alk-O-heteroaryl, said heteroaryl is indolyl, indol-6-yl, indazolyl, indazol-6-yl, quinolinyl, aminoquinolinyl, aminohaloquinolinyl, 2-amino-3-bromoquinolin-7-yl, 2-amino-3-chloroquinolin-7-yl, 2-amino-3-fluoroquinolin-7-yl, 2- ((cyclopropylmethyl) amino) quinolin-7-yl, 2- (methylamino) quinolin-7-yl, or 2-aminoquinolin-7-yl. Thus, in some embodiments, R1Is ((2-amino-3-bromoquinolin-7-yl) oxy) methyl (i.e., -CH)2-O- (2-amino-3-bromoquinolin-7-yl)), ((2-amino-3-chloroquinolin-7-yl) oxy) methyl, ((2-amino-3-fluoroquinolin-7-yl) oxy) methyl, ((2- ((cyclopropylmethyl) amino) quinolin-7-yl) oxy) methyl, ((2- (methylamino) quinolin-7-yl) oxy) methyl, ((2-aminoquinolin-7-yl) oxy) methyl, ((indol-6-yl) oxy) methyl, or ((indazol-6-yl) oxy) methyl.

In some aspects, R1is-C1-C6alk-S-heteroaryl, e.g., -C1alkyl-S-heteroaryl, -C2alkyl-S-heteroaryl, -C3alkyl-S-heteroaryl, -C4alkyl-S-heteroaryl, -C5alk-S-heteroaryl and-C6alkyl-S-heteroaryl. In which R is1is-C1-C6In some embodiments of the alk-S-heteroaryl, said heteroaryl is indolyl, indol-6-yl, indazolyl, indazol-6-yl, quinolinyl, aminoquinolinyl, aminohaloquinolinyl, 2-amino-3-bromoquinolin-7-yl, 2-amino-3-chloroquinolin-7-yl, 2-amino-3-fluoroquinolin-7-yl, 2- ((cyclopropylmethyl) amino) quinolin-7-yl, 2- (methylquinolyl)Arylamino) quinolin-7-yl or 2-aminoquinolin-7-yl. Thus, in some embodiments, R1Is ((2-amino-3-bromoquinolin-7-yl) thio) methyl (i.e., -CH)2-S- (2-amino-3-bromoquinolin-7-yl)), ((2-amino-3-chloroquinolin-7-yl) thio) methyl, ((2-amino-3-fluoroquinolin-7-yl) thio) methyl, ((2- ((cyclopropylmethyl) amino) quinolin-7-yl) thio) methyl, ((2- (methylamino) quinolin-7-yl) thio) methyl, ((2-aminoquinolin-7-yl) thio) methyl, ((indol-6-yl) thio) methyl, or ((indazol-6-yl) thio) methyl. In which R is1is-C1-C6In some embodiments of the alk-S-heteroaryl, the heteroaryl is 3-methylimidazo [1,2-a ]]Pyridin-7-yl, and R1Is ((3-methylimidazo [1, 2-a))]Pyridin-7-yl) thio) methyl.

In some aspects, R1is-C1-C6alkyl-NH-heteroaryl, e.g., -C1alkyl-NH-heteroaryl, -C2alkyl-NH-heteroaryl, -C3alkyl-NH-heteroaryl, -C4alkyl-NH-heteroaryl, -C5alkyl-NH-heteroaryl and-C6alkyl-NH-heteroaryl. In which R is1is-C1-C6In some embodiments of the alk-NH-heteroaryl, the heteroaryl is indolyl, indol-6-yl, indazolyl, indazol-6-yl, quinolinyl, aminoquinolinyl, aminohaloquinolinyl, 2-amino-3-bromoquinolin-7-yl, 2-amino-3-chloroquinolin-7-yl, 2-amino-3-fluoroquinolin-7-yl, 2- ((cyclopropylmethyl) amino) quinolin-7-yl, 2- (methylamino) quinolin-7-yl, or 2-aminoquinolin-7-yl. Thus, in some embodiments, R1Is ((2-amino-3-bromoquinolin-7-yl) amino) methyl (i.e., -CH)2-NH- (2-amino-3-bromoquinolin-7-yl)), ((2-amino-3-chloroquinolin-7-yl) amino) methyl, ((2-amino-3-fluoroquinolin-7-yl) amino) methyl, ((2- ((cyclopropylmethyl) amino) quinolin-7-yl) amino) methyl, ((2- (methylamino) quinolin-7-yl) amino) methyl, ((2-aminoquinolin-7-yl) amino) methyl, ((indol-6-yl) amino) methyl, or ((indazol-6-yl) amino) methyl. In which R is1is-C1-C6In some embodiments of the alk-NH-heteroaryl, the heteroaryl is 3-methylimidazo [1,2-a ]]Pyridin-7-yl.Thus, in some embodiments, R1Is ((3-methylimidazo [1, 2-a))]Pyridin-7-yl) amino) methyl.

In some aspects, R1is-C (O) -NH-aryl. In which R is1In some embodiments of-c (o) -NH-aryl, said-aryl is-4-chlorophenyl, -3, 4-dichlorophenyl, -3, 4-difluorophenyl, -3-fluoro-4-chlorophenyl, 3-methyl-4-chlorophenyl, 3-fluoro-4-trifluoromethylphenyl or-3-chloro-4-fluorophenyl, -phenyl, -3- (aminomethyl) phenyl, 3- (urea) phenyl, 3-methyl-4-chlorophenyl, 3-fluoro-4-chlorophenyl, -3-fluoro-4-trifluoromethylphenyl, difluorophenyl, chlorophenyl, 4-chlorophenyl, dichlorophenyl, 3, 4-dichlorophenyl, bromophenyl, iodophenyl, chlorophenyl or benzo [ d ]][1,3]IIAnd (3) azole. In which R is1In some embodiments of-c (o) -NH-aryl, the-aryl is-4-chloro-2- (hydroxymethyl) phenyl, -4-chloro-2- (aminomethyl) phenyl, -4-chloro-2- ((methylamino) methyl) phenyl, -4-trifluoromethylphenyl, 4-fluoro-3-trifluoromethylphenyl, -4-isopropylphenyl, or-4- (trifluoromethoxy) phenyl.

In some aspects, R1is-C1-C6alkyl-S (O) aryl, e.g., -C1alkyl-S (O) aryl, -C2alkyl-S (O) aryl, -C3alkyl-S (O) aryl, -C4alkyl-S (O) aryl, -C5alkyl-S (O) aryl and-C6alkyl-S (O) aryl, wherein aryl is phenyl, naphthyl, fluorophenyl, difluorophenyl, fluoronaphthyl, chlorophenyl, bromophenyl, iodophenyl, methylphenyl, and the like.

In some aspects, R1is-C1-C6alkane-S (O)2Aryl radicals, e.g. C1alkane-S (O)2Aryl radical, -C2alkane-S (O)2Aryl radical, -C3alkane-S (O)2Aryl radical, -C4alkane-S (O)2Aryl radical, -C5alkane-S (O)2Aryl and-C6alkane-S (O)2Aryl, wherein aryl is phenyl, naphthyl, fluorophenyl, difluorophenyl, fluoronaphthyl, chlorophenyl, bromophenyl, iodophenyl, methylPhenyl, and the like.

In some aspects, R1is-C1-C6alkyl-S (O) heteroaryl, e.g., -C1alkyl-S (O) heteroaryl, -C2alkyl-S (O) heteroaryl, -C3alkyl-S (O) heteroaryl, -C4alkyl-S (O) heteroaryl, -C5alkyl-S (O) heteroaryl and-C6alkyl-S (O) heteroaryl, wherein heteroaryl is indolyl, indol-6-yl, indazolyl, indazol-6-yl, quinolinyl, aminoquinolinyl, aminohaloquinolinyl, 2-amino-3-bromoquinolin-7-yl, 2-amino-3-chloroquinolin-7-yl, 2-amino-3-fluoroquinolin-7-yl, 2- ((cyclopropylmethyl) amino) quinolin-7-yl, 2- (methylamino) quinolin-7-yl, or 2-aminoquinolin-7-yl.

In some aspects, R1is-C1-C6alkane-S (O)2Heteroaryl, e.g., -C1alkane-S (O)2Heteroaryl, -C2alkane-S (O)2Heteroaryl, -C3alkane-S (O)2Heteroaryl, -C4alkane-S (O)2Heteroaryl, -C5alkane-S (O)2Heteroaryl and-C6alkane-S (O)2Heteroaryl, wherein heteroaryl is indolyl, indol-6-yl, indazolyl, indazol-6-yl, quinolinyl, aminoquinolinyl, aminohaloquinolinyl, 2-amino-3-bromoquinolin-7-yl, 2-amino-3-chloroquinolin-7-yl, 2-amino-3-fluoroquinolin-7-yl, 2- ((cyclopropylmethyl) amino) quinolin-7-yl, 2- (methylamino) quinolin-7-yl, or 2-aminoquinolin-7-yl.

In the compounds of the present disclosure, R2is-C1-C6Alkyl, -C1-C6Haloalkyl, -C2-C6Alkenyl or-C2-C6Alkynyl.

In some embodiments, R2is-C1-C6Alkyl, -C2-C6Alkenyl or-C2-C6Alkynyl.

In some aspects, R2is-C1-C6Alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and the like. In some embodiments, R2Is methyl.

In other aspects, R2is-C1-C6Haloalkyl radicals, e.g., -CF3or-CHF2. In some embodiments, R2is-CF3。

In some aspects, R2is-C2-C6Alkenyl, preferably being-C2-C4Alkenyl groups such as vinyl, allyl, and the like.

In other aspects, R2is-C2-C6Alkynyl, preferably being-C2-C4Alkynyl groups such as ethynyl, propargyl and the like.

In the compounds of the present disclosure, R3Is H, halogen, -C1-C6Alkyl or NH2. Thus, in some embodiments, R3Is H. In other embodiments, R3Is halogen, for example F, Cl, Br or I. In other embodiments, R3is-C1-C6Alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and the like. Thus, in some embodiments, R3Is methyl (Me). In other embodiments, R3Is NH2. In a most preferred embodiment, R3Is H.

In the compounds of the present disclosure, R4Is H, halogen, -C1-C6Alkyl, -C1-C6alkyl-O-C1-C6Alkyl, -NR6R6'、-NHCONR6R6'、NHC(S)NR6R6'、-NH-O-R6or-NH-NR6R6'. In some embodiments, R4Is halogen, -C1-C6Alkyl, -C1-C6alkyl-O-C1-C6Alkyl, -NR6R6'、-NHCONR6R6'、NHC(S)NR6R6'、-NH-O-R6or-NH-NR6R6'。

In some aspects, R4Is H.

In some aspects, R4Is halogen, such as chlorine, fluorine, bromine or iodine. In some embodiments, R4Is chlorine.

In some aspects, R4is-C1-C6Alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and the like. In some embodiments, R4Is methyl.

In some aspects, R4is-C1-C6alkyl-O-C1-C6Alkyl radicals, e.g., -C1-C6alkyl-O-C1-C6Alkyl, -C1-C5alkyl-O-C1-C6Alkyl, -C1-C4alkyl-O-C1-C6Alkyl, -C1-C3alkyl-O-C1-C6Alkyl, -C1-C2alkyl-O-C1-C6Alkyl, -C1alkyl-O-C1-C6Alkyl, -C1-C6alkyl-O-C1-C5Alkyl, -C1-C6alkyl-O-C1-C4Alkyl, -C1-C6alkyl-O-C1-C3Alkyl, -C1-C6alkyl-O-C1-C2Alkyl or-C1-C6alkyl-O-C1An alkyl group. In some embodiments, R4is-CH2CH2-O-CH3。

In some aspects, R4is-NR6R6'. Thus, in which R6And R6'In some embodiments where both are H, R4is-NH2. In which R is6And R6'In some embodiments where both are methyl, R4is-N (CH)3)2. In which R is6Is H and R6'In an embodiment where R is methyl4is-NH (CH)3)。

In some aspects, R4is-NHCONR6R6'. Thus, in which R6And R6'In some embodiments where both are H, R4is-NHCONH2. In which R is6And R6'In embodiments where both are methyl, R4is-NHCON (CH)3)2. In which R is6Is H and R6'In an embodiment where R is methyl4is-NHCONHCH3。

In some aspects, R4Is NHC (S) NR6R6'. Thus, in which R6And R6'In some embodiments where both are H, R4is-NHC (S) NH2. In which R is6And R6'In embodiments where both are methyl, R4is-NHC (S) N (CH)3)2. In which R is6Is H and R6'In an embodiment where R is methyl4is-NHC (S) NHCH3。

In some aspects, R4is-NH-O-R6. In which R is6Is C1-C6In some embodiments of alkyl groups, such as methyl, R4is-NH-OCH3. In which R is6In some embodiments that are ethyl, R4is-NH-OCH2CH3. In which R is6In some embodiments of H, R4is-NH-OH.

In some aspects, R4is-NH-NR6R6'. In which R is6And R6'In some embodiments where both are H, R4is-NH2. In which R is6And R6'Are all C1-C6In embodiments of alkyl groups such as methyl, R4is-NH-N (CH)3)2. In which R is6Is H and R6'Is C1-C6In embodiments of alkyl groups such as methyl, R4is-NH-NHCH3。

It is obvious that when R is4is-NH-O-R6or-NH-NR6R6'When present, the compounds of formula I may exist as tautomers having an (E) -or (Z) -geometry at the exocyclic carbon-nitrogen double bond. The compounds of formula I described and claimed herein are intended to encompass all such tautomers and geometric isomers. For a particular tautomer or tautomerThe description of which isomer is not intended to be limiting. For example, when R is4is-NH-O-R6When the compound of formula I is represented by any one of the following equivalent structures:

similarly, when R is4is-NH-NR6R6'When the compound of formula I is represented by any one of the following equivalent structures:

in the compounds of the present disclosure, R5Is H, halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -C2-C6Alkenyl, -C2-C6Alkynyl or-C1-C6alkyl-OH. In some aspects, R5Is H.

In other aspects, R5Is halogen, for example, fluorine, chlorine, bromine or iodine. In some embodiments, R5Is fluorine.

In some aspects, R5is-C1-C6Alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and the like. In other aspects, R5is-C2-C6Alkenyl, preferably being-C2-C4Alkenyl groups such as vinyl, allyl, and the like. In other aspects, R5is-C2-C6Alkynyl, preferably being-C2-C4Alkynyl groups such as ethynyl, propargyl and the like.

In other aspects, R5is-C1-C6Haloalkyl radicals, e.g., -CF3or-CHF2. In some embodiments, R5is-CF3。

In some aspects, R5is-C1-C6alkyl-OH, e.g., -C1-C6An alkyl-OH,-C1-C5alkyl-OH, -C1-C4alkyl-OH, -C1-C3alkyl-OH, -C1-C2alkyl-OH or-C1alkyl-OH. In some embodiments, R5is-CH2OH。

In the compounds of the present disclosure, R6And R6'Each independently is H, C1-C6Alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, etc.), or-C1-C6alkane-OC1-C6Alkyl (e.g. C)1-C6alkane-OC1-C6Alkyl radical, C1-C5alkane-OC1-C6Alkyl radical, C1-C4alkane-OC1-C6Alkyl radical, C1-C3alkane-OC1-C6Alkyl radical, C1-C2alkane-OC1-C6Alkyl radical, C1alkane-OC1-C6Alkyl radical, C1-C6alkane-OC1-C5Alkyl radical, C1-C6alkane-OC1-C4Alkyl radical, C1-C6alkane-OC1-C3Alkyl radical, C1-C6alkane-OC1-C2Alkyl or C1-C6alkane-OC1Alkyl groups).

