Isoindolone inhibitors of MDM2-P53 interaction with anticancer activity

Abstract

The present invention provides a compound of formula (I): (I) or its tautomer or solvate or pharmaceutically acceptable salt, wherein various substituents are as defined in the claims. Also provided are a pharmaceutical composition containing the compound of formula (I), a method for preparing the compound and the medical use of the compound.

Description

[0001] This application is a divisional application. The application number of the original application is 201680056529.2, the application date is September 29, 2016, the priority date is September 29, 2015, and the name of the invention is "Isoindolinone inhibitors of MDM2-P53 interaction with anti-cancer activity". Technical Field

[0002] The present invention relates to novel isoindolin-1-one derivatives, pharmaceutical compositions comprising said compounds and the use of said compounds for treating diseases such as cancer.

[0003] Related Applications

[0004] This application is related to UK patent application number 1517217.4 filed on September 29, 2015, the contents of which are incorporated herein by reference in their entirety. Background Art

[0005] The transformation-related protein 53 (TP53) gene encodes a 53KDa protein p53. The tumor suppressor protein p53 responds to cellular stresses such as hypoxia, DNA damage, and oncogenic activation via many post-translational modifications including phosphorylation, acetylation, and methylation, and serves as a signal transduction node in different pathways that are activated. p53 has additional roles in other physiological processes, including autophagy, cell adhesion, cell metabolism, fertility, and stem cell aging and development. The phosphorylation of p53 caused by the activation of kinases including ATM, CHK1 and CHK2, and DNA-PK produces a stabilized and transcriptionally active form of the protein, thereby producing a series of gene products. The response to p53 activation includes apoptosis, survival, cell cycle arrest, DNA repair, angiogenesis, invasion, and self-regulation. Its specific combination and the genetic background of the cell jointly produce the observed cellular effects, i.e., apoptosis, cell cycle arrest, or aging. For tumor cells, the apoptotic pathway may be promoted due to the loss of tumor suppressor proteins and related cell cycle checkpoint control in conjunction with oncogenic stress.

[0006] Under conditions of stress such as hypoxia and DNA damage, cellular levels of the protein p53 are known to increase. p53 is known to initiate transcription of many genes that determine progression through the cell cycle, initiation of DNA repair, and programmed cell death. This provides a mechanism for the tumor suppressor role of p53 that has been confirmed by genetic studies.

[0007] The binding interaction with the MDM2 protein negatively and tightly regulates the activity of p53, whose transcription is itself directly regulated by p53. When the transactivation domain of p53 is bound by the MDM2 protein, it is inactivated. Once inactivated, the function of p53 is repressed and the p53-MDM2 complex becomes a target for ubiquitination.

[0008] In normal cells, the balance between active p53 and inactive MDM2-bound p53 is maintained in an autoregulatory negative feedback loop. That is, p53 can activate MDM2 expression, which in turn leads to the repression of p53.

[0009] Inactivation of p53 by mutation has been found to be common in about half of all common adult sporadic cancers. In addition, in about 10% of tumors, gene amplification and overexpression of MDM2 leads to loss of functional p53, causing malignant transformation and uncontrolled tumor growth.

[0010] Inactivation of p53 by a variety of mechanisms is a common causal event in the development and progression of cancer. These include inactivation caused by mutation, targeting by oncogenic viruses, and in a large proportion of cases, amplification of the MDM2 gene and / or increased transcription rate, resulting in overexpression or increased activation of the MDM2 protein. Gene amplification of MDM2 resulting in overexpression of the MDM2 protein has been observed in tumor samples taken from common sporadic cancers. Overall, approximately 10% of tumors have MDM2 amplification, with the highest incidence found in hepatocellular carcinoma (44%), lung (15%), sarcomas and osteosarcomas (28%), and Hodgkin disease (67%) (Danovi et al., Mol. Cell. Biol. 2004, 24, 5835-5843; Toledo et al., Nat Rev Cancer 2006, 6, 909-923; Gembarska et al., Nat Med 2012, 18, 1239-1247). Normally, transcriptional activation of MDM2 by activated p53 results in increased MDM2 protein levels, thereby forming a negative feedback loop. The fundamental nature of p53 regulation by MDM2 and MDMX is demonstrated by knockout mouse models. MDM2- / - knockout mice experience embryonic lethality at approximately the time of implantation. The lethality was rescued in double knockout of Mdm2 and Trp53. MDM2 directly inhibits the activity of p53 by binding and blocking the p53 transactivation domain and promoting proteasomal destruction of the complex via its E3-ubiquitin ligase activity. In addition, MDM2 is a transcriptional target of p53, and thus, the two proteins are linked in an autoregulatory feedback loop, ensuring that p53 activation is transient.

[0011] Induction of the p14ARF protein, the product of the alternate reading frame (ARF) of the p16INK4a locus, is also a mechanism for negatively regulating the p53-MDM2 interaction. p14ARF directly interacts with MDM2 and causes upregulation of the p53 transcriptional response. Loss of p14ARF caused by homozygous mutations in the CDKN2A (INK4A) gene will result in elevated levels of MDM2 and, thereby, loss of p53 function and cell cycle control.

[0012] Although MDMX shows strong amino acid sequence and structural homology with MDM2, neither protein can replace the loss of the other; MDMX-deficient mice die in utero, while MDM2 knockout is lethal during early embryogenesis, however, both can be rescued by p53 knockout, which indicates the p53 dependence of the lethality. MDMX also binds to p53 and inhibits p53-dependent transcription, but unlike MDM2, it is not activated by p53 transcriptionally, and therefore, does not form the same autoregulatory loop. In addition, MDMX has neither E3 ubiquitin ligase activity nor nuclear localization signal, yet it is thought to promote p53 degradation by forming heterodimers with MDM2 and promoting MDM2 stabilization.

[0013] The therapeutic rationale for MDM2-p53 inhibition is that potent inhibitors of protein-protein interactions will free p53 from the repressive control of MDM2 and activate p53-mediated cell death in tumors. In tumors, the selectivity is envisioned to result from p53 sensing pre-existing DNA damage or oncogenic activation signals that were previously blocked by normal or overexpressed levels of MDM2. In normal cells, p53 activation is expected to result in activation of non-apoptotic pathways and protective growth inhibitory responses, if any. Furthermore, due to their non-genotoxic mechanism of action, MDM2-p53 inhibitors are suitable for the treatment of cancer, particularly in the pediatric population.

[0014] About 50% of cancers contain mutations in the gene TP53 encoding p53, resulting in loss of the protein's tumor suppressor function and sometimes even giving rise to cells with versions of the p53 protein that acquire new oncogenic functions.

[0015] Cancers in which high levels of MDM2 amplification are present include liposarcoma (88%), soft tissue sarcoma (20%), osteosarcoma (16%), esophageal cancer (13%), and certain pediatric malignancies, including B-cell malignancies.

[0016] The present invention describes a series of novel compounds that selectively inhibit MDM2-p53 interaction and possess anticancer activity. Summary of the invention

[0017] In one aspect, the present invention provides a compound of formula (I):

[0018]

[0019] or a tautomer or solvate or a pharmaceutically acceptable salt thereof, wherein:

[0020] R 1 are independently selected from hydroxy, halogen, nitro, nitrile, C 1-4 Alkyl, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 2-6 Alkenyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 2-4 Alkynyl, -O 0,1 -(CR x R y ) v -CO 2 H, -(CR x R y ) v -CO 2 C 1-4 Alkyl, -(CR x R y ) v -CON(C 1-4 alkyl) 2 ,-P(=O)(R x ) 2 、-S(O) d -R x 、-S(O) d -heterocyclyl having 3 to 6 ring members and -S(O) d -N(R 8 ) 2 ;

[0021] R 2 Selected from hydrogen, C 1-4 Alkyl, C 2-6 Alkenyl, hydroxyl C 1-4 Alkyl, -(CR x R y ) u -CO 2 H, -(CR x R y ) u -CO 2 C 1-4 Alkyl, and -(CR x R y ) u-CONR x R y ;

[0022] s is selected from 0 and 1;

[0023] R 3 is hydrogen or -(A) t -(CR x R y ) q -X;

[0024] t is selected from 0 and 1;

[0025] q is selected from 0, 1 and 2;

[0026] When R 3 Yes - (A) t -(CR x R y ) q -X, then (i) at least one of s, t, and q is not 0; and (ii) when t is 0, then s is 1 and q is not 0;

[0027] A is for C 3-6 Cycloalkyl or heterocyclyl having 3 to 6 ring members, wherein the heterocyclyl contains one or more (e.g. 1, 2, or 3) heteroatoms selected from N, O, S and oxidized forms thereof;

[0028] X is selected from hydrogen, halogen, -CN, -OR 9 、-(CH 2 ) v -CO 2 H, -(CH 2 ) v -CO 2 C 1-4 Alkyl, -S(O) d -R x , -C(=O)-C 1-4 Alkyl, -S(O) d -N(H) e (C 1-4 alkyl) 2-e 、-NR x R y 、-NHSO 2 R x 、-NR x COR y , and -C(=O)NR x R y ;