In some embodiments, R6Is H or C1-C6An alkyl group. In some embodiments, R6'Is H or C1-C6An alkyl group.

In some embodiments, R6And R6'Each is H.

In other embodiments, R6And R6'Each independently is C1-C6An alkyl group. Thus, in some embodiments, R6Is methyl and R6'Is methyl.

In some aspects, R6Is C1-C6Alkyl and R6'Is H. Thus, in some embodiments, R6Is methyl and R6'Is H.

In other aspects, R6And R6'Each independently is-C1-C6alkane-OC1-C6An alkyl group.

In other aspects, R6is-C1-C6alkane-OC1-C6Alkyl and R6'Is H.

In some embodiments of the disclosure, R6And R6'Together with the atom to which they are attached form C2-C6Heterocycloalkyl rings, such as azepanyl, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, oxazepanyl, piperazinyl, and the like. In some preferred embodiments, R6And R6'Together with the atom to which they are attached form C3-C6Heterocycloalkyl rings, such as azepanyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, oxazepanyl, piperazinyl, and the like.

Preferred embodiments are those of the following: wherein R is1is-CH2-O-CH3、-CH2-S-CH3、-CH2-S-CH2CH2CH(NH2)-CO2H. -CH (OH) -4-chlorophenyl, -CH (OH) -3, 4-dichlorophenyl, -CH (OH) -3, 4-difluorophenyl, -CH (OH) -3-fluoro-4-chlorophenyl, -CH (OH) -3-chloro-4-fluorophenyl, -CH (OH) -3-methyl-4-chlorophenyl, -CH (OH) -3-fluoro-4-trifluoromethylphenyl, -CH (F) -4-chlorophenyl, -CH (F) -3, 4-dichlorophenyl, -CH (F) -3, 4-difluorophenyl, -CH (F) -3-fluoro-4-chlorophenyl, -CH (F) -3-chloro-4-fluorophenyl, and, -CH (F) -3-methyl-4-chlorophenyl, -CH (F) -3-fluoro-4-trifluoromethylphenyl, -C (Me) (OH) -4-chlorophenyl, -C (Me) (OH) -3, 4-dichlorophenyl, -C (Me) (OH) -3, 4-difluorophenyl, -C (Me) (OH) -3-fluoro-4-chlorophenyl, -C (Me) (OH) -3-chloro-4-fluorophenyl, -C (Me) (OH) -3-methyl-4-chlorophenyl, -C (Me) (OH) -3-fluoro-4-trifluoromethylphenyl, -CH (OH)2-O-phenyl, -CH2-O-difluorophenyl, -CH2-O-3, 4-difluorophenyl, -CH2-O-4-chlorophenyl, -CH2-O-3-chloro-4-fluorophenyl, -CH2-O-4-chloro-3-fluorophenyl, -CH2-O-dichlorophenyl, -CH2-O-3, 4-dichlorophenyl, -CH2-O-3-methyl-4-chlorophenyl, -CH2-O-3-fluoro-4-trifluoromethylphenyl, -CH2-O-3- (aminomethyl) phenyl, -CH2-O-3- (urea) phenyl, ((2-amino-3-bromoquinolin-7-yl) oxy) methyl (i.e., -CH)2-O- (2-amino-3-bromoquinolin-7-yl)), ((2-amino-3-chloroquinolin-7-yl) oxy) methyl, ((2-amino-3-fluoroquinolin-7-yl) oxy) methyl, ((2- (methylamino) quinolin-7-yl) oxy) methyl, ((2-aminoquinolin-7-yl) oxy) methyl, ((indol-6-yl) oxy) methyl, ((indazol-6-yl) oxy) methyl, 2- (2-aminoquinolin-7-yl) ethyl, ((2-aminoquinolin-7-yl) thio) methyl, and ((2-aminoquinolin-7-yl) amino) methyl. Other preferred embodiments are those of the following: wherein R is1Is ((3-methylimidazo [1, 2-a))]Pyridin-7-yl) oxy) methyl (i.e., -CH2-O-3-methylimidazo [1,2-a]Pyridin-7-yl, -CH (OH) -4-isopropylphenyl, -CH (OH) -4-trifluoromethylphenyl, -CH (OH) -4- (trifluoromethoxy) phenyl, -CH (OH) -4-fluoro-3-trifluoromethylphenyl, -CH2- (4-chloro-2- (hydroxymethyl) phenyl), -CH2- (4-chloro-2- (aminomethyl) phenyl) or-CH2- (4-chloro-2- ((methylamino) methyl) phenyl).

Preferred embodiments are those wherein R is2Those that are methyl.

In some aspects, the disclosure relates to compounds of formula I-A

Wherein R is1is-C0-C6alkyl-C1-C6Alkyl, -C0-C6alkyl-C1-C6Haloalkyl, -C1-C6alkyl-O-C1-C6Alkyl, -C1-C6alkane-S-C1-C6Alkyl, -C1-C6alkane-S-C1-C6alkane-CO2H、-C1-C6Alkyl-Aryl radical, -C1-C6alkyl-O-aryl, -C0-C6Alkyl-heteroaryl, -C1-C6alkyl-O-heteroaryl, -C1-C6alk-S-heteroaryl or-C1-C6alkyl-NH-heteroaryl; r2Is methyl, trifluoromethyl, ethynyl or ethenyl; r4Is halogen, C1-C6Alkyl, -NHC (O) NR6R6'、-NR6R6'、-NH-O-R6or-NH-NR6R6'；R5Is H or F; and R is6And R6'Each independently is H or-C1-C6An alkyl group.

In some embodiments, the compounds of formula I-a are those of: wherein R is1is-C0-C6alkyl-C1-C6Alkyl, -C0-C6alkyl-C1-C6Haloalkyl, -C1-C6alkyl-O-C1-C6Alkyl, -C1-C6alkane-S-C1-C6Alkyl, -C1-C6alkane-S-C1-C6alkane-CO2H、-C1-C6Alkyl-aryl, -C1-C6alkyl-O-aryl, -C0-C6Alkyl-heteroaryl, -C1-C6alkyl-O-heteroaryl, -C1-C6alk-S-heteroaryl or-C1-C6alkyl-NH-heteroaryl; r2Is methyl, ethynyl or vinyl; r4Is halogen, C1-C6Alkyl, -NHC (O) NR6R6'、-NR6R6'、-NH-O-R6or-NH-NR6R6'；R5Is H or F; and R is6And R6'Each independently is H or-C1-C6An alkyl group.

In some embodiments, the compounds of formula I-a are those of: wherein R is1is-C1-C6Alkyl-aryl or-C1-C6alkyl-O-heteroaryl; -R2Is methyl, ethynyl or vinyl; r4Is halogen, C1-C6Alkyl, -NHC (O) NR6R6'、-NR6R6'、-NH-O-R6or-NH-NR6R6'；R5Is H or F; and R is6And R6'Each independently is H or-C1-C6An alkyl group.

In some embodiments, the compounds of formula I-a are those of: wherein R is1is-C1-C6alkyl-O-heteroaryl; r2Is methyl, ethynyl or vinyl; r4Is halogen, C1-C6Alkyl, -NHC (O) NR6R6'、-NR6R6'、-NH-O-R6or-NH-NR6R6'；R5Is H or F; and R is6And R6'Each independently is H or-C1-C6An alkyl group.

In some embodiments, the compounds of formula I-a are those of: wherein R is1is-C1-C6An alkyl-aryl group; r2Is methyl, ethynyl or vinyl; r4Is halogen, C1-C6Alkyl, -NHC (O) NR6R6'、-NR6R6'、-NH-O-R6or-NH-NR6R6'；R5Is H or F; and R is6And R6'Each independently is H or-C1-C6An alkyl group.

In some embodiments, the compounds of formula I-a are those of: wherein R is1is-C1-C6An alkyl-aryl group, wherein the aryl group is a monocyclic or bicyclic aromatic hydrocarbon ring structure having 6 or 10 carbon atoms in the ring, wherein one or more carbon atoms in the ring are optionally replaced by a halogen atom, -C1-C3Alkyl radical, amino-substituted-C1-C3Alkyl radical, C1-C3Haloalkyl groups, amino groups (i.e. -NH)2) Or substituted with a substituted amino group; -R2Is methyl, ethynyl or vinyl; r4Is halogen, C1-C6Alkyl, -NHC (O) NR6R6'、-NR6R6'、-NH-O-R6or-NH-NR6R6'；R5Is H or F; and R is6And R6'Each independently is H or-C1-C6An alkyl group.

In some aspects, the disclosure relates to compounds of formula I-B

Wherein R is1is-C0-C6Alkyl-heteroaryl, -C1-C6alkyl-O-heteroaryl, -C1-C6alk-S-heteroaryl or-C1-C6alkyl-NH-heteroaryl; r4is-NR6R6'、-NH-O-R6or-NH-NR6R6'；R5Is H or F; and R is6And R6'Each independently is H or-C1-C6An alkyl group. In some preferred embodiments, the compounds of formula I-B are those of the following: wherein R is1is-C1-C6alkyl-O-heteroaryl; r4is-NR6R6'、-NH-O-R6or-NH-NR6R6'；R5Is H or F; and R is6And R6'Each independently is H or-C1-C6An alkyl group.

In some preferred embodiments, the compounds of formula I-B are those of the following: wherein R is1Is ((2-amino-3-bromoquinolin-7-yl) oxy) methyl (i.e., -CH)2-O- (2-amino-3-bromoquinolin-7-yl)), ((2-amino-3-chloroquinolin-7-yl) oxy) methyl, ((2-amino-3-fluoroquinolin-7-yl) oxy) methyl, ((2- (methylamino) quinolin-7-yl) oxy) methyl, ((2-aminoquinolin-7-yl) oxy) methyl, ((indol-6-yl) oxy) methyl, ((indazol-6-yl) oxy) methyl, 2- (2-aminoquinolin-7-yl) ethyl, ((2-aminoquinolin-7-yl) thio) methyl, or ((2-aminoquinolin-7-yl) amino) methyl; r4is-NH2、-NH-O-CH3or-NH-NHCH3(ii) a And R is5Is H or F.

In some preferred embodiments, the compounds of formula I-B are those of the following: wherein R is1Is ((quinoline)-7-yl) oxy) methyl, ((2-amino-3-bromoquinolin-7-yl) oxy) methyl (i.e., -CH2-O- (2-amino-3-bromoquinolin-7-yl)), ((2-amino-3-chloroquinolin-7-yl) oxy) methyl, ((2-amino-3-fluoroquinolin-7-yl) oxy) methyl, ((2- (methylamino) quinolin-7-yl) oxy) methyl, ((2- (methoxyamino) quinolin-7-yl) oxy) methyl, ((2-aminoquinolin-7-yl) oxy) methyl, ((indol-6-yl) oxy) methyl, ((indazol-6-yl) oxy) methyl, 2- (2-aminoquinolin-7-yl) ethyl, ((2-aminoquinolin-7-yl) thio) methyl, ((3-methylimidazo [1, 2-a))]Pyridin-7-yl) oxy) methyl or ((2-aminoquinolin-7-yl) amino) methyl; r4is-NH2、-NH-OH、-NH-O-CH3or-NH-NHCH3(ii) a And R is5Is H or F.

In some preferred embodiments, the compounds of formula I-B are those of the following: wherein R is1Is ((quinolin-7-yl) oxy) methyl, ((2-amino-3-bromoquinolin-7-yl) oxy) methyl (i.e., -CH)2-O- (2-amino-3-bromoquinolin-7-yl)), ((2-amino-3-chloroquinolin-7-yl) oxy) methyl, ((2-amino-3-fluoroquinolin-7-yl) oxy) methyl, ((2- (methylamino) quinolin-7-yl) oxy) methyl, ((2- (methoxyamino) quinolin-7-yl) oxy) methyl, ((2-aminoquinolin-7-yl) oxy) methyl, ((indol-6-yl) oxy) methyl, ((indazol-6-yl) oxy) methyl, 2- (2-aminoquinolin-7-yl) ethyl, ((2-aminoquinolin-7-yl) thio) methyl, ((3-methylimidazo [1, 2-a))]Pyridin-7-yl) oxy) methyl or ((2-aminoquinolin-7-yl) amino) methyl; r4is-NR6R6'、-NH-O-R6or-NH-NR6R6'；R5Is H or F; and R is6And R6'Each independently is H or-C1-C6An alkyl group.

In some aspects, the disclosure relates to compounds of formula I-B, wherein R1is-C1-C6Alkyl-aryl radical, R4is-NR6R6'、-NH-O-R6or-NH-NR6R6'；R5Is H or F; and R is6And R6'Each independently is H or-C1-C6An alkyl group.

In some casesIn embodiments, the compounds of formula I-B are those of: wherein R is1is-C1-C6An alkyl-aryl group, wherein the aryl group is a monocyclic or bicyclic aromatic hydrocarbon ring structure having 6 or 10 carbon atoms in the ring, wherein one or more carbon atoms in the ring are optionally replaced by a halogen atom, -C1-C3Alkyl radical, amino-substituted-C1-C3Alkyl radical, C1-C3Haloalkyl groups, amino groups (i.e. -NH)2) Or substituted with a substituted amino group; r4is-NR6R6'、-NH-O-R6or-NH-NR6R6'；R5Is H or F; and R is6And R6'Each independently is H or-C1-C6An alkyl group.

In some preferred embodiments, the compounds of formula I-B are those of the following: wherein R is1is-C1Alkyl-aryl, and R4is-NR6R6'、-NH-O-R6or-NH-NR6R6'；R5Is H or F; and R is6And R6'Each independently is H or-C1-C6An alkyl group.

In other preferred embodiments, the compounds of formula I-B are those of the following: wherein R is1is-C1Alkyl-aryl radical, R4is-NH2、-NH-O-CH3or-NH-NHCH3(ii) a And R is5Is H or F.

In other preferred embodiments, the compounds of formula I-B are those of the following: wherein R is1is-CH (OH) -4-chlorophenyl, -CH (OH) -4-chloro-2- (hydroxymethyl) phenyl, -CH (OH) -3, 4-dichlorophenyl, -CH (OH) -3, 4-difluorophenyl, -CH (OH) -3-fluoro-4-chlorophenyl, -CH (OH) -3-methyl-4-chlorophenyl, -CH (OH) -3-fluoro-4-trifluoromethylphenyl, -CH (OH) -4- (trifluoromethoxy) phenyl, -CH (OH) -4-fluoro-3-trifluoromethylphenyl, -CH (OH) -benzo [ d ].][1,3]IIOxazole, -ch (oh) -4-isopropylphenyl or-ch (oh) -3-chloro-4-fluorophenyl; r4is-NR6R6'、-NH-O-R6or-NH-NR6R6'；R5Is H or F; and R is6And R6'Each independently is H or-C1-C6An alkyl group.