[0029] R 4 and R 5 independently selected from halogen, nitrile, C1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy and halogenated C 1-4 Alkoxy;

[0030] R 6 and R 7 are independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Hydroxyl, Hydroxyl C 1-6 Alkyl, -COOC 1-6 Alkyl, -(CH 2 ) j -OC 1-6 Alkyl, -(CH 2 ) j -O-(Hydroxy C 1-6 Alkyl), -C 1-6 Alkyl-NR x R y 、-(CR x R y ) p -CONR x R y 、-(CR x R y ) p -NR x COR y 、-(CR x R y ) p -O-CH 2 -CONR x R y , a heterocyclic group having 3 to 7 ring members, -CH 2 -heterocyclyl having 3 to 7 ring members, -CH 2 -O-heterocyclic group having 3 to 7 ring members, -CH 2 -NH-heterocyclic group having 3 to 7 ring members, -CH 2 -N(C 1-6 -C(=O)NH-heterocyclic group having 3 to 7 ring members, C 3-8 Cycloalkyl, -CH 2 -C 3-8 Cycloalkyl, -CH 2 -OC 3-8 Cycloalkyl, and C 3-8 Cycloalkenyl, wherein the cycloalkyl, cycloalkenyl or heterocyclic group may be optionally substituted by one or more R zsubstituted with a group, and wherein in each case, the heterocyclyl contains one or more (e.g., 1, 2, or 3) heteroatoms selected from N, O, S, and oxidized forms thereof;

[0031] or the R 6 Group and R 7 The groups together with the carbon atoms to which they are attached can be linked to form C 3-6 Cycloalkyl or heterocyclyl having 3 to 6 ring members, wherein the heterocyclyl contains one or more (e.g., 1, 2, or 3) heteroatoms selected from N, O, S and oxidized forms thereof, and wherein the C 3-6 Cycloalkyl and heterocyclyl groups may be optionally substituted with one or more R z Group substitution;

[0032] R 8 and R 9 are independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, -(CH 2 ) k -OC 1-6 Alkyl, -(CH 2 ) k -O-(Hydroxy C 1-6 Alkyl), hydroxyl C 1-6 Alkoxy, -(CH 2 ) k -CO 2 C 1-6 Alkyl, -(CH 2 ) k -CO 2 H, -C 1-6 Alkyl-N(H) e (C 1-4 alkyl) 2-e 、-(CH 2 ) j -C 3-8 Cycloalkyl and -(CH 2 ) j -C 3-8 Cycloalkenyl;

[0033] R x and R y are independently selected from hydrogen, halogen, nitro, nitrile, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Hydroxyl, Hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, -(CH 2 )k -OC 1-6 Alkyl, hydroxyl C 1-6 Alkoxy, -COOC 1-6 Alkyl, -N(H) e (C 1-4 alkyl) 2-e , -C 1-6 Alkyl-N(H) e (C 1-4 alkyl) 2-e 、-(CH 2 ) k -C(=O)N(H) e (C 1-4 alkyl) 2-e , C 3-8 Cycloalkyl and C 3-8 Cycloalkenyl;

[0034] or the R x Group and R y The groups together with the carbon or nitrogen atoms to which they are attached can be linked to form C 3-6 a cycloalkyl group or a saturated heterocyclic group having 3 to 6 ring members, which may be optionally condensed with an aromatic heterocyclic group having 3 to 5 ring members;

[0035] or when on a carbon atom, the R x Group and R y The groups can be linked together to form =CH 2 Group;

[0036] R z are independently selected from halogen, nitro, nitrile, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, =O, Hydroxyl, Hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, -(CH 2 ) k -OC 1-6 Alkyl, hydroxyl C 1-6 Alkoxy, -C(=O)C 1-6 Alkyl, -C(=O)C 1-6 Alkyl-OH, -C(=O)C 1-6 Alkyl-N(H) e (C 1-4 alkyl) 2-e 、-C(=O)N(H) e (C 1-4 alkyl) 2-e 、-(CH 2 ) r-CO 2 C 1-6 Alkyl, -(CH 2 ) r -CO 2 H, -N(H) e (C 1-4 alkyl) 2-e , -C 1-6 Alkyl-N(H) e (C 1-4 alkyl) 2-e , a heterocyclic group having 3 to 6 ring members, a -C(=O)C 1-4 Alkyl-substituted heterocyclic radical having 3 to 6 ring members, -C(=O)OC 1-4 Alkyl-substituted heterocyclic radical having 3 to 6 ring members, -C(=O)N(H) e (C 1-4 alkyl) 2-e substituted heterocyclic radical having 3 to 6 ring members, -C(=O) heterocyclic radical having 3 to 6 ring members, C 3-8 Cycloalkyl and C 3-8 Cycloalkenyl, where R 7 is pyridine, then R z No -NH 2 ;

[0037] a, j, d, e, n, r and p are independently selected from 0, 1 and 2;

[0038] k and m are independently selected from 1 and 2;

[0039] u is selected from 0, 1, 2 and 3; and

[0040] v and w are independently selected from 0 and 1.

[0041] In another aspect, the present invention provides a compound of formula (I):

[0042]

[0043] or a tautomer or solvate or a pharmaceutically acceptable salt thereof, wherein:

[0044] R 1 are independently selected from hydroxy, halogen, nitro, nitrile, C 1-4 Alkyl, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 2-6 Alkenyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 2-4 Alkynyl, -(CR x Ry ) v -CO 2 H, -(CR x R y ) v -CO 2 C 1-4 Alkyl, -(CR x R y ) v -CON(C 1-4 alkyl) 2 ,-P(=O)(R x ) 2 、-S(O) d -R x 、-S(O) d -heterocyclyl having 3 to 6 ring members and -S(O) d -N(R 8 ) 2 ;

[0045] R 2 Selected from hydrogen, C 1-4 Alkyl, C 2-6 Alkenyl, hydroxyl C 1-4 Alkyl, -(CR x R y ) u -CO 2 H, -(CR x R y ) u -CO 2 C 1-4 Alkyl, and -(CR x R y ) u -CONR x R y ;

[0046] s is selected from 0 and 1;

[0047] R 3 is hydrogen or -(A) t -(CR x R y ) q -X;

[0048] t is selected from 0 and 1;

[0049] q is selected from 0, 1 and 2;

[0050] When R 3 Yes - (A) t -(CR x R y ) q-X, then (i) at least one of s, t, and q is not 0; and (ii) when t is 0, then s is 1 and q is not 0;

[0051] A is for C 3-6 Cycloalkyl or heterocyclyl having 3 to 6 ring members, wherein the heterocyclyl contains one or more (e.g. 1, 2, or 3) heteroatoms selected from N, O, S and oxidized forms thereof;

[0052] X is selected from hydrogen, halogen, -CN, -OR 9 、-(CH 2 ) v -CO 2 H, -(CH 2 ) v -CO 2 C 1-4 Alkyl, -S(O) d -R x , -C(=O)-C 1-4 Alkyl, -S(O) d -N(H) e (C 1-4 alkyl) 2-e 、-NR x R y 、-NHSO 2 R x 、-NR x COR y , and -C(=O)NR x R y ;

[0053] R 4 and R 5 independently selected from halogen, nitrile, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy and halogenated C 1-4 Alkoxy;

[0054] R 6 and R 7 are independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Hydroxyl, Hydroxyl C 1-6 Alkyl, -COOC 1-6 Alkyl, -(CH 2 ) j -OC 1-6 Alkyl, -(CH 2 ) j -O-(Hydroxy C 1-6Alkyl), -C 1-6 Alkyl-NR x R y 、-(CR x R y ) p -CONR x R y 、-(CR x R y ) p -NR x COR y 、-(CR x R y ) p -O-CH 2 -CONR x R y , a heterocyclic group having 3 to 7 ring members, -CH 2 -heterocyclyl having 3 to 7 ring members, -CH 2 -O-heterocyclic group having 3 to 7 ring members, -CH 2 -NH-heterocyclic group having 3 to 7 ring members, -CH 2 -N(C 1-6 -C(=O)NH-heterocyclic group having 3 to 7 ring members, C 3-8 Cycloalkyl, -CH 2 -C 3-8 Cycloalkyl, -CH 2 -OC 3-8 Cycloalkyl, and C 3-8 Cycloalkenyl, wherein the cycloalkyl, cycloalkenyl or heterocyclic group may be optionally substituted by one or more R z substituted with a group, and wherein in each case, the heterocyclyl contains one or more (e.g., 1, 2, or 3) heteroatoms selected from N, O, S, and oxidized forms thereof;

[0055] or the R 6 Group and R 7 The groups together with the carbon atoms to which they are attached can be linked to form C 3-6 Cycloalkyl or heterocyclyl having 3 to 6 ring members, wherein the heterocyclyl contains one or more (e.g., 1, 2, or 3) heteroatoms selected from N, O, S and oxidized forms thereof, and wherein the C 3-6 Cycloalkyl and heterocyclyl groups may be optionally substituted with one or more R z Group substitution;

[0056] R 8 and R 9 are independently selected from hydrogen, C 1-6Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, -(CH 2 ) k -OC 1-6 Alkyl, -(CH 2 ) k -O-(Hydroxy C 1-6 Alkyl), hydroxyl C 1-6 Alkoxy, -(CH 2 ) k -CO 2 C 1-6 Alkyl, -(CH 2 ) k -CO 2 H, -C 1-6 Alkyl-N(H) e (C 1-4 alkyl) 2-e 、-(CH 2 ) j -C 3-8 Cycloalkyl and -(CH 2 ) j -C 3-8 Cycloalkenyl;

[0057] R x and R y are independently selected from hydrogen, halogen, nitro, nitrile, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Hydroxyl, Hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, -(CH 2 ) k -OC 1-6 Alkyl, hydroxyl C 1-6 Alkoxy, -COOC 1-6 Alkyl, -N(H) e (C 1-4 alkyl) 2-e , -C 1-6 Alkyl-N(H) e (C 1-4 alkyl) 2-e 、-(CH 2 ) k -C(=O)N(H) e (C 1-4 alkyl) 2-e , C 3-8 Cycloalkyl and C 3-8 Cycloalkenyl;

[0058] or the R xGroup and R y The groups together with the carbon or nitrogen atoms to which they are attached can be linked to form C 3-6 a cycloalkyl group or a saturated heterocyclic group having 3 to 6 ring members, which may be optionally condensed with an aromatic heterocyclic group having 3 to 5 ring members;

[0059] or when on a carbon atom, the R x Group and R y The groups can be linked together to form =CH 2 Group;

[0060] R z are independently selected from halogen, nitro, nitrile, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, =O, Hydroxyl, Hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, -(CH 2 ) k -OC 1-6 Alkyl, hydroxyl C 1-6 Alkoxy, -C(=O)C 1-6 Alkyl, -C(=O)C 1-6 Alkyl-OH, -C(=O)C 1-6 Alkyl-N(H) e (C 1-4 alkyl) 2-e 、-C(=O)N(H) e (C 1-4 alkyl) 2-e 、-(CH 2 ) r -CO 2 C 1-6 Alkyl, -(CH 2 ) r -CO 2 H, -N(H) e (C 1-4 alkyl) 2-e , -C 1-6 Alkyl-N(H) e (C 1-4 alkyl) 2-e , a heterocyclic group having 3 to 6 ring members, a -C(=O)C 1-4 Alkyl-substituted heterocyclic radical having 3 to 6 ring members, -C(=O)OC 1-4 Alkyl-substituted heterocyclic radical having 3 to 6 ring members, -C(=O)N(H) e (C 1-4 alkyl) 2-esubstituted heterocyclic radical having 3 to 6 ring members, -C(=O) heterocyclic radical having 3 to 6 ring members, C 3-8 Cycloalkyl and C 3-8 Cycloalkenyl, where R 7 is pyridine, then R z No -NH 2 ;

[0061] a, j, d, e, n, r and p are independently selected from 0, 1 and 2;

[0062] k and m are independently selected from 1 and 2;

[0063] u is selected from 0, 1, 2 and 3; and

[0064] v and w are independently selected from 0 and 1.

[0065] In further aspects of the invention, provided is a compound of formula (I) for use in preventing or treating a disease or condition as described herein; a method for preventing or treating a disease or condition as described herein, the method comprising administering a compound of formula (I) to a patient; a pharmaceutical composition comprising a compound of formula (I); and a method for synthesizing a compound of formula (I).

[0066] definition

[0067] Unless the context indicates otherwise, reference to formula (I) in all parts of this document (including uses, methods and other aspects of the invention) includes reference to all other subformulae, subgroups, embodiments and examples as defined herein.

[0068] "Potency" is a measure of drug activity expressed as the amount required to produce an effect of a given intensity. Highly potent drugs elicit a greater response at low concentrations. Potency is proportional to affinity and efficacy. Affinity is the ability of a drug to bind to a receptor. Efficacy is the relationship between receptor occupancy and the ability to elicit a response at the molecular, cellular, tissue, or system level.

[0069] The term "antagonist" refers to a type of receptor ligand or drug that blocks or inhibits agonist-mediated biological responses. Antagonists have affinity to their cognate receptors, but do not have agonistic effects, and in combination will destroy the interaction of any ligand (e.g., endogenous ligand or substrate, agonist or inverse agonist) at the receptor and inhibit the function of the ligand. Antagonism can be produced directly or indirectly, and can be mediated by any mechanism and at any physiological level. Therefore, the antagonism of the ligand can be manifested in functionally different ways under different circumstances. Antagonists mediate their effects by binding to the active site or allosteric site on the receptor, or they can interact at a unique binding site that is not usually involved in biological regulation of receptor activity. Antagonist activity can be reversible or irreversible, depending on the life span of the antagonist-receptor complex, which in turn depends on the nature of the antagonist receptor binding.

[0070] As used herein, the term "mediate", as used, for example, in conjunction with MDM2 / p53 as described herein (and applied, for example, to various physiological processes, diseases, states, conditions, therapies, treatments, or interventions), is intended to operate restrictively such that the various processes, diseases, states, conditions, treatments, and interventions to which the term applies are those in which the protein plays a biological role. In cases where the term is applied to a disease, state, or condition, the biological role played by the protein may be direct or indirect and may be necessary and / or sufficient for the manifestation of the symptoms of the disease, state, or condition (or its cause or progression). Thus, protein function (and particularly abnormal levels of function, such as overexpression or underexpression) is not necessarily the proximate cause of the disease, state, or condition; rather, it is contemplated that the mediated disease, state, or condition includes those with multifactorial etiologies and complex progressions in which the protein under consideration is only partially involved. In cases where the term is applied to treatment, prevention, or intervention, the role played by the protein may be direct or indirect and may be necessary and / or sufficient for the operation of the treatment, prevention, or the outcome of the intervention. Thus, disease states or conditions mediated by the protein include the development of resistance to any particular cancer drug or treatment.

[0071] The term "treatment" as used herein in the context of treating a condition, i.e., a state, disorder, or disease, generally refers to treatment and therapy, whether for humans or animals (e.g., in veterinary applications), in which a certain desired therapeutic effect is achieved, such as inhibiting the progression of the condition, and includes a reduction in the rate of progression, a halt in the rate of progression, an improvement in the condition, a reduction or alleviation of at least one symptom associated with or caused by the condition being treated, and a cure for the condition. For example, treatment can be a reduction in one or several symptoms of a condition or a complete eradication of the condition.

[0072] The term "prevention" as used herein in the context of treating a condition, i.e., a state, disorder, or disease (i.e., using a compound as a preventative measure) generally refers to prophylaxis or protection, whether for humans or animals (e.g., in veterinary applications), in which some desired preventive effect is achieved, e.g., preventing the onset of a disease or guarding against a disease. Prevention includes complete and total prevention of all symptoms of a disorder for an indefinite period of time; merely slowing the onset of one or several symptoms of the disease; or making the disease less likely to occur.

[0073] References to the prevention or treatment of a disease state or condition, such as cancer, include within their scope the alleviation or reduction of the incidence of, for example, cancer.

[0074] The combinations of the present invention may produce therapeutically effective effects relative to the therapeutic effects of the individual compounds / agents when administered alone.

[0075] The term 'effective' includes beneficial effects such as additive effects, synergistic effects, reduced side effects, reduced toxicity, prolonged time to disease progression, prolonged survival, sensitization or resensitization of one agent to another, or improved response rate. Advantageously, an effective effect can allow a lower dose of each or any component to be administered to the patient, thereby reducing the toxicity of chemotherapy while producing and / or maintaining the same therapeutic effect. A "synergistic" effect in the context of the present invention refers to a therapeutic effect produced by a combination that is greater than the sum of the therapeutic effects of the agents of the combination when presented alone. An "additive" effect in the context of the present invention refers to a therapeutic effect produced by a combination that is greater than the therapeutic effect of any of the agents of the combination when presented alone. The term "response rate" as used herein refers to the extent to which the tumor size is reduced at a given time point, such as 12 weeks, in the case of solid tumors. Thus, for example, a 50% response rate means a 50% reduction in tumor size. When "clinical response" is mentioned herein, a response rate of 50% or greater is referred to. A "partial response" is defined herein as a response rate of less than 50%.

[0076] As used herein, the term "combination" as applied to two or more compounds and / or agents is intended to define a material in which the two or more agents are associated. In this context, the terms "combined" and "combination" will be interpreted accordingly.