In other preferred embodiments, the compounds of formula I-B are those of the following: wherein R is1is-CH (OH) -4-chlorophenyl, -CH (OH) -4-chloro-2- (hydroxymethyl) phenyl, -CH (OH) -3, 4-dichlorophenyl, -CH (OH) -3, 4-difluorophenyl, -CH (OH) -3-fluoro-4-chlorophenyl, -CH (OH) -3-methyl-4-chlorophenyl, -CH (OH) -3-fluoro-4-trifluoromethylphenyl, -CH (OH) -4- (trifluoromethoxy) phenyl, -CH (OH) -4-fluoro-3-trifluoromethylphenyl, -CH (OH) -benzo [ d ].][1,3]IIOxazole, -ch (oh) -4-isopropylphenyl or-ch (oh) -3-chloro-4-fluorophenyl; r4is-NH2、-NH-O-CH3or-NH-NHCH3(ii) a And R is5Is H or F.

In other preferred embodiments, the compounds of formula I-B are those of the following: wherein R is1is-CH2-4-chloro-2- (hydroxymethyl) phenyl, -CH2-4-chloro-2- (aminomethyl) phenyl, -CH2- (4-chloro-2- (methylamino) methyl) phenyl, -CH2-3, 4-dichlorophenyl, -CH2-benzo [ d ]][1,3]IIAzole; r4Is H, -NR6R6'、-NH-O-R6or-NH-NR6R6'；R5Is H or F; and R is6And R6'Each independently is H or-C1-C6An alkyl group.

In other preferred embodiments, the compounds of formula I-B are those of the following: wherein R is1is-CH2-4-chloro-2- (hydroxymethyl) phenyl, -CH2-4-chloro-2- (aminomethyl) phenyl, -CH2- (4-chloro-2- (methylamino) methyl) phenyl, -CH2-3, 4-dichlorophenyl, -CH2-benzo [ d ]][1,3]IIAzole; r4Is H, -NH2、-NH-OH、-NH-O-CH3or-NH-NHCH3(ii) a And R is5Is H or F.

In other preferred embodiments, the compounds of formula I-B are those of the following: wherein R is1is-CH (OH) -4-chlorophenyl, -CH (OH) -3, 4-dichlorophenyl, -CH (OH) -3, 4-difluorophenyl, -CH (OH) -3-fluoro-4-chlorophenyl, -CH (OH) -3-chloro-4-fluorophenyl, -CH (OH) -3-methyl-4-chlorophenyl, -CH (OH) -3-fluoro-4-trifluoromethylphenyl, -C (Me) (OH) -4-chlorophenyl, -C (Me) (OH) -3, 4-dichlorophenyl, -C (Me) (OH) -3, 4-difluorophenyl, -C (Me) (OH) -3-fluoro-4-chlorophenyl, -c (me) (oh) -3-chloro-4-fluorophenyl, -c (me) (oh) -3-methyl-4-chlorophenyl, or-c (me) (oh) -3-fluoro-4-trifluoromethylphenyl; r4is-NR6R6'、-NH-O-R6or-NH-NR6R6'；R5Is H or F; and R is6And R6'Each independently is H or-C1-C6An alkyl group.

In other preferred embodiments, the compounds of formula I-B are those of the following: wherein R is1is-CH (OH) -4-chlorophenyl, -CH (OH) -3, 4-dichlorophenyl, -CH (OH) -3, 4-difluorophenyl, -CH (OH) -3-fluoro-4-chlorophenyl, -CH (OH) -3-chloro-4-fluorophenyl, -CH (OH) -3-methyl-4-chlorophenyl, -CH (OH) -3-fluoro-4-trifluoromethylphenyl, -C (Me) (OH) -4-chlorophenyl, -C (Me) (OH) -3, 4-dichlorophenyl, -C (Me) (OH) -3, 4-difluorophenyl, -C (Me) (OH) -3-fluoro-4-chlorophenyl, -c (me) (oh) -3-chloro-4-fluorophenyl, -c (me) (oh) -3-methyl-4-chlorophenyl, or-c (me) (oh) -3-fluoro-4-trifluoromethylphenyl; r4is-NH2、-NH-O-CH3or-NH-NHCH3(ii) a And R is5Is H or F.

In other preferred embodiments, the compounds of formula I-B are those of the following: wherein R is1is-CH (OH) -4-chlorophenyl, -CH (OH) -3, 4-dichlorophenyl or-CH (OH) -3-methyl-4-chlorophenyl; r4is-NH2、-NH-O-CH3or-NH-NHCH3(ii) a And R is5Is H or F. In other preferred aspectsIn embodiments of (a), the compounds of formula I-B are those of: wherein R is1is-CH (OH) -4-chlorophenyl, -CH (OH) -3, 4-dichlorophenyl or-CH (OH) -3-methyl-4-chlorophenyl; r4is-NH2、-NH-OH、-NH-O-CH3or-NH-NHCH3(ii) a And R is5Is H or F.

In some aspects, the disclosure relates to compounds of formula I-B, wherein R1is-C1-C6Alkyl-aryl radical, R4is-C1-C6An alkyl group; and R is5Is H or F. Some preferred embodiments are those of: wherein R is1is-C1Alkyl-aryl, and R4is-CH3(ii) a And R is5Is H or F.

In some aspects, the disclosure relates to compounds of formula I-B, wherein R1is-C1-C6An alkyl-aryl group, wherein the aryl group is a monocyclic or bicyclic aromatic hydrocarbon ring structure having 6 or 10 carbon atoms in the ring, wherein one or more carbon atoms in the ring are optionally replaced by a halogen atom, -C1-C3Alkyl radical, amino-substituted-C1-C3Alkyl radical, C1-C3Haloalkyl groups, amino groups (i.e. -NH)2) Or substituted with a substituted amino group; r4is-C1-C6An alkyl group; and R is5Is H or F.

In preferred embodiments, the compounds of formula I-B are those of the following: wherein R is1is-CH (OH) -4-chlorophenyl, -CH (OH) -4-chloro-2- (hydroxymethyl) phenyl, -CH (OH) -3, 4-dichlorophenyl, -CH (OH) -3, 4-difluorophenyl, -CH (OH) -3-fluoro-4-chlorophenyl, -CH (OH) -3-methyl-4-chlorophenyl, -CH (OH) -3-fluoro-4-trifluoromethylphenyl, -CH (OH) -4- (trifluoromethoxy) phenyl, -CH (OH) -4-fluoro-3-trifluoromethylphenyl, -CH (OH) -benzo [ d ].][1,3]IIOxazole, -ch (oh) -4-isopropylphenyl or-ch (oh) -3-chloro-4-fluorophenyl; r4is-CH3(ii) a And R is5Is H.

In other placesIn preferred embodiments, the compounds of formula I-B are those of the following: wherein R is1is-CH (OH) -4-chlorophenyl, -CH (OH) -3, 4-dichlorophenyl or-CH (OH) -3-methyl-4-chlorophenyl; r4is-CH3(ii) a And R is5Is H or F.

In some preferred embodiments, the compounds of formula I-B are those of the following: wherein R is1is-CH (OH) -4-chlorophenyl, -CH (OH) -3, 4-dichlorophenyl, -CH (OH) -3, 4-difluorophenyl, -CH (OH) -3-fluoro-4-chlorophenyl, -CH (OH) -3-chloro-4-fluorophenyl, -CH (OH) -3-methyl-4-chlorophenyl, -CH (OH) -3-fluoro-4-trifluoromethylphenyl, -C (Me) (OH) -4-chlorophenyl, -C (Me) (OH) -3, 4-dichlorophenyl, -C (Me) (OH) -3, 4-difluorophenyl, -C (Me) (OH) -3-fluoro-4-chlorophenyl, -c (me) (oh) -3-chloro-4-fluorophenyl, -c (me) (oh) -3-methyl-4-chlorophenyl, or-c (me) (oh) -3-fluoro-4-trifluoromethylphenyl; r4is-CH3(ii) a And R is5Is H.

In other preferred embodiments, the compounds of formula I-B are those of the following: wherein R is1is-CH (OH) -4-chlorophenyl, -CH (OH) -3, 4-dichlorophenyl, -CH (OH) -3-methyl-4-chlorophenyl, -CH (OH) -4-trifluoromethylphenyl, -CH (OH) -4-fluoro-3-trifluoromethylphenyl, -CH (OH) -3-fluoro-4-trifluoromethylphenyl, -CH (OH) -4-chloro-2- (hydroxymethyl) phenyl; r4is-CH3(ii) a And R is5Is H.

In some preferred embodiments, the compounds of formula I-B are those of the following: wherein R is1is-C1-C6alkyl-O-aryl, and R4is-NR6R6'、-NH-O-R6or-NH-NR6R6'；R5Is H or F; and R is6And R6'Each independently is H or-C1-C6An alkyl group.

In other preferred embodiments, the compounds of formula I-B are those of the following: wherein R is1is-C1-C6alkyl-O-aryl, R4is-NH2、-NH-O-CH3or-NH-NHCH3(ii) a And R is5Is H or F.

In other preferred embodiments, the compounds of formula I-BAre those of: wherein R is1is-CH2-O-3- (aminomethyl) phenyl; r4is-NH2、-NH-O-CH3or-NH-NHCH3(ii) a And R is5Is H or F.

In some aspects, the disclosure relates to compounds of formula I-B, wherein R1is-C1-C6alkane-S-C1-C6Alkyl radical, R4is-NR6R6'、-NH-O-R6or-NH-NR6R6'(ii) a And R is6And R6'Each independently is H or-C1-C6An alkyl group.

In some aspects, the disclosure relates to compounds of formula I-B, wherein R1is-C1-C6alkyl-O-C1-C6Alkyl radical, R4is-NR6R6'、-NH-O-R6or-NH-NR6R6'(ii) a And R is6And R6'Each independently is H or-C1-C6An alkyl group.

In some preferred embodiments, the present disclosure relates to compounds of formula I-C

Wherein R is4is-NR6R6'、-NH-O-R6or-NH-NR6R6'；R5Is H or F; and R is6And R6'Each independently is H or-C1-C6An alkyl group. Other preferred embodiments are compounds of formula I-C, wherein R4is-NR6R6'、-NH-O-R6or-NH-NR6R6'；R5Is H or F; r6And R6'Each independently is H or-C1-C6Alkyl, and heteroaryl is quinolinyl, substituted quinolinyl, indolyl, substituted indolyl, indazolyl, or substituted indazolyl.

Other preferred embodiments are compounds of formula I-C, wherein R4is-NH2、-NH-O-CH3or-NH-NHCH3(ii) a And R is5Is H or F.

Other preferred embodiments are compounds of formula I-C, wherein R4is-NH2、-NH-OH、-NH-O-CH3or-NH-NHCH3；R5Is H or F, R6And R6'Each independently is H or-C1-C6Alkyl, and heteroaryl is quinolinyl, substituted quinolinyl, indolyl, substituted indolyl, indazolyl, substituted indazolyl, imidazo [1,2-a ]]Pyridyl or substituted imidazo [1,2-a ]]A pyridyl group.

A further preferred embodiment are compounds of formula I-C wherein heteroaryl is (2-amino-3-bromoquinolin-7-yl), (2-amino-3-chloroquinolin-7-yl), (2-amino-3-fluoroquinolin-7-yl), (2- (methylamino) quinolin-7-yl), (2-aminoquinolin-7-yl), 2- (methoxyamino) quinolin-7-yl, (indol-6-yl), (indazol-6-yl), and R is4is-NR6R6'、-NH-O-R6or-NH-NR6R6'；R5Is H or F; and R is6And R6'Each independently is H or-C1-C6An alkyl group.

A further preferred embodiment are compounds of formula I-C wherein heteroaryl is (2-amino-3-bromoquinolin-7-yl), (2-amino-3-chloroquinolin-7-yl), (2-amino-3-fluoroquinolin-7-yl), (2- (methylamino) quinolin-7-yl), (2-aminoquinolin-7-yl), (indol-6-yl), (indazol-6-yl), and R4is-NR6R6'、-NH-O-R6or-NH-NR6R6'；R5Is H or F; and R is6And R6'Each independently is H or-C1-C6An alkyl group.

Other preferred embodiments are compounds of formula I-C wherein heteroaryl is quinolinyl, substituted quinolinyl, indolyl, substituted indolyl, indazolyl, substituted indazolyl, imidazo [1,2-a ]]Pyridyl or substituted imidazo [1,2-a ]]A pyridyl group; r4is-NR6R6'、-NH-O-R6or-NH-NR6R6'；R5Is H or F; and R is6And R6'Each independentlyIs H or-C1-C6An alkyl group.

A further preferred embodiment are compounds of the formula I-C, wherein heteroaryl is quinolin-7-yl, (2-amino-3-bromoquinolin-7-yl), (2-amino-3-chloroquinolin-7-yl), (2-amino-3-fluoroquinolin-7-yl), (2- (methylamino) quinolin-7-yl), (2-aminoquinolin-7-yl), 2- (methoxyamino) quinolin-7-yl, (indol-6-yl), (indazol-6-yl), or (3-methylimidazo [1,2-a ] -]Pyridin-7-yl); r4is-NR6R6'、-NH-O-R6or-NH-NR6R6'；R5Is H or F; and R is6And R6'Each independently is H or-C1-C6An alkyl group.

In some preferred embodiments, the present disclosure relates to compounds of formula I-D

Wherein R is4is-NR6R6'、-NH-O-R6or-NH-NR6R6'；R5Is H or F; and R is6And R6'Each independently is H or-C1-C6An alkyl group. Other preferred embodiments are compounds of formula I-D, wherein R4is-NR6R6'、-NH-O-R6or-NH-NR6R6'；R5Is H or F; r6And R6'Each independently is H or-C1-C6Alkyl, and aryl is phenyl or substituted phenyl.

Some embodiments of the compounds of formulae I-D are those of the following: wherein R is4is-NR6R6'、-NH-O-R6or-NH-NR6R6'；R5Is H or F; r6And R6'Each independently is H or-C1-C6Alkyl, and aryl is a monocyclic or bicyclic aromatic hydrocarbon ring structure having 6 or 10 carbon atoms in the ring, wherein one or more carbon atoms in the ring are optionally substituted by a halogen atom, -C1-C3Alkyl radical, amino-substituted-C1-C3Alkyl radical, C1-C3Haloalkyl groups, amino groups (i.e. -NH)2) Or substituted with a substituted amino group.

Other preferred embodiments are compounds of formula I-D, wherein R4is-NH2、-NH-O-CH3or-NH-NHCH3(ii) a And R is5Is H or F.

Other preferred embodiments are compounds of formula I-D, wherein R4is-NH2、-NH-OH、-NH-O-CH3or-NH-NHCH3(ii) a And R is5Is H or F, R6And R6'Each independently is H or-C1-C6Alkyl, and aryl is phenyl or substituted phenyl.

A further preferred embodiment are the compounds of the formulae I to D, in which aryl is-4-chlorophenyl, -3, 4-dichlorophenyl, -3, 4-difluorophenyl, -3-fluoro-4-chlorophenyl, -3-chloro-4-fluorophenyl, -3-methyl-4-chlorophenyl, -3-fluoro-4-trifluoromethylphenyl, R4is-NR6R6'、-NH-O-R6or-NH-NR6R6'；R5Is H or F; and R is6And R6'Each independently is H or-C1-C6An alkyl group.