[0077] The association of the two or more compounds / agents in the combination may be physical or non-physical. Examples of physically associated combined compounds / agents include:

[0078] a composition (e.g., a single formulation) comprising a mixture (e.g., within the same unit dose) of the two or more compounds / agents;

[0079] Compositions comprising materials in which two or more compounds / agents are chemically / physicochemically linked (e.g., by cross-linking, molecular agglomeration, or association with a common vehicle moiety);

[0080] a composition comprising a material in which the two or more compounds / agents are chemically / physicochemically co-packaged (e.g. disposed on or within a lipid vesicle, particle (e.g. microparticle or nanoparticle) or emulsion);

[0081] a pharmaceutical kit, pharmaceutical pack or patient pack in which the two or more compounds / agents are co-packaged or co-present (e.g. as part of a series of unit doses);

[0082] Examples of non-physically associated combined compounds / agents include:

[0083] Materials (e.g., non-unitary formulations) that include at least one of the two or more compounds / agents and instructions for temporarily associating the at least one compound to form a physical association of the two or more compounds / agents;

[0084] Materials (e.g., not a single formulation) that include at least one of the two or more compounds / agents and instructions for using the two or more compounds / agents for combination therapy;

[0085] Materials comprising at least one of the two or more compounds / agents and instructions for administration to a patient population, wherein one or more other of the two or more compounds / agents have been (or are being) administered;

[0086] - A material comprising at least one of the two or more compounds / agents in an amount or form particularly suitable for use in combination with one or more other of the two or more compounds / agents.

[0087] As used herein, the term "combination therapy" is intended to define a treatment including the use of a combination (as defined above) of two or more compounds / agents. Therefore, when "combination therapy", "combination" and the use of compound / agent "combination" in the present application are mentioned, it can refer to a compound / agent administered as part of the same overall treatment regimen. Thus, the posology of each of the two or more compounds / agents may be different: each can be administered simultaneously or at different times. Therefore, it will be understood that the compound / agent of the combination can be administered sequentially (e.g., before or after) or simultaneously with the same pharmaceutical preparation (i.e., together) or with different pharmaceutical preparations (i.e., separately). It is used as a single preparation to administer the same preparation simultaneously, and it is a non-single preparation to administer the same preparation simultaneously with different pharmaceutical preparations. The posology of each of the two or more compounds / agents described in the combination therapy can also be different in terms of route of administration.

[0088] As used herein, the term "drug kit" defines a series of one or more unit doses of pharmaceutical compositions and dosing devices (e.g., measuring devices) and / or delivery devices (e.g., inhalers or syringes), all of which are optionally contained in a common outer package. In a drug kit comprising a combination of two or more compounds / agents, a single compound / agent may be a single formulation or a non-single formulation. The one or more unit doses may be contained in a blister pack. The drug kit may also optionally include instructions for use.

[0089] As used herein, the term "pharmaceutical package" defines a series of one or more unit doses of pharmaceutical compositions, optionally contained in a common outer package. In a pharmaceutical package comprising a combination of two or more compounds / agents, a single compound / agent may be a single formulation or a non-single formulation. The one or more unit doses may be contained in a blister pack. The pharmaceutical package may also optionally include instructions for use.

[0090] The term 'optionally substituted' as used herein refers to a group which may be unsubstituted or substituted with a substituent as defined herein.

[0091] As used herein, the prefix "C x-y ” (where x and y are integers) refers to the number of carbon atoms in a given group. Thus, C 1-6 Alkyl groups contain 1 to 6 carbon atoms. 3-6 Cycloalkyl contains 3 to 6 carbon atoms. 1-4 Alkoxy groups contain from 1 to 4 carbon atoms, and so forth.

[0092] The term 'halo' or 'halogen' as used herein refers to fluorine, chlorine, bromine or iodine, in particular fluorine or chlorine.

[0093] Each hydrogen in a compound (e.g., in an alkyl group or otherwise referred to as hydrogen) includes all isotopes of hydrogen, particularly 1 H and 2 H (deuterium).

[0094] The term 'oxo' as used herein refers to the group =0.

[0095] As used herein as a group or part of a group, the term 'C 1-4 Alkyl' refers to a straight or branched chain saturated hydrocarbon group containing 1 to 4 carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc.

[0096] As used herein as a group or part of a group, the term 'C 2-4 Alkenyl' or 'C 2-6 Alkenyl' refers to a straight or branched hydrocarbon group containing 2 to 4 or 2 to 6 carbon atoms and containing a carbon-carbon double bond. Examples of such groups include C 3-4 Alkenyl or C 3-6 Alkenyl groups, such as ethenyl / vinyl, 1-propenyl, 2-propenyl (allyl), isopropenyl, butenyl, buta-1,4-dienyl, pentenyl, and hexenyl.

[0097] As used herein as a group or part of a group, the term 'C 2-4 Alkynyl' or 'C 2-6 Alkynyl' refers to a straight or branched hydrocarbon group having 2 to 4 or 2 to 6 carbon atoms and containing a carbon-carbon triple bond. Examples of such groups include C 3-4 Alkynyl or C 3-6 Alkynyl groups, such as ethynyl and 2-propynyl (propargyl).

[0098] As used herein as a group or part of a group, the term 'C 1-4 Alkoxy' refers to -OC 1-4 Alkyl, where C 1-4 Alkyl is as defined herein. Examples of such groups include methoxy, ethoxy, propoxy, butoxy, and the like.

[0099] As used herein, the term 'C 3-6 Cycloalkyl refers to a saturated monocyclic hydrocarbon ring having 3 to 6 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, etc.

[0100] As used herein, the term 'C 3-6Cycloalkenyl' refers to a partially saturated monocyclic hydrocarbon ring having 3 to 6 carbon atoms with one or more (usually one) carbon-carbon double bonds. Examples of such groups include cyclopentenyl, cyclohexenyl, and cyclohexadienyl.

[0101] As used herein as a group or part of a group, the term 'hydroxy 1-4 Alkyl refers to a C 1-4 An alkyl group in which one or more than one (e.g., 1, 2, or 3) hydrogen atoms are replaced by hydroxy groups. 1-4 Alkyl groups thus include monohydroxy C 1-4 Alkyl and polyhydroxy C 1-4 Alkyl. One, two, three or more hydrogen atoms may be replaced by hydroxyl groups, so that hydroxyl C 1-4 The alkyl group may have one, two, three or more hydroxyl groups. Examples of such groups include hydroxymethyl, hydroxyethyl, hydroxypropyl, and the like.

[0102] As used herein as a group or part of a group, the term 'halo 1-4 Alkyl refers to a C 1-4 Alkyl, wherein one or more than one (e.g., 1, 2 or 3) hydrogen atoms are replaced by halogen. 1-4 Alkyl' therefore includes monohalogenated C 1-4 Alkyl and polyhalogenated C 1-4 Alkyl. One, two, three or more hydrogen atoms may be replaced by halogen, so that the halogenated C 1-4 The alkyl group may have one, two, three or more halogens. Examples of such groups include fluoroethyl, fluoromethyl, difluoromethyl, trifluoromethyl or trifluoroethyl and the like.

[0103] As used herein as a group or part of a group, the term 'halo 1-4 Alkoxy' refers to -OC as defined herein 1-4 Alkyl, wherein one or more than one (e.g., 1, 2 or 3) hydrogen atoms are replaced by halogen. 1-4 Alkoxy' thus includes monohalogenated C 1-4 Alkoxy and polyhalogenated C 1-4 Alkoxy. One, two, three or more hydrogen atoms may be replaced by halogen, so that the halogenated C 1-4 Alkoxy groups may have one, two, three or more halogens. Examples of such groups include fluoroethoxy, difluoromethoxy or trifluoromethoxy and the like.

[0104] Unless the context otherwise states, the term "heterocyclic radical" as used herein should include both aromatic ring systems and non-aromatic ring systems. Therefore, for example, the term "heterocyclic radical" includes aromatic, non-aromatic, unsaturated, partially saturated and saturated heterocyclic ring systems within their scope. In general, unless the context otherwise states, such a group can be monocyclic or bicyclic (including condensed, spirocyclic and bridged bicyclic groups) and can contain, for example, 3 to 12 ring members, more generally containing 5 to 10 ring members. When mentioning 4 to 7 ring members, include 4, 5, 6 or 7 atoms in the ring, and when mentioning 4 to 6 ring members, include 4, 5 or 6 atoms in the ring. The example of a monocyclic group is to contain 3, 4, 5, 6, 7 and 8 ring members, more generally 3 to 7 or 4 to 7 and preferably 5, 6 or 7 ring members, more preferably the group of 5 or 6 ring members. Examples of bicyclic groups are those containing 8, 9, 10, 11 and 12 ring members, and more typically 9 or 10 ring members. A heterocyclyl group may be a heteroaryl group having 5 to 12 ring members, more typically 5 to 10 ring members. Where heterocyclyl is mentioned herein, unless the context indicates otherwise, the heterocyclyl ring may be optionally substituted, i.e. unsubstituted or substituted, by one or more (e.g. 1, 2, 3, or 4, particularly one or two) substituents as defined herein.