A further preferred embodiment are compounds of the formula I-D, in which aryl is-4-chlorophenyl, -3, 4-dichlorophenyl, -3, 4-difluorophenyl, -3-fluoro-4-chlorophenyl, -3-chloro-4-fluorophenyl, -3-methyl-4-chlorophenyl, -3-fluoro-4-trifluoromethylphenyl or-4-fluoro-3-trifluoromethylphenyl, R4is-NR6R6'、-NH-O-R6or-NH-NR6R6'；R5Is H or F; and R is6And R6'Each independently is H or-C1-C6An alkyl group.

Other preferred embodiments are compounds of formula I-D wherein aryl is-4-chlorophenyl, -3, 4-dichlorophenyl, -3, 4-difluorophenyl, -3-fluoro-4-chlorophenyl, -3-chloro-4-fluorophenyl, -3-methyl-4-chlorophenyl, or-3-fluoro-4-trifluoromethylphenyl; r4is-NH2、-NH-O-CH3or-NH-NHCH3(ii) a And R is5Is H or F.

A further preferred embodiment are the compounds of the formulae I to D, in which aryl is-4-chlorophenyl, -4-chloro-2- (hydroxymethyl) phenyl, -3, 4-dichlorophenyl, -3, 4-difluorophenyl, -3-fluoro-4-chlorophenyl, -3-methyl-4-chlorophenyl, -3-fluoro-4-trifluoromethylphenyl, -4- (trifluoromethoxy) phenyl, -4-fluoro-3-trifluoromethylphenyl, -benzo [ D ] phenyl][1,3]IIOxazole, -4-isopropylphenyl or-3-chloro-4-fluorophenyl; r4is-NH2、-NH-O-CH3or-NH-NHCH3(ii) a And R is5Is H or F.

In some preferred embodiments, the present disclosure relates to compounds of formula I-E

Wherein R is4is-NR6R6'、-NH-O-R6or-NH-NR6R6'；R5Is H or F; and R is6And R6'Each independently is H or-C1-C6An alkyl group.

Other preferred embodiments are compounds of formula I-E, wherein R4is-NH2、-NHCH3、-NH-O-CH3or-NH-NHCH3(ii) a And R is5Is H or F.

In some preferred embodiments, the present disclosure relates to compounds of formula I-F

Wherein R is4is-NR6R6'、-NH-O-R6or-NH-NR6R6'；R5Is H or F; and R is6And R6'Each independently is H or-C1-C6An alkyl group.

Other preferred embodiments are compounds of formula I-F, wherein R is4is-NH2、-NHCH3、-NH-O-CH3or-NH-NHCH3(ii) a And R is5Is H or F.

In some preferred embodiments, the present disclosure relates to compounds of formula I-G

Wherein R is1is-C0-C6alkyl-C1-C6Alkyl, -C0-C6alkyl-C1-C6Haloalkyl, -C1-C6alkyl-O-C1-C6Alkyl, -C1-C6alkane-S-C1-C6Alkyl, -C1-C6Alkyl-aryl, -C1-C6alkyl-O-aryl, -C0-C6Alkyl-heteroaryl, -C1-C6alkyl-O-heteroaryl, -C1-C6alk-S-heteroaryl or-C1-C6alkyl-NH-heteroaryl; and R is5Is H or F.

In some embodiments, the compounds of formula I-G are those of: wherein R is1is-C1-C6Alkyl-aryl or-C1-C6alkyl-O-heteroaryl; and R is5Is H or F.

In some embodiments, the compounds of formula I-G are those of: wherein R is1is-C1-C6Alkyl-aryl and R5Is H or F. In some embodiments, the compounds of formula I-G are those of: wherein R is1is-C1-C6Alkyl-aryl, wherein aryl is a monocyclic or bicyclic aromatic hydrocarbon ring structure having 6 or 10 carbon atoms in the ring, wherein one or more carbon atoms in the ring are optionally replaced by a halogen atom, -C1-C3Alkyl radical, amino-substituted-C1-C3Alkyl radical, C1-C3Haloalkyl groups, amino groups (i.e. -NH)2) Or substituted with a substituted amino group; and R is5Is H or F.

In some embodiments, the compounds of formula I-G are those of: it is composed ofIn R1is-C1-C6alkyl-O-heteroaryl and R5Is H or F.

In other preferred embodiments, the disclosure relates to compounds of formula I-H

Wherein R is1is-C0-C6alkyl-C1-C6Alkyl, -C0-C6alkyl-C1-C6Haloalkyl, -C1-C6alkyl-O-C1-C6Alkyl, -C1-C6alkane-S-C1-C6Alkyl, -C1-C6Alkyl-aryl, -C1-C6alkyl-O-aryl, -C0-C6Alkyl-heteroaryl, -C1-C6alkyl-O-heteroaryl, -C1-C6alk-S-heteroaryl or-C1-C6alkyl-NH-heteroaryl; r5Is H or F; and R is6And R6'Each independently is H or-C1-C6An alkyl group.

Some preferred embodiments are compounds of formula I-H, wherein R1is-C1-C6alkyl-O-C1-C6Alkyl, -C1-C6alkane-S-C1-C6Alkyl, -C1-C6Alkyl-aryl, -C0-C6Alkyl-heteroaryl, -C1-C6alkyl-O-heteroaryl, -C1-C6alk-S-heteroaryl or-C1-C6alkyl-NH-heteroaryl; r5Is H or F; and R is6Is H and R6'Is methyl.

In some embodiments, the compounds of formula I-H are those of the following: wherein R is1is-C1-C6Alkyl-aryl or-C1-C6alkyl-O-heteroaryl; and R is5Is H or F; and R is6And R6'Each independently is H or-C1-C6An alkyl group.

In some embodiments, the formula I-HThe compounds are those of: wherein R is1is-C1-C6An alkyl-aryl group; r5Is H or F; and R is6And R6'Each independently is H or-C1-C6An alkyl group. In some embodiments, the compounds of formula I-H are those of the following: wherein R is1is-C1-C6Alkyl-aryl, wherein aryl is a monocyclic or bicyclic aromatic hydrocarbon ring structure having 6 or 10 carbon atoms in the ring, wherein one or more carbon atoms in the ring are optionally replaced by a halogen atom, -C1-C3Alkyl radical, amino-substituted-C1-C3Alkyl radical, C1-C3Haloalkyl groups, amino groups (i.e. -NH)2) Or substituted with a substituted amino group; r5Is H or F; and R is6And R6'Each independently is H or-C1-C6An alkyl group.

In some embodiments, the compounds of formula I-H are those of the following: wherein R is1is-C1-C6alkyl-O-heteroaryl; r5Is H or F; and R is6And R6'Each independently is H or-C1-C6An alkyl group.

In other preferred embodiments, the disclosure relates to compounds of formula I-J

Wherein R is1is-C0-C6alkyl-C1-C6Alkyl, -C0-C6alkyl-C1-C6Haloalkyl, -C1-C6alkyl-O-C1-C6Alkyl, -C1-C6alkane-S-C1-C6Alkyl, -C1-C6Alkyl-aryl, -C1-C6alkyl-O-aryl, -C0-C6Alkyl-heteroaryl, -C1-C6alkyl-O-heteroaryl, -C1-C6alk-S-heteroaryl or-C1-C6alkyl-NH-heteroaryl; r5Is H or F; and R is6Is H or-C1-C6An alkyl group.

Some preferred embodiments are compounds of formula I-J, wherein R is1is-C1-C6alkyl-O-C1-C6Alkyl, -C1-C6alkane-S-C1-C6Alkyl, -C1-C6Alkyl-aryl, -C0-C6Alkyl-heteroaryl, -C1-C6alkyl-O-heteroaryl, -C1-C6alk-S-heteroaryl or-C1-C6alkyl-NH-heteroaryl; r5Is H or F; and R is6Is methyl.

In some embodiments, the compounds of formula I-J are those of: wherein R is1is-C1-C6Alkyl-aryl or-C1-C6alkyl-O-heteroaryl; and R is5Is H or F; and R is6And R6'Each independently is H or-C1-C6An alkyl group.

In some embodiments, the compounds of formula I-J are those of: wherein R is1is-C1-C6An alkyl-aryl group; r5Is H or F; and R is6And R6'Each independently is H or-C1-C6An alkyl group. In some embodiments, the compounds of formula I-J are those of: wherein R is1is-C1-C6Alkyl-aryl, wherein aryl is a monocyclic or bicyclic aromatic hydrocarbon ring structure having 6 or 10 carbon atoms in the ring, wherein one or more carbon atoms in the ring are optionally replaced by a halogen atom, -C1-C3Alkyl radical, amino-substituted-C1-C3Alkyl radical, C1-C3Haloalkyl groups, amino groups (i.e. -NH)2) Or substituted with a substituted amino group; r5Is H or F; and R is6And R6'Each independently is H or-C1-C6An alkyl group.

In some embodiments, the compounds of formula I-J are those of: wherein R is1is-C1-C6alkyl-O-heteroaryl; r5Is H or F; and R is6And R6'Each independently is H or-C1-C6An alkyl group.

References herein to formula I also refer to formulae I-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H and I-J.

The present disclosure also encompasses stereoisomers of the compounds of formula I. Accordingly, the present disclosure encompasses all stereoisomers and structural isomers of any compound disclosed or claimed herein, including all enantiomers and diastereomers.

Pharmaceutically acceptable salts and solvates of the compounds of formula I are also within the scope of the present disclosure.

Isotopic variations of the compounds of formula I are also contemplated by the present disclosure.

Pharmaceutical compositions and methods of administration

The pharmaceutical compositions of the present invention are generally formulated to provide a therapeutically effective amount of a compound of the present disclosure as the active ingredient, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof. If desired, the pharmaceutical compositions comprise a pharmaceutically acceptable salt and/or coordination complex thereof, together with one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers and adjuvants.

The pharmaceutical compositions of the present invention may be administered alone or in combination with one or more other agents, which are also typically administered in the form of pharmaceutical compositions. If desired, one or more compounds of the present invention and other agents may be mixed into a formulation, or the two components may be formulated into separate formulations to use them separately or in combination at the same time.

In some embodiments, the concentration of one or more compounds provided in a pharmaceutical composition of the invention is less than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.6%, 0.0005%, 0.4%, 0.0003%, 0.0002%, or any two or more of the numerical ranges including any two or more of the numerical values w% (w/w) defined by the above(s) of the number) w/v or v/v.

In some embodiments, the concentration of one or more compounds of the invention is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25%, 18%, 17.75%, 17.50%, 17.25%, 17%, 16.75%, 16.50%, 16.25%, 16%, 15.75%, 15.50%, 15.25%, 15%, 14.75%, 14.50%, 14.25%, 14%, 13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%, 12%, 11.75%, 11.50%, 11.25%, 11%, 10.75%, 10.50%, 10.25%, 10%, 9.75%, 9.50%, 9.25%, 9%, 8.75%, 8.50%, 8.25%, 8%, 7.75%, 7.50%, 7.25%, 6.75%, 6.50%, 6.75%, 3.5%, 3.75%, 3.25%, 3.75%, 3.50%, 3.75%, 3.25%, 3.75%, 3.25%, 3.50%, 3.75%, 3.25%, 3.75%, 3.25%, 3.50%, 3.25%, 3., 2.25%, 2%, 1.75%, 1.50%, 1.25%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% (or a number defined by and including any two numbers above) w/w, w/v or v/v.

In some embodiments, the concentration of one or more compounds of the invention ranges from about 0.0001% to about 50%, from about 0.001% to about 40%, from about 0.01% to about 30%, from about 0.02% to about 29%, from about 0.03% to about 28%, from about 0.04% to about 27%, from about 0.05% to about 26%, from about 0.06% to about 25%, from about 0.07% to about 24%, from about 0.08% to about 23%, from about 0.09% to about 22%, from about 0.1% to about 21%, from about 0.2% to about 20%, from about 0.3% to about 19%, from about 0.4% to about 18%, from about 0.5% to about 17%, from about 0.6% to about 16%, from about 0.7% to about 15%, from about 0.8% to about 14%, from about 0.9% to about 12%, from about 1% to about 10% w/w, w/v, or v/v.

In some embodiments, the concentration of one or more compounds of the invention ranges from about 0.001% to about 10%, from about 0.01% to about 5%, from about 0.02% to about 4.5%, from about 0.03% to about 4%, from about 0.04% to about 3.5%, from about 0.05% to about 3%, from about 0.06% to about 2.5%, from about 0.07% to about 2%, from about 0.08% to about 1.5%, from about 0.09% to about 1%, from about 0.1% to about 0.9% w/w, w/v, or v/v.

In some embodiments, the amount of one or more compounds of the invention is equal to or less than 10g, 9.5g, 9.0g, 8.5g, 8.0g, 7.5g, 7.0g, 6.5g, 6.0g, 5.5g, 5.0g, 4.5g, 4.0g, 3.5g, 3.0g, 2.5g, 2.0g, 1.5g, 1.0g, 0.95g, 0.9g, 0.85g, 0.8g, 0.75g, 0.7g, 0.65g, 0.6g, 0.55g, 0.5g, 0.45g, 0.4g, 0.35g, 0.3g, 0.25g, 0.2g, 0.15g, 0.1g, 0.09g, 0.08g, 0.06g, 0.008g, 0.03g, 0.35g, 0000.3 g, 0000.25 g, 0.2g, 0.15g, 0.1g, 0.09g, 0.06g, 00006 g, 0.04g, 0.01g, or a number within any of the above including the range of numbers of g, including any of the above (g).

In some embodiments, the amount of one or more of the compounds of the invention is greater than 0.0001g, 0.0002g, 0.0003g, 0.0004g, 0.0005g, 0.0006g, 0.0007g, 0.0008g, 0.0009g, 0.001g, 0.0015g, 0.002g, 0.0025g, 0.003g, 0.0035g, 0.004g, 0.0045g, 0.005g, 0.0055g, 0.006g, 0.0065g, 0.007g, 0.0075g, 0.008g, 0.0085g, 0.009g, 0.0095g, 0.01g, 0.015g, 0.02g, 0.025g, 0.03g, 0.035g, 0.04g, 0.045g, 0.05g, 060.06 g, 0.06g, 0.01g, 0.015g, 0.15g, 0.085g, 0.15g, 0.7g, 0.15g, 0.7g, 8.5g, 9g, 9.5g or 10g (or a number defined by and including any two of the above numbers).

In some embodiments, the amount of one or more compounds of the invention is in the range of 0.0001 to 10g, 0.0005 to 9g, 0.001 to 8g, 0.005 to 7g, 0.01 to 6g, 0.05 to 5g, 0.1 to 4g, 0.5 to 4g, or 1 to 3 g.

The compounds according to the invention are effective over a wide dosage range. For example, in the treatment of adults, dosages of 0.01 to 1000mg, 0.5 to 100mg, 1 to 50mg, and 5 to 40mg per day are examples of dosages that may be used. An exemplary dose is 10 to 30mg per day. The exact dosage will depend upon the route of administration, the form of administration of the compound, the subject to be treated, the weight of the subject to be treated and the preferences and experience of the attending physician.