[0105] The heterocyclyl group can be, for example, a five-membered or six-membered monocyclic structure or a bicyclic structure, formed by a fused five-membered ring and a six-membered ring or two fused six-membered rings, or two fused five-membered rings. Each ring can contain up to five heteroatoms, particularly selected from nitrogen, sulfur and oxygen, and oxidized forms of nitrogen or sulfur. Specifically, the heterocyclyl ring will contain up to 4 heteroatoms, more particularly up to 3 heteroatoms, more generally up to 2, such as a single heteroatom. In one embodiment, the heterocyclyl ring will contain one or two heteroatoms selected from N, O, S, and oxidized forms of N or S. In one embodiment, the heterocyclyl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heterocyclyl ring can be basic, as in the case of imidazole or pyridine; or substantially non-basic, as in the case of indole or pyrrole nitrogen. In general, the number of basic nitrogen atoms present in the heterocyclyl group (including any amino substituents of the ring) will be less than five.

[0106] The heterocyclic group may be attached via a carbon atom or a heteroatom (such as nitrogen). Likewise, the heterocyclic group may be substituted on a carbon atom or a heteroatom (such as nitrogen).

[0107] Examples of five-membered aromatic heterocyclic groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, Azolyl, Oxazolyl, Triazole, iso oxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl.

[0108] Examples of six-membered aromatic heterocyclic groups include, but are not limited to, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl.

[0109] The term "heteroaryl" is used herein to refer to a heterocyclic group having aromaticity. The term "heteroaryl" includes polycyclic (e.g., bicyclic) ring systems in which one or more rings are non-aromatic, provided that at least one ring is aromatic. In such polycyclic systems, the groups may be connected via aromatic rings or via non-aromatic rings.

[0110] Examples of heteroaryl groups are monocyclic and bicyclic groups containing from five to twelve ring members, and more usually five to ten ring members.

[0111] Examples of five-membered heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, Azolyl, Oxazolyl, Triazole, iso oxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl.

[0112] Examples of six-membered heteroaryl groups include, but are not limited to, pyridine, pyrazine, pyridazine, pyrimidine, and triazine.

[0113] The bicyclic heteroaryl group may be, for example, a group selected from the following:

[0114] a) a benzene ring fused to a 5-membered or 6-membered ring containing 1, 2 or 3 ring heteroatoms;

[0115] b) a pyridine ring fused to a 5-membered or 6-membered ring containing 0, 1, 2 or 3 ring heteroatoms;

[0116] c) a pyrimidine ring fused to a 5-membered or 6-membered ring containing 0, 1 or 2 ring heteroatoms;

[0117] d) a pyrrole ring fused to a 5-membered or 6-membered ring containing 0, 1, 2 or 3 ring heteroatoms;

[0118] e) a pyrazole ring fused to a 5-membered or 6-membered ring containing 0, 1 or 2 ring heteroatoms;

[0119] f) an imidazole ring fused to a 5-membered or 6-membered ring containing 0, 1 or 2 ring heteroatoms;

[0120] g) fused to a 5-membered or 6-membered ring containing 0, 1 or 2 ring heteroatoms Azole ring;

[0121] h) an isocyclic ring fused to a 5-membered or 6-membered ring containing 0, 1 or 2 ring heteroatoms Azole ring;

[0122] i) a thiazole ring fused to a 5-membered or 6-membered ring containing 0, 1 or 2 ring heteroatoms;

[0123] j) an isothiazole ring fused to a 5-membered or 6-membered ring containing 0, 1 or 2 ring heteroatoms;

[0124] k) a thiophene ring fused to a 5-membered or 6-membered ring containing 0, 1, 2 or 3 ring heteroatoms;

[0125] 1) a furan ring fused to a 5-membered or 6-membered ring containing 0, 1, 2 or 3 ring heteroatoms;

[0126] m) a cyclohexyl ring fused to a 5-membered or 6-membered ring containing 1, 2 or 3 ring heteroatoms; and

[0127] n) a cyclopentyl ring fused to a 5-membered or 6-membered ring containing 1, 2 or 3 ring heteroatoms.

[0128] Specific examples of bicyclic heteroaryl groups containing a five-membered ring fused to another five-membered ring include, but are not limited to, imidazothiazole (eg, imidazo[2,1-b]thiazole) and imidazoimidazole (eg, imidazo[1,2-a]imidazole).

[0129] Specific examples of bicyclic heteroaryl groups containing a six-membered ring fused to a five-membered ring include, but are not limited to, benzofuranyl, benzothiophenyl, benzimidazolyl, benzo Azolyl, isobenzo Azolyl, benzyl oxazolyl, benzothiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolyl, isoindolyl, purinyl (e.g., adeninyl, guaninyl), indazolyl, pyrazolopyrimidinyl (e.g., pyrazolo[1,5-a]pyrimidinyl), triazolopyrimidinyl (e.g., [1,2,4]triazolo[1,5-a]pyrimidinyl), benzodioxolyl, imidazopyridinyl, and pyrazolopyridinyl (e.g., pyrazolo[1,5-a]pyridinyl).

[0130] Specific examples of bicyclic heteroaryl groups containing two fused six-membered rings include, but are not limited to, quinolinyl, isoquinolinyl, chromanyl, dihydrochromanyl, isochromanyl, benzopyranyl, isobenzopyranyl, benzodihydropyranyl, Alkyl, quinolizinyl, benzo oxazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl and pteridinyl.

[0131] Examples of polycyclic heteroaryl groups containing aromatic and non-aromatic rings include tetrahydroisoquinolyl, tetrahydroquinolyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,3]dioxolyl, 4,5,6,7-tetrahydrobenzofuranyl, tetrahydrotriazolopyrazinyl (e.g., 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl), chromanyl, dihydrobenzothiopyranyl, isochromanyl, benzopyranyl, isochromanyl, benzo[1,3]dioxolyl, benzo[1,4]dioxolyl, benzo[1,3]dioxolyl, 4,5,6,7-tetrahydrobenzofuranyl, tetrahydrotriazolopyrazinyl (e.g., 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl), benzo[1,4]dioxinyl, benzo[1,3]dioxolyl, benzo[1,4]dioxol ... Alkyl, benzo oxazinyl, benzodiazepinyl, and indolyl.

[0132] The nitrogen-containing heteroaromatic ring must contain at least one ring nitrogen atom. The nitrogen-containing heteroaromatic ring may be N-attached or C-attached. Each ring may additionally contain up to about four other heteroatoms, particularly selected from nitrogen, sulfur and oxygen. In particular, the heteroaromatic ring will contain up to 3 heteroatoms, such as 1, 2 or 3, more usually up to 2 nitrogens, such as a single nitrogen. The nitrogen atoms in the heteroaromatic ring may be basic, as in the case of imidazole or pyridine; or substantially non-basic, as in the case of indole or pyrrole nitrogen. In general, the number of basic nitrogen atoms present in the heteroaryl group (including any amino substituents of the ring) will be less than five.

[0133] Examples of nitrogen-containing heteroaryl groups include, but are not limited to, monocyclic groups such as pyridyl, pyrrolyl, imidazolyl, Azolyl, Oxazolyl, thiadiazolyl, Triazole, iso oxazolyl, thiazolyl, isothiazolyl, furazanyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl), tetrazolyl; and bicyclic groups such as quinolyl, isoquinolyl, benzimidazolyl, benzo Azolyl, benzyl oxazole, benzothiazolyl and benzisothiazole, indolyl, 3H-indolyl, isoindolyl, indolizinyl, isoindolyl, purinyl (e.g., adenine [6-aminopurine], guanine [2-amino-6-hydroxypurine]), indazolyl, quinolizinyl, benzo oxazinyl, benzodiazepinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl and pteridinyl.

[0134] Examples of the nitrogen-containing polycyclic heteroaryl group containing an aromatic ring and a non-aromatic ring include a tetrahydroisoquinolyl group, a tetrahydroquinolyl group, and an indolinyl group.

[0135] Unless the context indicates otherwise, the term "non-aromatic" encompasses unsaturated ring systems, partially saturated and saturated heterocyclic ring systems that lack aromaticity. The terms "unsaturated" and "partially saturated" refer to rings in which one or more ring structures contain atoms that share more than one valence bond, i.e., the ring contains at least one multiple bond, such as a C=C bond, a C≡C bond, or an N=C bond. The term "saturated" refers to rings in which there are no multiple bonds between ring atoms. Saturated heterocyclic groups include piperidinyl, morpholinyl, and thiomorpholinyl. Partially saturated heterocyclic groups include pyrazolinyl, such as pyrazolin-2-yl and pyrazolin-3-yl.

[0136] Examples of non-aromatic heterocyclic groups are groups having 3 to 12 ring members, more usually 5 to 10 ring members. Such groups may be monocyclic or bicyclic, for example having 3 to 7 ring members, particularly 4 to 6 ring members. Such groups particularly have 1 to 5 or 1 to 4 heteroatom ring members (more usually 1, 2 or 3 heteroatom ring members), the heteroatom ring members being generally selected from nitrogen, oxygen and sulfur and oxidized forms thereof. The heterocyclic group may contain, for example, a cyclic ether moiety (for example in tetrahydrofuran and dihydrofuran). Examples of the present invention include cyclic sulfones (e.g., in sulfolane and sulfolene), cyclic sulfide moieties (e.g., in tetrahydrothiophene and dithiane), cyclic amine moieties (e.g., in pyrrolidine), cyclic amide moieties (e.g., in pyrrolidone), cyclic thioamides, cyclic thioesters, cyclic ureas (e.g., in imidazolidin-2-one), cyclic ester moieties (e.g., in butyrolactone), cyclic sulfones (e.g., in sulfolane and sulfolene), cyclic sulfoxides, cyclic sulfonamides, and combinations thereof (e.g., thiomorpholine).

[0137] Specific examples include morpholinyl, piperidinyl (e.g., piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, and piperidin-4-yl), piperidonyl, pyrrolidinyl (e.g., pyrrolidin-1-yl, pyrrolidin-2-yl, and pyrrolidin-3-yl), pyrrolidinonyl, azetidinyl, pyranyl (2H-pyran or 4H-pyran), dihydrothiophenyl, dihydropyranyl, dihydrofuranyl, dihydrothiazolyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydrothioxanyl ... alkyl, Alkyl (also known as tetrahydropyranyl) (e.g. alkyl-4-yl), imidazolinyl, imidazolidinone, In some embodiments, the non-aromatic heterocyclic group includes saturated groups such as piperidinyl, pyrrolidinyl, azetidinyl, morpholinyl, piperazinyl and N-alkylpiperazines such as N-methylpiperazinyl.

[0138] As used herein, the term “ Alkane" and " "Alkyl" refers to the following groups:

[0139]

[0140] It may also be referred to as "tetrahydropyran" or "tetrahydropyranyl."

[0141] In a nitrogen-containing non-aromatic heterocyclyl ring, the ring must contain at least one ring nitrogen atom. The nitrogen-containing heterocyclyl ring may be N-attached or C-attached. The heterocyclyl may contain, for example, a cyclic amine moiety (e.g., in pyrrolidinyl), a cyclic amide (e.g., pyrrolidinone, piperidone, or caprolactam), a cyclic sulfonamide (e.g., isothiazolidinyl 1,1-dioxide, [1,2]thiazinyl 1,1-dioxide, or [1,2]thiazepanyl 1,1-dioxide), and combinations thereof.

[0142] Specific examples of nitrogen-containing non-aromatic heterocyclic groups include aziridinyl, morpholinyl, thiomorpholinyl, piperidinyl (e.g., piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, and piperidin-4-yl), pyrrolidinyl (e.g., pyrrolidin-1-yl, pyrrolidin-2-yl, and pyrrolidin-3-yl), pyrrolidinone, dihydrothiazolyl, imidazolinyl, imidazolidinone, oxazolinyl, thiazolinyl, 6H-1,2,5-thiadiazinyl, pyrazolin-2-yl, pyrazolin-3-yl, pyrazolidinyl, piperazinyl, and N-alkylpiperazines such as N-methylpiperazinyl.

[0143] The heterocyclic group can be a polycyclic fused ring system or a bridged ring system, such as oxa-analogs and aza-analogs (e.g., adamantane and oxaadamantane) of bicycloalkanes and tricycloalkanes. For an explanation of the difference between fused ring systems and bridged ring systems, see Advanced Organic Chemistry, Jerry March, 4th edition, Wiley Interscience, pp. 131-133, 1992.

[0144] In the definition of a cyclic group or ring, it is stated that the cyclic group contains a certain number of heteroatom ring members, for example in the phrase "a 5-membered or 6-membered ring containing 0, 1 or 2 nitrogen ring members", this should be understood to mean that apart from the specified number of heteroatom ring members, the remaining ring members are carbon atoms.

[0145] The compound of formula (I) can contain saturated cyclic group, and the saturated cyclic group can be connected with the rest of molecule by one or more bonds.When cyclic group is connected with the rest of molecule by two or more bonds, these bonds (or two of these bonds) can be formed with the same atom (usually carbon atom) of ring or the different atoms of ring.In the case where the bond is formed with the same atom of ring, this produces the cyclic group with the single atom (usually quaternary carbon) combined with two groups.In other words, when the compound of formula (I) includes cyclic group, the group can be connected with the rest of molecule by bond, or the cyclic group and the rest of molecule can have common atom, such as spiro compound.

[0146] Each heterocyclyl group may be unsubstituted or substituted by one or more (e.g. 1, 2 or 3) substituents. For example, a heterocyclyl or carbocyclyl group may be unsubstituted or substituted by 1, 2, 3 or 4 substituents, in particular, it is unsubstituted or has 1, 2 or 3 substituents as defined herein. In the case where the cyclic group is saturated, there may be 2 substituents attached to the same carbon (in the case where the substituents are the same, so-called geminal or 'geminal' disubstitution).

[0147] Combinations of substituents are permissible only if such combinations result in stable or chemically feasible compounds (ie, compounds that are not substantially altered when kept at 40°C or less for at least a week).

[0148] The various functional groups and substituents that make up the compounds of the present invention are specifically selected so that the molecular weight of the compounds of the present invention does not exceed 1000. More typically, the molecular weight of the compound will be less than 750, for example less than 700, or less than 650, or less than 600, or less than 550. More specifically, the molecular weight is less than 525 and for example is 500 or less. DETAILED DESCRIPTION

[0149] The present invention provides a compound of formula (I):

[0150]

[0151] or its tautomer or solvate or pharmaceutically acceptable salt, wherein Het, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , a, m, n and s are as defined herein.

[0152] The compounds of formula (I) have chiral centers, which are marked below with "*":

[0153]

[0154] The compound of formula (I) includes a stereocenter at the position shown (referred to herein as (3)) and is chiral non-racemic. The compound of formula (I) has the stereochemistry shown by the cut wedge bond and the solid wedge bond and this stereoisomer predominates.

[0155] Typically, at least 55% (e.g., at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) of the compound of formula (I) exists as the stereoisomer shown. In a general embodiment, 97% (e.g., 99%) or more (e.g., substantially all) of the total amount of the compound of formula (I) can exist as a single stereoisomer.

[0156] The compounds may also include one or more additional chiral centers (e.g., at -CR 6 R 7 OH groups and / or in R 3 In the group and / or in -CHR 2 group).

[0157] Typically, the compound of formula (I) has an enantiomeric excess of at least 10% (e.g., at least 20%, 40%, 60%, 80%, 85%, 90% or 95%). In a general embodiment, the compound of formula (I) has an enantiomeric excess of 97% (e.g., 99%) or greater.

[0158] For the purposes of this section, the isoindolin-1-one ring is numbered as follows:

[0159]

[0160] Compounds were named according to the scheme utilized by a chemical nomenclature software package.

[0161] R 1 and n

[0162] R 1 is with -CHR 2 - one or more substituents on the phenyl group to which it is bonded.

[0163] n is 0, 1, 2 or 3. In other words, with -CHR 2 The phenyl group to which the - group is bonded may have 0, 1, 2 or 3 substituents R 1 .

[0164] In one embodiment, n is 1, 2 or 3. In one embodiment, n is 1 or 2. In another embodiment, n is 1.

[0165] When n is 2 or 3 (i.e., with -CHR 2 - group-bonded phenyl group is bound by more than one R 1 When substituted), the substituent R 1 can be the same or different (i.e. independently selected from R 1 definition of ).

[0166] R 1 The phenyl group may be attached at the ortho (or adjacent), meta (or meta) or para (or para) position, wherein the position is relative to the phenyl group and the group -CHR 2 - The connection point is defined.

[0167] R 1 are independently selected from hydroxy, halogen, nitro, nitrile, C 1-4 Alkyl, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 2-6 Alkenyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 2-4 Alkynyl, -O 0,1 -(CR x R y ) v -CO 2 H, -(CR x R y ) v -CO 2 C 1-4 Alkyl, -(CH 2 ) v -CON(C 1-4 alkyl) 2 ,-P(=O)(R x ) 2 、-S(O) d -R x 、-S(O) d -heterocyclyl having 3 to 6 ring members and -S(O) d -N(R 8 ) 2 .

[0168] R 1 are independently selected from hydroxy, halogen, nitro, nitrile, C 1-4 Alkyl, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 2-6 Alkenyl, C 1-4Alkoxy, halogenated C 1-4 Alkoxy, C 2-4 Alkynyl, -O 0,1 -(CH 2 ) v -CO 2 H, -(CH 2 ) v -CO 2 C 1-4 Alkyl, -(CH 2 ) v -CON(C 1-4 alkyl) 2 ,-P(=O)(R x ) 2 、-S(O) d -R x 、-S(O) d -heterocyclyl having 3 to 6 ring members and -S(O) d -N(R 8 ) 2 .

[0169] R 1 are independently selected from hydroxy, halogen, nitro, nitrile, C 1-4 Alkyl, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 2-6 Alkenyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 2-4 Alkynyl, -(CH 2 ) v -CO 2 H, -(CH 2 ) v -CO 2 C 1-4 Alkyl, -(CH 2 ) v -CON(C 1-4 alkyl) 2 ,-P(=O)(R x ) 2 、-S(O) d -R x 、-S(O) d -heterocyclyl having 3 to 6 ring members and -S(O) d -N(R 8 ) 2 .