The pharmaceutical compositions of the present invention generally comprise the active ingredient of the present invention (i.e., a compound of the present disclosure) or a pharmaceutically acceptable salt and/or coordination complex thereof, together with one or more pharmaceutically acceptable excipients, carriers, including but not limited to inert solid diluents and fillers, diluents, sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers and adjuvants.

Non-limiting exemplary pharmaceutical compositions and methods for their preparation are described below.

Pharmaceutical composition for oral administration

In some embodiments, the present invention provides pharmaceutical compositions for oral administration comprising a compound of the present invention and a pharmaceutical excipient suitable for oral administration.

In some embodiments, the present invention provides a solid pharmaceutical composition for oral administration comprising: (i) an effective amount of a compound of the present invention; optionally (ii) an effective amount of a second agent; and (iii) a pharmaceutical excipient suitable for oral administration. In some embodiments, the composition further comprises: (iv) an effective amount of a third agent.

In some embodiments, the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral administration. Pharmaceutical compositions of the invention suitable for oral administration may be presented in discrete dosage forms such as capsules, cachets or tablets, or as liquid or aerosol sprays, solutions, or suspensions in aqueous or non-aqueous liquids, oil-in-water emulsions or water-in-oil liquid emulsions each containing a predetermined amount of the active ingredient in powder or granular form. Such dosage forms may be prepared by any of the methods of pharmacy, but all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, when necessary, shaping the product into the desired presentation. For example, a tablet may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with excipients such as, but not limited to, binders, lubricants, inert diluents and/or surfactants or dispersants. Molded tablets may be prepared by forming in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

The invention also encompasses anhydrous pharmaceutical compositions and dosage forms comprising active ingredients, as water can promote the degradation of some compounds. For example, water (e.g., 5%) may be added in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics of the formulation such as shelf life or stability over time. Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture content ingredients and low moisture or low humidity conditions. The pharmaceutical compositions and dosage forms of the present invention containing lactose can be made anhydrous if sufficient contact with moisture and/or humidity during manufacture, packaging and/or storage is expected. Anhydrous pharmaceutical compositions can be prepared and stored so as to maintain their anhydrous nature. Thus, anhydrous compositions may be packaged using materials known to prevent exposure to water, such that they may be included in a suitable formulation kit. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics and the like, unit dose containers, blister packs and strip packs.

The active ingredient may be combined with the pharmaceutical carrier in intimate admixture according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the form of preparation desired for administration. In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed as the carrier, e.g., water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations (e.g., suspensions, solutions, and elixirs) or aerosols; or in the case of oral solid preparations, carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents may be used, with or without lactose in some embodiments. For example, in the case of solid oral preparations, suitable carriers include powders, capsules and tablets. If desired, the tablets may be coated by standard aqueous or non-aqueous techniques.

Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered astragalus, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pregelatinized starch, hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixtures thereof.

Examples of suitable fillers for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrin, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.

Disintegrants may be used in the compositions of the invention to provide tablets that disintegrate when exposed to an aqueous environment. Too much disintegrant may result in tablets that may disintegrate in the bottle. Too little may be insufficient for disintegration to occur and thus may alter the rate and extent of release of the active ingredient from the dosage form. Thus, a sufficient amount of disintegrant that is neither too little nor too much to detrimentally alter the release of the active ingredient can be used to form a dosage form of the compounds disclosed herein. The amount of disintegrant used may vary depending on the type of formulation and mode of administration, and is readily discernible to those of ordinary skill in the art. About 0.5 to about 15 weight percent of a disintegrant, or about 1 to about 5 weight percent of a disintegrant, may be used in the pharmaceutical composition. Disintegrants that can be used to form the pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium (polacrilin potassium), sodium starch glycolate, potato or tapioca starch, other starches, pregelatinized starches, other starches, clays, other algins, other celluloses, gums, or mixtures thereof.

Lubricants that may be used to form the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerol, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, or mixtures thereof. Additional lubricants include, for example, syloid silica gel, condensed aerosols of synthetic silica, or mixtures thereof. A lubricant may optionally be added in an amount of less than about 1% by weight of the pharmaceutical composition.

When aqueous suspensions and/or elixirs are desired for oral administration, the active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes, and emulsifying and/or suspending agents as may be desired, together with diluents such as water, ethanol, propylene glycol, glycerin and various combinations thereof.

The tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin; or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.

Surfactants that may be used to form the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants may be used, a mixture of lipophilic surfactants may be used, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant may be used.

Suitable hydrophilic surfactants may generally have an HLB value of at least 10, while suitable lipophilic surfactants may generally have an HLB value equal to or less than about 10. An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of nonionic amphiphilic compounds is the hydrophilic-lipophilic balance ("HLB" value). Surfactants with lower HLB values are more lipophilic or hydrophobic and have higher solubility in oils, while surfactants with higher HLB values have higher hydrophilicity and higher solubility in aqueous solutions.

Hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is generally not applicable. Similarly, lipophilic (i.e., hydrophobic) surfactants are compounds having an HLB value equal to or less than about 10. However, the HLB value of surfactants is only a rough guide commonly used to achieve the formulation of industrial, pharmaceutical and cosmetic emulsions.

The hydrophilic surfactant may be ionic or non-ionic. Suitable ionic surfactants include, but are not limited to, alkyl ammonium salts; fusidic acid (fusidic acid) salt; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; lecithin and hydrogenated lecithin; lysolecithin and hydrogenated lysolecithin; phospholipids and derivatives thereof; lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; alkyl sulfate salts; a fatty acid salt; docusate sodium (sodium docusate); acyl lactylate (acyl lactylate); monoacetylated and diacetylated tartaric acid esters of mono-and diglycerides; succinylated mono-and diglycerides; citric acid esters of mono-and diglycerides; and mixtures thereof.

Within the above group, ionic surfactants include, for example: lecithin, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; alkyl sulfate salts; a fatty acid salt; docusate sodium; acyl lactylates; monoacetylated and diacetylated tartaric acid esters of mono-and diglycerides; succinylated mono-and diglycerides; citric acid esters of mono-and diglycerides; and mixtures thereof.

The ionic surfactant may be an ionized form of: lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, fatty acid lactylate, stearoyl-2-lactate, stearoyl lactate, succinylated monoglyceride, monoacetylated/diacetylated tartaric acid esters of monoglyceride/diglyceride, citric acid esters of monoglyceride/diglyceride, cholic acid, caproic acid esters, caprylic acid esters, capric acid esters, lauric acid esters, myristic acid esters, palmitic acid esters, oleic acid esters, ricinoleic acid esters, linolic acid esters, linolenic acid esters, stearic acid esters, lauryl sulfate esters, tetradecyl sulfate esters (teraceecyl sulfate), docusate, lauroyl carnitine, palmitoyl carnitine, myristoyl carnitine and salts and mixtures thereof.

Hydrophilic nonionic surfactants may include, but are not limited to: an alkyl glucoside; an alkyl maltoside; an alkyl thioglucoside; lauryl macrogolglyceride (lauryl macrogolyceride); polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols, such as polyethylene glycol alkylphenols; polyoxyalkylene alkylphenol fatty acid esters such as polyethylene glycol fatty acid monoesters and polyethylene glycol fatty acid diesters; polyethylene glycol glycerol fatty acid ester; polyglyceryl fatty acid esters; polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene sterols, derivatives and analogs thereof; polyoxyethylated vitamins and their derivatives; polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; hydrophilic transesterification products of polyethylene glycol sorbitan fatty acid esters and polyols with at least one member of the group consisting of triglycerides, vegetable oils and hydrogenated vegetable oils. The polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol or a sugar.

Other hydrophilic-nonionic surfactants include, but are not limited to, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25 triolein, PEG-32 dioleate, PEG-20 laurin, PEG-30 laurin, PEG-20 stearin, PEG-20 olein, PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenated castor oil, PEG-60 corn oil, PEG-6 glyceryl capric/caprylate, PEG-8 glyceryl capric/caprylate, polyglycerol-10 laurate, PEG-30 cholesterol, PEG-25 phytosterol, PEG-30 soyasterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, polyglycerol-10 oleate, Tween 40, Tween60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, the PEG 10-100 nonylphenol series, the PEG 15-100 octylphenol series and poloxamers (poloxamer).

By way of example only, suitable lipophilic surfactants include: a fatty alcohol; glycerin fatty acid ester; acetylated glycerin fatty acid ester; lower alcohol fatty acid esters; a propylene glycol fatty acid ester; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterol and sterol derivatives; polyoxyethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono-and diglycerides; a hydrophobic transesterification product of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; oil-soluble vitamins/vitamin derivatives; and mixtures thereof. Within this group, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or are hydrophobic transesterification products of a polyol with at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides.

In one embodiment, the composition may comprise a solubilizing agent to ensure good solubilization and/or dissolution of the compounds of the present invention and to minimize precipitation of the compounds of the present invention. This may be particularly important for compositions that are not for oral use, such as injectable compositions. Solubilizers may also be added to increase the solubility of the hydrophilic drug and/or other components, such as surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion.

Examples of suitable solubilizing agents include, but are not limited to, the following: alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butylene glycol and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; ethers of polyethylene glycol having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (sugar furfuryl alcohol) or methoxy PEG; amides and other nitrogen-containing compounds, such as 2-pyrrolidone, 2-piperidone, -caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidinone, N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esters, such as ethyl propionate, tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, triethyl citrate, ethyl oleate, ethyl octanoate, ethyl butyrate, glycerol triacetate, propylene glycol monoacetate, propylene glycol diacetate, -caprolactone and its isomers, -valerolactone and its isomers, β -butyrolactone and its isomers; and other solubilizing agents known in the art, such as dimethylacetamide, dimethylisosorbide, N-methylpyrrolidone, caprylic acid monoglyceride, diethylene glycol monoethyl ether, and water.

Mixtures of solubilizers may also be used. Examples include, but are not limited to, triacetin, triethyl citrate, ethyl oleate, ethyl octanoate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcyclodextrin, ethanol, polyethylene glycol 200-. Particularly preferred solubilizers include sorbitol, glycerol triacetate, ethanol, PEG-400, furfuryl alcohol, and propylene glycol.

The amount of the solubilizer that may be contained is not particularly limited. The amount of a given solubilizer may be limited to a biologically acceptable amount, which can be readily determined by one skilled in the art. In certain instances, it may be advantageous to include an amount of solubilizing agent that is well beyond a biologically acceptable amount, for example, to maximize the concentration of the drug, wherein excess solubilizing agent is removed using conventional techniques such as distillation or evaporation prior to providing the composition to a subject. Thus, the weight ratio of the solubilizing agent, if present, can be 10 weight percent, 25 weight percent o, 50 weight percent, 100 weight percent o, or up to about 200 weight percent based on the combined weight of the drug and other excipients. Very small amounts of solubilizer, e.g., 5%, 2%, 1% or even less, may also be used if desired. Typically, the solubilizing agent can be present in an amount of from about 1% by weight > to about 100% by weight, more typically from about 5% by weight > to about 25% by weight.

The composition may further comprise one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, but are not limited to, detackifiers, defoamers, buffers, polymers, antioxidants, preservatives, chelating agents, viscosity modifiers, tonicity agents, flavoring agents, coloring agents, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

Additionally, acids or bases may be incorporated into the composition to facilitate processing, enhance stability, or for other reasons. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium bicarbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic hydrocalcite, aluminum magnesium hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, TRIS (hydroxymethyl) aminomethane (TRIS), and the like. Also suitable are bases which are salts of pharmaceutically acceptable acids, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, p-bromobenzenesulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid and the like. Salts of polyprotic acids such as sodium phosphate, disodium hydrogen phosphate and sodium dihydrogen phosphate may also be used. When the base is a salt, the cation may be any suitable and pharmaceutically acceptable cation, such as ammonium, alkali metals, alkaline earth metals, and the like. Examples may include, but are not limited to, sodium, potassium, lithium, magnesium, calcium, and ammonium.

Suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, and the like. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinonesulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid and the like.

Pharmaceutical composition for injection

In some embodiments, the invention provides a pharmaceutical composition for injection comprising a compound of the invention and a pharmaceutical excipient suitable for injection. The ingredients and amounts of the agents in the compositions are as described herein.

The novel compositions of the present invention may be incorporated in the form of aqueous or oily suspensions or emulsions for administration by injection (with sesame, corn, cottonseed or peanut oil), as well as elixirs (mannitol, dextrose), or sterile aqueous solutions (and similar pharmaceutical vehicles).

Aqueous solutions in saline are also commonly used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycols and the like (and suitable mixtures thereof), cyclodextrin derivatives and vegetable oils may also be used. Proper fluidity can be maintained, for example, in the case of dispersions, by the use of a coating, such as lecithin, to maintain the desired particle size, and by the use of surfactants. The action of microorganisms can be prevented by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

Sterile injectable solutions are prepared by incorporating the compound of the invention in the required amount in the appropriate solvent with various other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains a base dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, certain desirable methods of preparation are vacuum drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

Pharmaceutical compositions for topical (e.g. transdermal) delivery

In some embodiments, the present invention provides a pharmaceutical composition for transdermal delivery comprising a compound of the present invention and a pharmaceutical excipient suitable for transdermal delivery.

The compositions of the present invention may be formulated into solid, semi-solid or liquid form preparations suitable for topical or surface application, such as gels, water-soluble jellies, creams, lotions, suspensions, foams, powders, pastes, ointments, solutions, oils, pastes, suppositories, sprays, emulsions, saline solutions, Dimethylsulfoxide (DMSO) -based solutions. Generally, carriers with higher densities are able to provide areas of prolonged exposure to the active ingredient. In contrast, solution formulations may expose the active ingredient more directly to the selected area.

The pharmaceutical compositions may also contain suitable solid or gel phase carriers or excipients, which are compounds that allow for increased penetration or aid in delivery of the therapeutic molecule across the stratum corneum permeability barrier of the skin. There are many such penetration enhancing molecules known to those skilled in the art of topical formulations.

Examples of such carriers and excipients include, but are not limited to, humectants (e.g., urea), glycols (e.g., propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleic acid), surfactants (e.g., isopropyl myristate and sodium lauryl sulfate), pyrrolidones, glycerol monolaurate, sulfoxides, terpenes (e.g., menthol), amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starch, cellulose derivatives, gelatin, and polymers such as polyethylene glycol.

Another exemplary formulation for use in the methods of the present invention employs a transdermal delivery device ("patch"). Such transdermal patches may be used to provide continuous or discontinuous infusion of a controlled amount of a compound of the present invention, with or without another agent.

The construction and use of transdermal patches for delivering pharmaceutical agents is well known in the art. See, for example, U.S. Pat. nos. 5,023,252, 4,992,445, and 5,001,139. Such patches may be configured for continuous, pulsed, or on-demand delivery of a medical agent.

Pharmaceutical composition for inhalation

Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. Preferably, the composition is administered by the oral or nasal respiratory route to produce a local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by the use of inert gases. The nebulized solution may be inhaled directly from the nebulizing device, or the nebulizing device may be connected to a face mask or intermittent positive pressure ventilator. The solution, suspension or powder composition may preferably be administered orally or nasally from a device that delivers the formulation in a suitable manner.