[0170] In one embodiment, R 1 are independently selected from halogen, hydroxy, nitrile, C 1-4 Alkyl, C 2-4Alkynyl, or C 1-4 Alkoxy, such as R 1 are independently selected from chloro, hydroxy, nitrile, methyl or methoxy.

[0171] In one embodiment, R 1 independently selected from halogen (e.g. chlorine), C 1-4 Alkyl (such as methyl), C 1-4 Alkoxy (e.g., methoxy), -O 0,1 -(CR x R y ) v -CO 2 H (e.g. -CO 2 H, -(CH 2 )-CO 2 H, -(C(CH 3 ) 2 )-CO 2 H, or -O(CH 2 )-CO 2 H) or -S(O) d -R x (For example, SO 2 CH 3 ).

[0172] In one embodiment, R 1 Yes 0,1 -(CR x R y ) v -CO 2 H, especially -CO 2 H, -(CH 2 )-CO 2 H, -(C(CH 3 ) 2 )-CO 2 H, or -O(CH 2 )-CO 2 H, such as -(C(CH 3 ) 2 )-CO 2 H.

[0173] In one embodiment, R 1 is chlorine or nitrile, especially chlorine.

[0174] In one embodiment, R 1 is a nitro group (e.g., NO 2 ).

[0175] In one embodiment, R 1 It is a nitro group in the ortho or meta position.

[0176] In one embodiment, R 1 are independently selected from hydroxy, halogen, nitrile, C 1-4 Alkyl, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 2-6 Alkenyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 2-4 Alkynyl, -(CH 2 ) v -CO 2 H, -(CH 2 ) v -CO 2 C 1-4 Alkyl, -(CH 2 ) v -CON(C 1-4 alkyl) 2 ,-P(=O)(R x ) 2 、-S(O) d -C 1-6 Alkyl, -S(O) d -heterocyclyl having 3 to 6 ring members and -S(O) d -N(R 8 ) 2 .

[0177] In another embodiment, n is 1 and R 1 It is chlorine or nitrile.

[0178] In another embodiment, n is 1 and R 1 It's chlorine.

[0179] In another embodiment, n is 1 and R 1 It's nitrile.

[0180] In one embodiment, R 1 One of the groups or R 1 The group (where n=1) is in the para position (ie, para to the point of attachment to the benzene ring). In one embodiment, n is 1 and R 1 It is p-chlorine or p-nitrile.

[0181] In one embodiment, n is 1 and R 1 is halogen (such as Cl or F), nitrile, C 1-4 Alkoxy (e.g. -OCH 3 ) or C 1-4 Alkyl (e.g. -CH 3 ).

[0182] In one embodiment, R1 Yes-S(O) d -C 1-6 Alkyl, or -S(O) d -heterocyclyl having 3 to 6 ring members and -S(O) d -N(R 8 ) 2 In one embodiment, R 1 Yes-SC 1-6 Alkyl, -S(O)-C 1-6 Alkyl, -S(O) 2 -C 1-6 Alkyl, -S(O) d -heterocyclyl having 3 to 6 ring members or -S(O) d -N(C 1-6 alkyl) 2 .

[0183] In another embodiment, R 1 Yes-S-CH 3 、-S(O)-CH 3 、-S(O) 2 -CH 3 , or -S(O) 2 In another embodiment, one or more R 1 Yes-SO 2 CH 3 , or -SO 2 -Heterocyclic group with 6 ring members, such as -SO 2 -(morpholinyl), especially -SO 2 -(1-morpholinyl).

[0184] In one embodiment, R 1 is adjacent (-S(O) d -C 1-4 alkyl) or o-(-S(O) d -heterocyclyl having 3 to 6 ring members). In one embodiment, R 1 It is adjacent to SC 1-4 Alkyl, o-(-S(O) d -C 1-4 alkyl) or o-(-S(O) d -heterocyclyl having 3 to 6 ring members). In one embodiment, R 1 is adjacent (-S(O) 2 -CH 3 ).

[0185] In one embodiment, R 1 Yes-(CH 2 )u -CO 2 H. In one embodiment, R 1 Yes-CO 2 H. In one embodiment, R 1 Is in the meta or para position -(CH 2 ) u -CO 2 H. In one embodiment, R 1 It is in the ortho position -(CH 2 ) u -CO 2 H.

[0186] In one embodiment, R 1 are independently selected from hydroxy, halogen, nitrile, C 1-4 Alkyl, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 2-6 Alkenyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 2-4 Alkynyl, -(CH 2 ) v -CO 2 C 1-4 Alkyl, -(CH 2 ) v -CON(C 1-4 alkyl) 2 ,-P(=O)(R x ) 2 、-S(O) d -C 1-6 Alkyl, -S(O) d -heterocyclyl having 3 to 6 ring members and -S(O) d -N(R 8 ) 2 .

[0187] In one embodiment, n is 2. In one embodiment, when n is 2, the phenyl group is substituted with: (i) o-(-S(O) d -C 1-4 alkyl) or o-(-S(O) d - a heterocyclic group having 3 to 6 ring members); and (ii) a halogen (such as Cl or F), a nitrile, or a C 1-4 Alkyl, in particular chlorine, nitrile or methyl.

[0188] In one embodiment, n is 2 and R 1 Yes(i)-SO 2 CH 3 ; and (ii) chlorine.

[0189] In one embodiment, n is 2 and R 1 Yes(i)-SO 2 CH 3 ; and (ii) chloro, nitrile or methyl.

[0190] In one embodiment, n is 2 and R 1 Yes(i)-CO 2 H; and (ii) chlorine.

[0191] In one embodiment, n is 2 and R 1 Yes(i)-CO 2 H; and (ii) chlorine, or nitrile.

[0192] In one embodiment, when n is 2, with -CHR 2 -bound phenyl is substituted by: (i) hydroxy; and (ii) halogen (eg Cl or F), or nitrile, in particular chlorine or nitrile.

[0193] In one embodiment, with -CHR 2 -bonded phenyl and R 1 The following groups are formed:

[0194]

[0195] Specifically, R 1 is halogen (e.g. chlorine), nitrile or C 1-4 Alkyl (e.g. -CH 3 ) and R x It is C 1-4 Alkyl (e.g. -CH 3 ).

[0196] In one embodiment, with -CHR 2 -bonded phenyl and R 1 The following groups are formed:

[0197]

[0198] Specifically, R 1 It is C 1-4 Alkyl (e.g. -CH 3 ) and R x It is C 1-4 Alkyl (e.g. -CH 3 ).

[0199] In one embodiment, when n is 2, the phenyl group is substituted with: (i) o-OH or o-CH 2OH; and (ii) halogen (eg, Cl or F), nitrile, or C 1-4 In one embodiment, when n is 2, phenyl is substituted by (i) hydroxyl; and (ii) halogen (e.g., Cl or F) or nitrile, in particular chlorine or nitrile. In one embodiment, when n is 2, phenyl is substituted by (i) o-hydroxyl; and (ii) p-Cl or p-CN (e.g., p-Cl).

[0200] In one embodiment, n is 2 and R 1 is fluorine (for example in the ortho and para positions of the phenyl group).

[0201] In one embodiment, R 1 is a halogen (such as Cl or F), C 1-4 Alkynyl (e.g. -C≡CH), nitrile, -(CH 2 ) v COOH (e.g. -COOH) or SO 2 C 1-4 Alkyl (such as SO 2 CH 3 ) and n is 1 or 2.

[0202] In one embodiment, R 1 is a halogen (e.g. Cl), C 1-4 Alkynyl (e.g. -C≡CH), nitrile, hydroxyl C 1-4 Alkyl (e.g. CH 2 OH), -(CH 2 ) v COOH (e.g. -COOH), -S(O) d -C 1-4 Alkyl (e.g. SCH 3 、SOCH 3 , or SO 2 CH 3 ),-SO 2 -(1-morpholinyl) or -P(=O)(R x ) 2 (e.g. -P(=O)(CH 3 ) 2 ).

[0203] In one embodiment, n is 1 and R 1 is Cl (e.g., for Cl), CN (e.g., for CN), or C 2-4 Alkynyl (e.g., C 1 alkynyl), or n is 2 and (i) R 1 is for Cl, ortho-CH 2 OH; (ii) to CN, adjacent CH 2OH; or (iii) to Cl, o-COOH; (iv) to Cl, o-SCH 3 ; (v) for Cl, o-S(O)CH 3 ; (vi) for Cl, o-SO 2 CH 3 ; (vii) for Cl, o-SO 2 -(1-morpholinyl); or (viii) p-Cl, o-P(O)(CH 3 ) 2 .

[0204] In one embodiment, n is 1 and R 1 is Cl (e.g., for Cl), CN (e.g., for CN), or C 2-4 Alkynyl (e.g., C 1 alkynyl).

[0205] In one embodiment, n is 2 and (i) R 1 is for Cl, ortho-CH 2 OH; (ii) to CN, adjacent CH 2 OH; or (iii) to Cl, o-COOH; (iv) to Cl, o-SCH 3 ; (v) for Cl, o-S(O)CH 3 ; (vi) for Cl, o-SO 2 CH 3 ; (vii) for Cl, o-SO 2 -(1-morpholinyl); or (viii) p-Cl, o-P(O)(CH 3 ) 2 .