Other pharmaceutical compositions

Pharmaceutical compositions may also be prepared from the compositions described herein and one or more pharmaceutically acceptable excipients suitable for sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration. The preparation of such pharmaceutical compositions is well known in the art. See, e.g., Anderson, Philip o.; knoben, James e.; troutman, ed by William G, Handbook of Clinical Drug Data (Handbook of Clinical Drug Data), tenth edition, McGraw-Hill, 2002; pratt and Taylor, Principles of Drug Action (Principles of Drug Action), third edition, Churchill Livingston, New York, 1990; katzeng, Basic and clinical Pharmacology, ninth edition, McGraw Hill,20037 ybg; goodman and Gilman, eds. "Pharmacological Basis of Therapeutics" (The Pharmacological Basis of Therapeutics), tenth edition, McGraw Hill, 2001; remingtons Pharmaceutical Sciences, 20 th edition, Lippincott Williams & Wilkins, 2000; the large Martindale Pharmacopoeia (Martindale, The Extra Pharmacopoeia), thirty-second edition (The Pharmaceutical Press, London, 1999); all of which are incorporated herein by reference in their entirety.

Administration of the compounds or pharmaceutical compositions of the invention may be accomplished by any method capable of delivering the compound to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion), topical (e.g., transdermal administration), rectal administration, local delivery through a catheter or stent or by inhalation. The compounds may also be administered intraadiposally or intrathecally.

The amount of compound administered will depend on the subject being treated, the severity of the disorder or condition, the rate of administration, the configuration of the compound and the judgment of the prescribing physician. However, effective dosages will range from about 0.001 to about 100mg per kg of body weight per day, preferably from about 1 to about 35 mg/kg/day in single or divided doses. For a 70kg person, this would equate to about 0.05 to 7 grams per day, preferably about 0.05 to about 2.5 grams per day. In some cases dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effects, for example by dividing such larger doses into several small doses for administration throughout the day.

In some embodiments, the compounds of the present invention are administered in a single dose.

Typically, such administration will be by injection, for example intravenous injection, for rapid introduction of the agent. However, other approaches may be used as appropriate. A single dose of a compound of the invention may also be used to treat acute conditions.

In some embodiments, the compounds of the present invention are administered in multiple doses. The administration may be about once, twice, three times, four times, five times, six times, or more than six times per day. Administration may be about once a month, once every two weeks, once a week, or every other day. In another embodiment, the compound of the invention and the other agent are administered together from about once daily to about 6 times daily. In another embodiment, the administration of the compounds and agents of the present invention lasts less than about 7 days. In another embodiment, administration is for more than about 6, 10, 14, 28 days, two months, six months, or one year. In some cases, continuous administration can be achieved and maintained as long as desired.

The administration of the compounds of the invention may be continued as long as desired. In some embodiments, a compound of the invention is administered for more than 1,2, 3,4, 5, 6, 7, 14, or 28 days. In some embodiments, a compound of the invention is administered for less than 28, 14, 7, 6, 5, 4, 3,2, or 1 days. In some embodiments, the compounds of the invention are administered for extended periods of time, e.g., for the treatment of chronic effects.

An effective amount of a compound of the present invention may be administered in single or multiple doses by any acceptable mode of administration of agents with similar utility, including rectal, buccal, intranasal, and transdermal routes, by intra-arterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, or as an inhalant.

The compositions of the present invention may also be delivered via impregnated or coated devices such as stents or arterial-inserted cylindrical polymers. Such methods of administration may, for example, help to prevent or ameliorate restenosis following surgery, such as balloon angioplasty. Without being bound by theory, the compounds of the present invention may slow or inhibit the migration and proliferation of smooth muscle cells in the arterial wall that contribute to restenosis. The compounds of the invention may be administered, for example, by local delivery from the struts of the stent, from the stent graft, from the graft or from the cap or sheath of the stent. In some embodiments, the compounds of the present invention are mixed with a matrix. Such a matrix may be a polymer matrix and may be used to bind the compound to the scaffold. Polymeric matrices suitable for such use include, for example, lactone-based polyesters or copolyesters, such as polylactide, polycaprolactone glycolide, polyorthoesters, polyanhydrides, polyaminoacids, polysaccharides, polyphosphazenes, poly (ether-ester) copolymers (e.g., PEO-PLLA); polydimethylsiloxanes, poly (ethylene-vinyl acetate), acrylate-based polymers or copolymers (e.g., polyhydroxyethylmethacrylate, polyvinylpyrrolidone), fluorinated polymers such as polytetrafluoroethylene and cellulose esters. Suitable matrices may be non-degradable or may degrade over time, thereby releasing one or more compounds. The compounds of the present invention can be applied to the surface of the stent by various methods such as dip/spin coating, spray coating, dip coating and/or brush coating. The compound may be applied in a solvent, and the solvent may be evaporated, thereby forming a compound layer on the stent. Alternatively, the compound may be located in the body of the stent or graft, for example in a microchannel or micropore. When implanted, the compound diffuses out of the body of the stent to contact the arterial wall. Such scaffolds may be prepared by immersing a scaffold fabricated to contain such micropores or microchannels in a solution of a compound of the invention in a suitable solvent, followed by evaporation of the solvent. Excess drug on the stent surface can be removed via an additional brief solvent wash. In other embodiments, the compounds of the invention may be covalently attached to a stent or graft. Covalent linkers that degrade in vivo can be used, resulting in the release of the compounds of the invention. Any biologically labile linkage may be used for this purpose, such as an ester, amide, or anhydride linkage. The compounds of the invention may additionally be administered intravascularly from a balloon used during angioplasty. Extravascular administration of compounds to reduce restenosis may also be performed via the pericardium or via prior application of a formulation of the present invention.

Various stent devices that may be used as described are disclosed, for example, in the following references, all of which are incorporated herein by reference: U.S. patent No. 5451233; U.S. patent No. 5040548; U.S. patent No. 5061273; U.S. patent No. 5496346; U.S. patent No. 5292331; U.S. patent No. 5674278; U.S. patent No. 3657744; U.S. patent No. 4739762; U.S. patent No. 5195984; U.S. patent No. 5292331; U.S. patent No. 5674278; U.S. patent No. 5879382; U.S. patent No. 6344053.

The compounds of the invention may be administered in doses. It is known in the art that due to compound pharmacokinetic differences between subjects, individualization of the dosing regimen is necessary for optimal treatment. In light of the present disclosure, administration of the compounds of the present invention can be determined by routine experimentation.

When a compound of the invention is administered in a composition comprising one or more pharmaceutical agents having a shorter half-life than the compound of the invention, the unit dosage forms of the pharmaceutical agents and the compound of the invention can be adjusted accordingly.

The pharmaceutical compositions of the invention may be, for example, in a form suitable for oral administration, such as a tablet, capsule, pill, powder, sustained release formulation, solution, suspension, in a form suitable for parenteral injection, such as a sterile solution, suspension or emulsion, in a form suitable for topical administration, such as an ointment or cream, or in a form suitable for rectal administration, such as a suppository. The pharmaceutical composition may be in unit dosage form suitable for single administration of precise dosages. The pharmaceutical compositions will comprise conventional pharmaceutical carriers or excipients and, as active ingredient, a compound according to the invention. In addition, it may include other drugs or agents, carriers, adjuvants, and the like.

Exemplary parenteral administration forms include solutions or suspensions of the active compounds in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms may be suitably buffered if desired.

Application method

The methods generally comprise administering to a subject a therapeutically effective amount of a compound of the invention. The therapeutically effective amount of the combination of compounds of the invention may vary depending on the intended use (in vitro or in vivo) or the subject and disease condition being treated, e.g., weight and age of the subject, severity of the disease condition, mode of administration, and the like, as can be readily determined by one of ordinary skill in the art. The term also applies to doses that will induce a specific response in the target cell, e.g., reduced proliferation or down-regulation of the activity of the target protein. The specific dosage will vary according to: the particular compound selected, the dosage regimen to be followed, whether to be administered in combination with other compounds, the time of administration, the tissue to be administered and the physical delivery system that carries it.

As used herein, the term "IC50"refers to the maximum half inhibitory concentration of an inhibitor in inhibiting a biological or biochemical function. Such quantitative measure represents the needHow many specific inhibitors will inhibit a given biological process (or component of a process, i.e., an enzyme, cell receptor, or microorganism) by half. In other words, it is the maximum half (50%) Inhibitory Concentration (IC) of a substance (50% IC or IC 50). EC50 means that 50% is obtained>The plasma concentration required for maximal effect in vivo.

In some embodiments, the methods of the invention utilize a PRMT5 inhibitor having an IC50 value about equal to or less than a predetermined value as determined in an in vitro assay. In some embodiments, the PRMT5 inhibitor inhibits PRMT5 with the following IC50 values: less than about 1nM, less than 2nM, less than 5nM, less than 7nM, less than 10nM, less than 20nM, less than 30nM, less than 40nM, less than 50nM, less than 60nM, less than 70nM, less than 80nM, less than 90nM, less than 100nM, less than 120nM, less than 140nM, less than 150nM, less than 160nM, less than 170nM, less than 180nM, less than 190nM, less than 200nM, less than 225nM, less than 250nM, less than 275nM, less than 300nM, less than 325nM, less than 350nM, less than 375nM, less than 400nM, less than 425nM, less than 450nM, less than 475nM, less than 500nM, less than 550nM, less than 600nM, less than 650nM, less than 700nM, less than 750nM, less than 800nM, less than 850nM, less than 900nM, less than 950nM, less than 1 μ M, less than 1.1 μ M, 1.2 μ M, less than 1.3 μ M, less than 1.4 μ M, 1.5 μ M, 1.6 μ M, 1.6 μ M, 1.7 μ Μ or less, 1.8 μ Μ or less, 1.9 μ Μ or less, 2 μ Μ or less, 5 μ Μ or less, 10 μ Μ or less, 15 μ Μ or less, 20 μ Μ or less, 25 μ Μ or less, 30 μ Μ or less, 40 μ Μ or less, 50 μ Μ, 60 μ Μ, 70 μ Μ, 80 μ Μ, 90 μ Μ, 100 μ Μ,200 μ Μ, 300 μ Μ, 400 μ Μ or 500 μ Μ or less (or numbers within a range defined by and including any two of the above numbers).

In some embodiments, the PRMT5 inhibitor selectively inhibits PRMT5 with an IC50 value that is at least 2,3,4, 5, 6, 7, 8, 9,10, 15, 20, 25, 30, 35, 40, 45, 50, 100, or 1000 times less (or a number defined by and including any two numbers above) than its IC50 value for one, two, or three other PRMTs.

In some embodiments, the inhibitor of PRMT5 selectively inhibits PRMT5 with an IC50 value of less than about 1nM, 2nM, 5nM, 7nM, 10nM, 20nM, 30nM, 40nM, 50nM, 60nM, 70nM, 80nM, 90nM, 100nM, 120nM, 140nM, 150nM, 160nM, 170nM, 180nM, 190nM, 200nM, 225nM, 250nM, 275nM, 300nM, 325nM, 350nM, 375nM, 400nM, 425nM, 450nM, 475nM, 500nM, 550nM, 600nM, 650nM, 700nM, 750nM, 800nM, 850nM, 900nM, 950nM, 1 μm, 1.1 μm, 1.2 μm, 1.3 μm, 1.4 μm, 1.5 μm, 1.6 μm, 1.7 μm, 1.8 μm, 1.9 μm, 1.2 μm, 1.3 μm, 1.4 μm, 1.5 μm, 1.6 μm, 1.7 μm,10 μm, 100 μm,10 μm, 400 μ Μ or 500 μ Μ (or within a range defined by and including any two numbers above), and the IC50 value is at least 2,3,4, 5, 6, 7, 8, 9,10, 15, 20, 25, 30, 35, 40, 45, 50, 100 or 1000 times less (or a number within a range defined by and including any two numbers above) than its IC50 value for one, two or three other PRMTs.

The methods of the invention are useful for treating disease conditions associated with PRMT 5. Any disease condition that results directly or indirectly from an abnormal activity or expression level of PRMT5 may be the expected disease condition.

Different disease states have been reported to be associated with PRMT 5. PRMT5 is associated with, for example, various human cancers and many hemoglobinopathies.

Non-limiting examples of such conditions include, but are not limited to, acanthoma, acinar cell carcinoma, sononeuroma, acrochronic melanoma, acrosweat gland tumor, acute eosinophilic leukemia, acute lymphoblastic leukemia, acute lymphocytic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, mature acute myeloblastic leukemia, acute myelodendritic cell leukemia, acute myelogenous leukemia, acute promyelocytic leukemia, ameloblastic, adenocarcinomas, adenoid cystic carcinoma, adenomas, adenomatoid dental tumors, adrenocortical carcinoma, adult T cell leukemia, aggressive NK cell leukemia, AIDS-related cancer, AIDS-related lymphoma, alveolar soft part sarcoma, ameloblastic fibroma, anal carcinoma, anaplastic large cell lymphoma, anaplastic thyroid carcinoma, angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma, appendiceal carcinoma, astrocytoma, atypical teratoma-like rhabdoid tumor, basal cell carcinoma, basal-like carcinoma, B-cell leukemia, B-cell lymphoma, beline duct carcinoma (Bellini duct carcinoma), biliary tract carcinoma, bladder carcinoma, blastoma, bone carcinoma, bone tumor, brain stem glioma, brain tumor, breast carcinoma, brennetum tumor (brennetum or), bronchial tumor, bronchoalveolar carcinoma, brownian tumor (Brown), Burkitt's lymphoma (Burkitt's lymphoma), unknown primary site cancer, carcinoid, carcinoma in situ, penile carcinoma, unknown primary site carcinoma, carcinosarcoma, Karman's Disease, central nervous system embryonal tumor, cerebellar astrocytoma, cholangioma, chondroblastoma, chondrosarcoma, chordoma, choriocarcinoma, choroidal plexus papilloma, chronic lymphocytic leukemia, chronic monocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative disorder, chronic neutrophilic leukemia, clear cell tumor, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, Degos' disease (Degos disease), dermatofibrosarcoma protruberans, dermatocysts, desmoplastic small round cell tumors, diffuse large B-cell lymphoma, dysplastic neuroepithelial tumors of embryos, embryonic cancers, tumors of the intradermal sinus, endometrial cancer, endometrial uterine endometrioid tumor, enteropathy-related T-cell lymphoma, ependymoma, epidermoid carcinoma, epithelioid sarcoma, erythrocytic leukemia, esophageal cancer, olfactory neuroblastoma, ewings 'family tumor, ewings' family sarcoma, ewings 'sarcoma, extracranial germ cell tumor, extragonally germ cell tumor, extrahepatic bile duct cancer, Extramammary Paget's disease, fallopian tube cancer, inner tube of the fetus, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid cancer, gallbladder cancer, ganglioglioma, ganglioma, gastric cancer, gastric lymphoma, gastrointestinal cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, germ cell tumors, genital tumors, choriocarcinoma of pregnancy, gestational cell tumor, giant cell tumor of bone, glioblastoma multiforme, glioma, brain glioma disease, hemangioblastoma, glucagon tumor, gonablastoma, granulocytic tumor, hairy cell leukemia, head and neck cancer, heart cancer, hemoglobin diseases such as b-type thalassemia and Sickle Cell Disease (SCD), hemangioblastoma, hemangioepithelioma, angiosarcoma, hematological malignancy, hepatocellular carcinoma, hepatosplenic T-cell Lymphoma, hereditary mammary-ovarian cancer syndrome, Hodgkin Lymphoma (Hodgkin Lymphoma), Hodgkin's Lymphoma, hypopharyngeal carcinoma, hypothalamic glioma, inflammatory breast cancer, intraocular melanoma, islet cell carcinoma, islet cell tumor, juvenile myelomonocytic leukemia, Kaposi Sarcoma (Kaposi Sarcoma), Kaposi's Sarcoma (Kaposi's Sarcoma), kidney cancer, Clatt's Sarcoma (Klatskin tumor), Kluyugu root tumor (Krenberg tumor), laryngeal carcinoma, malignant melanoma, leukemia, lip and oral cavity cancer, liposarcoma, lung cancer, Lymphoma, lymphangioma, lymphoblastic Sarcoma, lymphoblastic leukemia, macroglobulinemia, malignant fibrous histiocytoma, malignant fibrous histiocytoma of bone, malignant glioma, malignant mesothelioma, malignant peripheral nerve sheath tumor, malignant rhabdomyoma, malignant newt tumor, MALT lymphoma, mantle Cell lymphoma, mast Cell leukemia, mastocytosis, mediastinal germ Cell tumor, mediastinal tumor, medullary thyroid Carcinoma, medulloblastoma, myelinated epithelial tumor, melanoma, meningioma, Merkel Cell Carcinoma (Merkel Cell sarcoma), mesothelioma, occult primary metastatic cervical squamous Carcinoma, metastatic urothelial Carcinoma, Mixed Mullerian tumor (Mixed Mullerian tumor), monocytic leukemia, oral cancer, mucinous tumor, multiple endocrine tumor syndrome, multiple myeloma, mycosis fungoides, myelodysplastic diseases, myelodysplastic syndromes, myelogenous leukemia, myelosarcoma, myeloproliferative diseases, myxoma, nasal cavity cancer, nasopharyngeal carcinoma, neoplasms, neuroma, neuroblastoma, neurofibroma, neuroma, nodular melanoma, non-hodgkin's lymphoma, non-melanoma skin cancer, non-small cell lung cancer, eye tumor, oligoastrocytoma, oligodendroglioma, eosinophilic tumor, optic nerve sheath meningioma, oral cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, low malignant potential tumor, Paget's disease of the breast, pancakest's tumor (Pancoast tumor), pancreatic cancer, papillary thyroid cancer, papillomatosis, paraganglioma, paranasal sinus cancer, parathyroid cancer, penile cancer, perivascular epithelioid cell tumor, throat cancer, pheochromocytoma, differentiated parenchymal tumor in pineal gland, pineal cell tumor, pituitary cytotumor, pituitary adenoma, pituitary tumor, plasma cell neoplasm, pleuropulmonoblastoma, polyembryonic tumor, precursor T lymphoblastic lymphoma, primary central nervous system lymphoma, primary effusion lymphoma, primary hepatocellular carcinoma, primary liver cancer, primary peritoneal cancer, primary neuroectodermal tumor, prostate cancer, peritoneal pseudomyxoma, rectal cancer, renal cell carcinoma, respiratory tract cancer involving the NUT gene on chromosome 15, retinoblastoma, rhabdomyosarcoma, Richter's transformation, sacrococcal teratoma, salivary gland cancer, sarcoma, schwannoma, sebaceous gland carcinoma, secondary neoplasm, seminoma, serous tumor, supportive-mesenchymal tumor, sex cord-mesenchymal tumor, Sezary Syndrome (Sezary Syndrome), signet ring cell carcinoma, skin cancer, small blue circular cell tumor, small cell cancer, small cell lung cancer, small cell lymphoma, small intestine cancer, soft tissue sarcoma, somatostatin tumor, drusen, spinal cord tumor, spinal tumor, marginal zone lymphoma, squamous cell carcinoma, gastric cancer, superficial diffuse melanoma, supratentorial primary neuroectodermal tumor, superficial epithelial-mesenchymal tumor, synovial sarcoma, T-cell acute lymphoblastic leukemia, T-cell large granular lymphocytic leukemia, T-cell lymphoma, T-cell prolymphocytic leukemia, teratoma, peripheral lymphoid carcinoma, testicular cancer, alveolar cell tumor, throat cancer, thymus cancer, thymoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, transitional cell carcinoma, urinary tract cancer, genitourinary neoplasm, uterine sarcoma, uveal melanoma, vaginal cancer, Verner-Morrison syndrome, verrucous cancer, visual pathway glioma, vulvar cancer, Waldenstrom's macroglobulinemia, Warthin's tumor, Wilms ' tumor, or any combination thereof.

In some embodiments, the method is for treating a disease selected from the group consisting of: tumor angiogenesis, chronic inflammatory diseases such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangiomas, gliomas, melanomas, kaposi's sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancers.

In some embodiments, the method is for treating a disease selected from the group consisting of: breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer, ovarian cancer, uterine cancer, cervical cancer, leukemias such as Acute Myelogenous Leukemia (AML), acute lymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia, myelodysplasia, myeloproliferative disorders, Acute Myelogenous Leukemia (AML), Chronic Myelogenous Leukemia (CML), mastocytosis, Chronic Lymphocytic Leukemia (CLL), Multiple Myeloma (MM), myelodysplastic syndrome (MDS), epidermoid cancer, or hemoglobinopathies such as b-type thalassemia and Sickle Cell Disease (SCD).

In other embodiments, the method is for treating a disease selected from the group consisting of: breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer, ovarian cancer, uterine cancer or cervical cancer.

In other embodiments, the method is for treating a disease selected from the group consisting of: leukemias such as Acute Myelogenous Leukemia (AML), acute lymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia, myelodysplasia, myeloproliferative disorders, Acute Myelogenous Leukemia (AML), Chronic Myelogenous Leukemia (CML), mastocytosis, Chronic Lymphocytic Leukemia (CLL), Multiple Myeloma (MM), myelodysplastic syndrome (MDS), epidermoid carcinoma, or hemoglobinopathies such as thalassemia type b and Sickle Cell Disease (SCD).

In other embodiments, the method is for treating a disease selected from the group consisting of: CDKN2A deficient cancers; 9P-deficient cancers; MTAP-deficient cancers; glioblastoma, NSCLC, head and neck cancer, bladder cancer or hepatocellular carcinoma.

The compounds of the present disclosure, as well as pharmaceutical compositions comprising them, may be administered alone or in combination with medical therapy to treat any of the mentioned diseases. Medical therapies include, for example, surgery and radiation therapy (e.g., gamma radiation, neutron beam radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy, systemic radioisotopes).

In other aspects, the compounds of the present disclosure, and pharmaceutical compositions containing them, can be administered alone or in combination with one or more other agents to treat any of the diseases.

In other methods, the compounds of the present disclosure, as well as pharmaceutical compositions comprising them, may be administered in combination with an agonist of a nuclear receptor agent.

In other methods, the compounds of the present disclosure, as well as pharmaceutical compositions comprising them, may be administered in combination with an antagonist of a nuclear receptor agent.

In other methods, the compounds of the present disclosure, as well as pharmaceutical compositions comprising them, may be administered in combination with an antiproliferative agent.

In other aspects, the compounds of the present disclosure, and pharmaceutical compositions containing them, can be administered alone or in combination with one or more other chemotherapeutic agents to treat any of the disorders. Examples of other chemotherapeutic agents include, for example, abarelix (abarelix), aldesleukin (aldesleukin), alemtuzumab (alemtuzumab), alitretinoin (alitretinoin), allopurinol (allopurinol), all-trans retinoic acid, altramine (altretamine), anastrozole (anastrozole), arsenic trioxide, asparaginase, azacitidine (azacitidine), bendamustine (bendamustine), bevacizumab (bevacizumab), bexarotene (bexarotene), bleomycin (bleomycin), bortezomib (bortezombi), bortezomib (bortezomib), intravenous busulfan (busufannetus), oral albuterol, cabbaguetrizan (calcistereone), capecitabine (capecitabine), carboplatin (clavine), carboplatin (carboplatin), cisplatin (capram), chloroplatine (capram), cisplatin (capreomycin (capram), cisplatin (capram), capram (capram), capram (capram), capram (capram), capram (capram) or capram (cap, actinomycin (dactinomycin), dalteparin sodium (dalteparin sodium), dasatinib (dasatinib), daunorubicin (daunorubicin), decitabine (decitabine), dinebin (deniukin), denylleukin (denylvanil), dexrazoxane (dexrazoxane), docetaxel (docetaxel), doxorubicin (doxorubicin), drostandrosterone (doxorubicin), drostasterone propionate (dromostanolone propionate), eculizumab (eculizumab), epirubicin (epirubicin), erlotinib (erlotinib), estramustine (estramustine), etoposide phosphate (etoposide phosphate), etoposide (etoposide), exemestane (exestine), citric acid (trafungitinib), norubine (flunaridine), flunaridine (flunaridine acetate), flunaridine (flunaridine), flunaridine (flurocidine acetate (flurocidine), doxorubine (flurocidine), gefitinib (flurocidine), gefitinib (flunarine (flurocidine), gefitinib (flurocine), gefitinib (flurocine), gefit, ibritumomab tiuxetan (ibritumomab tiuxetan), idarubicin (idarubicin), ifosfamide (ifosfamide), imatinib mesylate (imatinib mesylate), interferon alpha 2a, irinotecan (irinotecan), lapatinib ditosylate xylenesulfonate (lapatinib), lenalidomide (lenalidomide), letrozole (letrozole), leucovorin (leucovorin), leuprolide acetate (leuprolide acetate), levamisole (levamisole), lomustine (lostemustine), mechlorethamine (meclorethamine), megestrol acetate (megestrol acetate), phaymelaelan (melphalan), mercaptopurine (mercaptopridine), methotrexate (methoxitrexate), methoxsalen (methoxsalen), mitomycin C (mitomycin C), paclitaxel (mitomycin C (mitomycin), paclitaxel (oxyphotoxin), oxyphotoxin (oxyphenbutazone), pemetrexed (pegaspargease), pefilgrastim (pegfilgrastim), pemetrexed disodium (pemetrexed disodium), pentostatin (pentostatin), pipobroman (pipobroman), pyricamycin (plicamycin), procarbazine (procarbazine), quinacrine (quinacrine), labrarinase (rasburiricin), rituximab (rituximab), ruxolitinib (ruxolitinib), sorafenib (sorafenib), streptozotocin (strezocin), sunitinib (sunitinib), sunitinib maleate, tamoxifen (tamoxifen), temozolomide (temozolomide), teniposide (teiposide), testolactone (testotine), thalidomide (thalidomide), thioflavine (thioflavine), thioflavine (vincristothecin), vincristothecin (vincristothecine), vincristothecine (vincristothecin), vincristothecin (vincristothecin), vincristine (vincristothecin), vincristine (vincristine), rituximab (vincristine), vinifer-a), vinorelbine (vinorelbine), vorinostat (vorinostat) and zoledronate (zoledronate), and any combination thereof.

In other aspects, the other agent is a therapeutic agent that targets an epigenetic modulator. Examples of epigenetic modulators include, for example, bromodomain inhibitors, histone lysine methyltransferases, histone arginine methyltransferases, histone demethylases, histone deacetylases, histone acetylases, and DNA methyltransferases, and any combination thereof. Histone deacetylase inhibitors are preferred in some aspects and include, for example, vorinostat.

In other methods where the disease to be treated is cancer or another proliferative disease, the compounds of the present disclosure, as well as pharmaceutical compositions comprising them, may be administered in combination with a targeted therapeutic agent. Targeted therapies include, for example, JAK kinase inhibitors (e.g., ruxolitinib), PI3 kinase inhibitors (including PI 3K-selective and broad spectrum PI3K inhibitors), MEK inhibitors, cyclin-dependent kinase inhibitors (e.g., CDK4/6 inhibitors), BRAF inhibitors, mTOR inhibitors, proteasome inhibitors (e.g., bortezomib, Carfilzomib), HDAC inhibitors (e.g., panobinostat, vorinostat), DNA methyltransferase inhibitors, dexamethasone, bromo and extra-terminal family members, BTK inhibitors (e.g., ibrutinib, alcafatinib), BCL2 inhibitors (e.g., vernetocorx), MCL1 inhibitors, PARP inhibitors, FLT3 inhibitors, and LSD1 inhibitors, and any combination thereof.

In other methods where the disease to be treated is cancer or another proliferative disease, the compounds of the present disclosure, as well as pharmaceutical compositions comprising them, may be administered in combination with an immune checkpoint inhibitor. Immune checkpoint inhibitors include, for example, inhibitors of PD-1, such as anti-PD-1 monoclonal antibodies. Examples of anti-PD-1 monoclonal antibodies include, for example, nivolumab (nivolumab), pembrolizumab (also known as MK-3475), pidilizumab (pidilizumab), SHR-1210, PDR001, and AMP-224, and combinations thereof. In some aspects, the anti-PD 1 antibody is nivolumab. In some aspects, the anti-PD 1 antibody is pembrolizumab. In some aspects, the immune checkpoint inhibitor is an inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody. In some aspects, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446) or MSB0010718C, or any combination thereof. In some aspects, the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI 4736. In other aspects, the immune checkpoint inhibitor is an inhibitor of, e.g., CTLA-4 and an anti-CTLA-4 antibody. In some aspects, the anti-CTLA-4 antibody is ipilimumab (ipilimumab).

In other methods where the disease to be treated is cancer or another proliferative disease, the compounds of the present disclosure, and pharmaceutical compositions comprising them, may be administered in combination with: alkylating agents (e.g., Cyclophosphamide (CY), Melphalan (MEL), and bendamustine), proteasome inhibitors (e.g., carfilzomib), corticosteroid agents (e.g., Dexamethasone (DEX)) or immunomodulatory agents (e.g., Lenalidomide (LEN) or Pomalidomide (POM)) or any combination thereof.

In some embodiments, the disease to be treated is an autoimmune condition or an inflammatory condition. In these aspects, the compounds of the present disclosure, and pharmaceutical compositions comprising them, may be administered in combination with: corticosteroid agents such as triamcinolone (triamcinolone), dexamethasone, fluocinolone (fluocinolone), cortisone (cortisone), prednisolone (prednisolone) or fluorometholone (flumetholone) or any combination thereof.

In other methods where the disease to be treated is an autoimmune condition or an inflammatory condition, the compounds of the present disclosure, and pharmaceutical compositions comprising them, may be administered in combination with: immunosuppressant such as fluocinolone acetonide (RETISERT)TM) Rimexolone (AL-2178, VEXOL)TM、ALCOTM) Or cyclosporin (RESTASIS)TM) Or any combination thereof.

In these aspects, the compounds of the present disclosure, and pharmaceutical compositions comprising them, may be combined with one or more agents such as, for example, hydeaTM(hydroxyurea) in combination.

The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and methods of making such compounds. It should be understood that the scope of the present invention is not limited in any way by the following examples and preparation ranges. In the following examples, molecules having a single chiral center are present as a racemic mixture, unless otherwise indicated. Unless otherwise indicated, those molecules having two or more chiral centers exist as racemic mixtures of diastereomers. The single enantiomers/diastereomers may be obtained by methods known to those skilled in the art.

The compounds of the present disclosure may be prepared, for example, by reference to the following schemes.

Scheme 1

Scheme 2

In some aspects, compounds of the present disclosure include synthetic intermediates useful for preparing other compounds of the present disclosure. In this regard, the compounds of the present disclosure include, for example, compounds of formula SI-1, formula SI-2, formula SI-3, and formula SI-4:

wherein

Aryl is substituted or unsubstituted phenyl;

x is a halogen selected from fluorine, chlorine or bromine; and is

PG1 is a hydroxyl protecting group;

PG2 is a hydroxyl protecting group; or PG1 and PG2 together with the atoms to which they are attached form a cyclic 1, 2-dihydroxy protecting group.

In some embodiments of the compounds of formulae SI-1, SI-2, SI-3, and SI-4, aryl is-4-chlorophenyl, 4-chloro-2- (hydroxymethyl) phenyl, -3, 4-dichlorophenyl, -3, 4-difluorophenyl, -3-fluoro-4-chlorophenyl, 3-methyl-4-chlorophenyl, 3-fluoro-4-trifluoromethylphenyl, 4- (trifluoromethoxy) phenyl, 4-fluoro-3-trifluoromethylphenyl, benzo [ d ] phenyl][1,3]IIOxazole, 4-isopropylphenyl or 3-chloro-4-fluorophenyl.

In some embodiments of the compounds of formulas SI-1 and SI-2, X is chloro. In other embodiments, X is fluorine. In other embodiments, X is bromine.

In some embodiments of the compounds of formulae SI-1, SI-2, SI-3, and SI-4, PG1 and PG2 are each hydroxy protecting groups, or PG1 and PG2 together with the atoms to which they are attached form cyclic 1, 2-dihydroxy protecting groups.

In some embodiments of the compounds of formulas SI-1, SI-2, SI-3, and SI-4, PG1 and PG2 are each hydroxy protecting groups. In other embodiments, PG1 and PG2, together with the atoms to which they are attached, form a cyclic 1, 2-dihydroxy protecting group. Suitable protecting groups are well known to those skilled in the art. See, e.g., Wuts, Peter GM and theodora w.greene, "protective groups in organic synthesis of green" (Greene's protective groups in organic synthesis), John Wiley & Sons, 2006. In some embodiments, PG1 and PG2 together form a ketal. In other embodiments, PG1 and PG2 together form a dialkyl acetal. In some embodiments, PG1 and PG2 together form an acetonide protecting group, and the compounds have the formulae SI-1a, SI-2a, SI-3a, and SI-4 a:

specific embodiments of the compounds of formulae SI-1, SI-2, SI-3, and SI-4 are described in the Experimental procedures section set forth below.

Compounds of the present disclosure include, for example, the compounds identified in table a.

TABLE A

Experimental procedures

Synthesis of intermediates

Synthesis of Int-1

Step 1 Synthesis of ((3aR,5R,6S,6aR) -6-hydroxy-2, 2-dimethyltetrahydrofuro [2,3-d ] [1,3] dioxol-5-yl) methyl benzoate (Int-1-2)

At 0 ℃ under N2To a mixture of compound Int-1-1(40.00g, 210.31mmol, 1 eq) in DCM (400mL) was added TEA (63.84g, 630.94mmol, 87.82mL, 3 eq) dropwise. At 0 ℃ under N2BzCl (32.52g, 231.34mmol, 26.88mL, 1.1 equiv.) is added dropwise to the mixture. In N2The mixture was then stirred at 0 ℃ for 1 hour, the mixture was combined with another reaction mixture having 10g Int-1-1, the combined mixture was quenched with water (600mL), the organic layer was separated, the aqueous layer was extracted with DCM (300mL × 3), the combined organic layers were extracted with saturated NaHCO3The solution (400mL) was washed with Na2SO4Dried, filtered and concentrated. By column chromatography (SiO)2Petroleum ether/ethyl acetate 50/1 to 2/1) to give compound 2(67.00g, 227.66mmol, 86.60% yield) as a yellow solid.1H NMR (400MHz, chloroform-d) 8.12-7.95(m,2H),7.66-7.53(m,1H),7.51-7.41(m,2H),5.97(d, J ═ 3.7Hz,1H),4.87-4.75(m,1H),4.60(d, J ═ 3.5Hz,1H),4.47-4.35(m,2H),4.19(dd, J ═ 2.2,4.0Hz,1H),3.27(d, J ═ 4.0Hz,1H),1.52(s,3H),1.33(s, 3H).

Step 2 Synthesis of ((3aR,5R,6aS) -2, 2-dimethyl-6-oxotetrahydrofuro [2,3-d ] [1,3] dioxol-5-yl) methyl benzoate (Int-1)

Two batches were run in parallel: to a mixture of compound Int-1-2(10.00g, 33.98mmol, 1 eq) in DCM (100mL) was added DMP (43.24g, 101.94mmol, 31.56mL, 3 eq) at 0 ℃. The mixture was stirred at 15 ℃ for 4 hours. The mixture was filtered and the filtrate was concentrated. The residue was diluted with EtOAc (500mL) and the mixture was filtered. With saturated NaHCO3The filtrate was diluted (300mL), the mixture was extracted with EtOAc (200mL × 3), the combined organic layers were washed with brine (300mL), and Na2SO4Dried, filtered and concentrated. By column chromatography (SiO)2Petroleum ether/ethyl acetate 20/1 to 3/1) to yield a white solidInt-1(17.00g, 58.16mmol, 85.59% yield) from somatic.1H NMR (400MHz, chloroform-d) ═ 8.00-7.91(m,2H),7.65-7.53(m,1H),7.50-7.40(m,2H),6.15(d, J ═ 4.4Hz,1H),4.78-4.67(m,2H),4.54-4.41(m,2H),1.53(s,3H),1.44(s,3H)

Synthesis of 2-chloroquinolin-7-ol (Int-2)

To a mixture of quinoline-2, 7-diol (Int-2-1, 5.00g, 31.03mmol, 1 eq) in DMF (50mL) was added dropwise thionyl chloride (14.76g, 124.10mmol, 9.00mL, 4 eq) at 0 ℃. The mixture was stirred at 20 ℃ for 30 minutes and then at 70 ℃ for 2 hours. The mixture was concentrated to a residue. With saturated NaHCO3The residue was diluted with solution (100mL), the mixture was extracted with EtOAc (30mL × 4), the combined organic layers were washed with brine (40mL), and Na2SO4Dried, filtered and concentrated. By column chromatography (SiO)2Petroleum ether/ethyl acetate 50/1 to 3/1) to give compound Int-2(5.30g, 29.51mmol, 95.11% yield) as a yellow solid.1H NMR (400MHz, chloroform-d) 8.03(d, J8.4 Hz,1H),7.73(d, J8.8 Hz,1H),7.34(d, J2.3 Hz,1H),7.25(s,1H),7.20(dd, J2.5, 8.9Hz,1H),5.45(s, 1H).

Synthesis of Int-3

To a mixture of compound Int-3-1(200mg, 1.62mmol, 1 equiv.) in THF (6mL) at 25 ℃ was added Boc2O (425.32mg, 1.95mmol, 447.71uL, 1.2 equiv.). The mixture was stirred at 25 ℃ for 3 hours. LCMS showed consumption of compound Int-3-1 and desired MS was observed. The reaction was passed through saturated NaHCO3The solution was quenched (10mL), extracted with EtOAc (5mL × 3) and the combined organic layers were washed with Na2SO4Dried, filtered and concentrated. By column chromatography (SiO)2Petroleum ether/ethyl acetate 1/0 to 1/1) to yield as colorless oilCompound Int-3(180mg, 789.36umol, 48.61% yield, LCMS purity 97.91%).1H NMR (400MHz, chloroform-d) 7.20(t, J7.8 Hz,1H),6.91-6.69(m,3H),4.81(s,1H),4.28(br d, J5.5 Hz,2H),1.47(s,9H)

Synthesis of Int-4

To a mixture of compound Int-4-1(14.5g, 94.42mmol, 1 equiv.) and Selectfluor (50.17g, 141.63mmol, 1.5 equiv.) was added ACN (725mL), AcOH (152.25g, 2.54mol, 145mL, 26.85 equiv.) and degassed and then N2Purge 3 times, then at N2The mixture was stirred at 70 ℃ for 16 hours under an atmosphere. LCMS showed no residue of compound Int-4-1. Several new peaks were shown on LCMS and-45% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with toluene (200mL) and concentrated twice under reduced pressure to remove the solvent. By column chromatography (SiO)2Petroleum ether/ethyl acetate 30/1 to 8/1) to yield compound Int-4(10g, 54.46mmol, 57.68% yield, LCMS purity 93.43%) as a yellow solid.1H NMR(400MHz,DMSO-d6)ppm12.49(brs,1H)8.55-8.67(m,1H)7.71(t,J＝2.63Hz,1H)；LCMS:(M+H+):171.9。

Synthesis of Int-5

Step 1.7 preparation of bromoquinolin-2-amine (Int-5-2)

Compound Int-5-1(6g, 24.74mmol, 1 eq.) in NH3·H2O (80mL) and twoThe solution in alkane (80mL) was stirred at 120 ℃ for 6 hours (50 psi). TLC showed that compound Int-1-1 remained and a new spot was formed. According to TLC (petroleum ether/ethyl acetate 5:1, R) f 0.08), the reaction was clean. Mixing the reactionThe mixture was concentrated under reduced pressure to remove the solvent. The residue is washed with H2O (100mL) diluted and extracted with EtOAc (50mL × 3) the combined organic layers were taken over Na2SO4Dried, filtered and concentrated under reduced pressure to give a residue. By column chromatography (SiO)2Petroleum ether/ethyl acetate 50:1 to 1:1) purification residue. Compound Int-5-2(3.25g, 14.29mmol, 57.77% yield, 98.11% purity) was obtained as a yellow solid. LCMS (M + H)+) 223.0; TLC (petroleum ether: ethyl acetate ═ 5:1) Rf＝0.08。

Step 2.7 preparation of bromo-N-tritylquinolin-2-amine (Int-5-3)

To a solution of compound Int-5-2(0.2g, 896.58umol, 1 eq) in ACN (10mL) at 25 deg.C was added TEA (181.45mg, 1.79mmol, 249.59uL, 2 eq) and TrtCl (299.93mg, 1.08mmol, 1.2 eq). The mixture was stirred at 80 ℃ for 0.5 hour. TLC showed compound Int-5-2 remained and formed a new spot (petroleum ether: ethyl acetate ═ 3:1, R)f0.68). The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue is washed with H2O15 mL diluted and extracted with DCM (10mL × 3.) the combined organic layers were washed with brine (20mL × 2) and Na2SO4Dried, filtered and concentrated under reduced pressure to give a residue. By column chromatography (SiO)2Petroleum ether/ethyl acetate 1:0 to 5:1) and based on TLC (petroleum ether: ethyl acetate 3:1, R)f0.68) the residue was purified. Compound Int-5-3(2g, 3.45mmol, 76.90% yield, 80.22% purity) was obtained as a white solid. TLC (petroleum ether: ethyl acetate ═ 3:1) Rf＝0.68；LCMS:(M+H+):467.0. LCMS purity 80.22%;1h NMR (400MHz, chloroform-d) 7.69(s,1H),7.39(d, J9.04 Hz,1H),7.13-7.35(m,15H),6.46(s,1H),6.15(d, J9.04 Hz, 1H).

Step 3.2 preparation of 2- (tritylamino) quinolin-7-ol (Int-5)

In N2To compound Int-5-3(0.6g, 1.29mmol, 1 eq.) in bis at 25 deg.CAlkane (3mL) and H2In O (3mL)To the solution of (3) was added KOH (289.36mg, 5.16mmol, 4 equiv.), X-PPHOS (95.48mg, 193.39umol, 0.15 equiv.), and Pd2(dba)3(118.06mg, 128.93umol, 0.1 equiv.). The mixture was stirred at 80 ℃ for 16 hours. LC-MS showed no residue of compound Int-5-3. One major peak was shown on LC-MS and the desired compound was detected. The reaction mixture was filtered, and the solution was concentrated under reduced pressure to remove the solvent. The residue is washed with H2O10 mL diluted and extracted with DCM (15mL × 2.) the combined organic layers were washed with brine (10mL × 2) and Na2SO4Dried, filtered and concentrated under reduced pressure to give a residue. By preparative TLC (SiO)2Petroleum ether/ethyl acetate 1:1, 5% TEA) and based on TLC (petroleum ether/ethyl acetate 1:1, R)f0.21, 5% TEA) the residue was purified. Compound Int-5(0.23g, crude material) was obtained as a yellow solid. TLC (Petroleum ether: ethyl acetate ═ 1:1, 5% TEA) Rf＝0.21；LCMS:(M+H+):403.1。

Synthesis of Int-6

At 40 ℃ under N2Next, to a solution of Mg (979.09Mg, 40.28mmol, 1.3 equivalents) was added THF (26mL) containing compound Int-6-1(7g, 30.99mmol, 1 equivalent). The mixture was stirred at 40 ℃ for 0.5 h. Mg is consumed. Compound Int-6(7.75g, crude material) in THF (26mL) was used in the next step as a yellow liquid without further purification.

Synthesis of Int-7

At 25 ℃ under N2Down-ward Mg (362.73Mg, 14.92mmol, 1.5 equiv.) and I2(252.52mg, 994.94umol, 200.42uL, 0.1 eq.) to a mixture was added THF (20mL) containing compound Int-7-1(2g, 9.95mmol, 1.19mL, 1 eq.). The mixture was stirred at 25 ℃ for 0.5 hour. Mg is consumed. Compound Int-7(2.24g, crude) obtained in THF (20mL)Material) which was used in the next step as a brown oil.

Synthesis of Int-8

A50 mL RBF with septum containing Mg (34.01Mg, 1.42mmol) was dried under high vacuum with a heat gun and cooled under Ar. The flask was charged with THF (0.40mL), 2/5 parts of 4-bromo-1-chloro-2-methylbenzene (0.19mL, 1.34mmol), and one drop of DIBAL (1M, toluene). The reaction was stirred at room temperature, but no exotherm was observed, which could mean that the magnesium did not initiate. Another drop of DIBAL was added, this time with some exotherm. After stirring for 10 minutes, the remaining 4-bromo-1-chloro-2-methylbenzene and additional THF (0.30mL) were added and stirring was continued for 1 hour. When all magnesium was dissolved, Grignard reagent (Grignard reagent) Int-8 was used as such.

Synthesis of Int-9

To a solution of 3-bromo-2-chloro-7-methoxy-quinoline (Int-9-1, WO2017/032840a1) (640.mg, 2.35mmol) in chloroform (70mL) at 0 ℃ was added boron tribromide (4.4mL, 46.97mmol) and the reaction mixture was stirred at 80 ℃ overnight. TLC (PE: EA ═ 1:1, Rf ═ 0.5) and LCMS showed 12% SM remaining. The reaction was quenched slowly with MeOH at 0 deg.C, EA was added and NaHCO was used3The aqueous solution was adjusted to pH 8. The organic phase was separated and washed with brine. The organic phase was concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (PE: EA ═ 2:1 to PE: EA ═ 1:1) to give 3-bromo-2-chloro-quinolin-7-ol (Int-9) (339mg, 1.2852mmol, 54.727% yield) as a white solid. LCMSM + H+:258/260.1/262

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