[0206] In one embodiment, n is 1 and R 1 is -Cl, -CN or -OMe (e.g. p-Cl, p-CN or p-OMe). In one embodiment, n is 1 and R 1 is -Cl or -CN (eg, p-Cl or p-CN).

[0207] In one embodiment, n is 2. When n is 2, typically, the phenyl group is substituted at the ortho and para positions. Specifically, n is 2 and R 1 By para-chloro and o-(-S(O) d -C 1-4 alkyl) or o-(-S(O) d -heterocyclyl having 3 to 6 ring members).

[0208] In one embodiment, n is 2 and R 1 It is o-CO 2 H and para-chlorine.

[0209] In one embodiment, n is 2 and R 1 It is o-CO 2 H and p-nitrile.

[0210] In one embodiment, n is 2 and R 1 It is adjacent to CH 2 OH and p-chlorine.

[0211] In one embodiment, n is 2 and R 1 It is adjacent to CH 2 OH and p-nitrile.

[0212] In one embodiment, n is 2 and R 1 It is o-OH and p-chlorine.

[0213] In one embodiment, n is 2 and R 1 It is o-OH and p-nitrile.

[0214] In one embodiment, n is 2 and R 1 It's neighbor SO 2 CH 3 and parachlorine.

[0215] In one embodiment, n is 2 and R 1 Yes-SO 2 -(1-morpholinyl) and p-chloro.

[0216] In one embodiment, R 1 Yes-O 0,1 (CR x R y ) v COOH (e.g. -COOH, -CH 2 COOH, -OCH 2 COOH or -C(CH 3 ) 2 COOH).

[0217] In one embodiment, n is 2 and R 1 is for Cl and o-O 0,1 (CR x R y ) v COOH (e.g. -COOH, -CH 2 COOH, -OCH 2 COOH or -C(CH 3 ) 2 COOH).

[0218] In one embodiment, R 1 is a halogen (e.g. Cl), a hydroxyalkyl (e.g. -CH2 OH), C 1-4 Alkynyl (e.g. -C≡CH), nitrile, -O 0,1 (CR x R y ) v COOH (e.g. -COOH, -CH 2 COOH, -OCH 2 COOH or -C(CH 3 ) 2 COOH) or -SO 2 C 1-4 Alkyl (e.g. -SO 2 CH 3 ) and n is 1 or 2.

[0219] In one embodiment, R 1 is a halogen (e.g. Cl), a hydroxyalkyl (e.g. -CH 2 OH), C 1-4 Alkynyl (e.g. -C≡CH), nitrile, -(CH 2 ) v COOH (e.g. -COOH) or -SO 2 C 1-4 Alkyl (e.g. -SO 2 CH 3 ) and n is 1 or 2.

[0220] In one embodiment, R 1 are independently selected from hydroxy, halogen, nitrile, C 1-4 Alkyl, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 2-6 Alkenyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 2-4 Alkynyl, -(CH 2 ) v -CO 2 H, -O 0,1 -(CR x R y ) v -CO 2 C 1-4 Alkyl (e.g. -(CH 2 ) v -CO 2 C 1-4 alkyl), -(CH 2 ) v -CON(C 1-4 alkyl) 2 ,-P(=O)(R x )2 、-S(O) d -C 1-6 Alkyl, -S(O) d -heterocyclyl having 3 to 6 ring members and -S(O) d -N(R 8 ) 2 .

[0221] In one embodiment, wherein n is 2, and one R 1 Yes-O 0,1 -(CR x R y ) v -CO 2 C 1-4 Alkyl, o-(-S(O) d -C 1-4 alkyl) or o-(-S(O) d - a heterocyclyl group having 3 to 6 ring members) and one R 1 is halogen (such as Cl or F), nitrile, or C 1-4 Alkyl, in particular chlorine, nitrile or methyl.

[0222] In one embodiment, wherein n is 2, and one R 1 is adjacent (-S(O) d -C 1-4 alkyl) or o-(-S(O) d - a heterocyclyl group having 3 to 6 ring members) and one R 1 is halogen (such as Cl or F), nitrile, or C 1-4 Alkyl, in particular chlorine, nitrile or methyl.

[0223] In one embodiment, wherein n is 2, and one R 1 Yes-O 0,1 -(CR x R y ) v -CO 2 C 1-4 Alkyl, and one R 1 is halogen (such as Cl or F), nitrile, or C 1-4 Alkyl, in particular chlorine, nitrile or methyl, such as chlorine.

[0224] R 2

[0225] R 2 Selected from hydrogen, C 1-4 Alkyl, C 2-6 Alkenyl, hydroxyl C 1-4 Alkyl, -(CR x R y )u -CO 2 H, -(CR x R y ) u -CO 2 C 1-4 Alkyl, and -(CR x R y ) u -CONR x R y .

[0226] In one embodiment, u is selected from 0, 1, or 2. In one embodiment, u is selected from 0 or 1.

[0227] In one embodiment, R 2 Selected from hydrogen, C 1-4 Alkyl, C 2-6 Alkenyl, hydroxyl C 1-4 Alkyl and -(CR x R y ) u -CO 2 H. In one embodiment, R 2 Selected from hydrogen, C 1-4 Alkyl, hydroxyl C 1-4 Alkyl and -(CR x R y ) u -CO 2 H. In one embodiment, R 2 Selected from hydrogen, C 1-4 Alkyl, C 2-6 Alkenyl, and hydroxyl C 1-4 In another embodiment, R 2 Selected from hydrogen and -(CH 2 ) u -CO 2 H (e.g. -CH 2 -CO 2 H).

[0228] In one embodiment, R 2 It is hydrogen, C 1-4 Alkyl (e.g. -CH 3 ), hydroxyl C 1-4 Alkyl (e.g. CH 2 OH) or -(CH 2 ) u COOH (e.g. -COOH, -CH 2 COOH, -CH 2 CH 2 -CO 2 H, -(CH(CH3 ))-CO 2 H or -(C(CH 3 ) 2 -CO 2 H, such as -COOH, -CH 2 COOH, -CH 2 CH 2 -CO 2 H, or -(CH(CH 3 ))-CO 2 H).

[0229] In one embodiment, R 2 Selected from hydrogen, C 1-4 Alkyl, C 2-6 Alkenyl, and hydroxyl C 1-4 alkyl.

[0230] In one embodiment, R 2 It is hydrogen, C 1-4 Alkyl (e.g. -CH 3 ), hydroxyl C 1-4 Alkyl (e.g. CH 2 OH) or -(CH 2 ) u COOH (e.g. -CH 2 In one embodiment, R 2 Selected from hydrogen, -CH 3 、-CH 2 OH, and -CH 2 CO 2 H.

[0231] In one embodiment, R 2 Selected from hydrogen, -CH 3 、-CH 2 OH, -CH=CH 2 and -CH(OH)CH 2 OH.

[0232] In one embodiment, R 2 Selected from hydrogen, -CH 3 、-CH 2 OH, and -CH 2 CO 2 H.

[0233] In one embodiment, R 2 is hydrogen or C 1-4 Alkyl (e.g. -CH 3 or -CH 2 CH 3 ).

[0234] In one embodiment, R 2 Selected from hydrogen, -CH 3 and -CH 2 CH 3 In one embodiment, R 2 is selected from hydrogen and methyl.

[0235] In one embodiment, R 2 Selected from hydrogen and -(R x R y ) u -CO 2 H (e.g. -COOH, -CH 2 COOH, -CH 2 CH 2 -CO 2 H, -(CH(CH 3 ))-CO 2 H and -(C(CH 3 ) 2 -CO 2 H).

[0236] In one embodiment, R 2 Yes-(R x R y ) u COOH (e.g. -CH 2 COOH, -CH 2 CH 2 -CO 2 H, -(CH(CH 3 ))-CO 2 H (e.g. ) or -(C(CH 3 ) 2 -CO 2 H).

[0237] In one embodiment, R 2 It is hydrogen, C 1-4 Alkyl (e.g. -CH 3 ) or -(CH 2 ) u COOH (e.g. -CH 2 COOH, -CH 2 CH 2 -CO 2 H or -(CH(CH 3 ))-CO 2 H).

[0238] In one embodiment, R 2 It is hydrogen, C 1-4 Alkyl (e.g. -CH 3) or -(CH 2 ) u COOH (e.g. -CH 2 COOH).

[0239] In one embodiment, R 2 Yes-(CR x R y ) u -CO 2 H (e.g. -CH 2 -CO 2 H).

[0240] In another embodiment, R 2 Selected from -(CH(CH 3 ))-CO 2 H and -(C(CH 3 ) 2 -CO 2 H)(e.g. or -(C(CH 3 ) 2 -CO 2 H).

[0241] In another embodiment, R 2 is hydrogen and the compound of formula (I) is a compound of formula (Ie) or a tautomer or solvate or a pharmaceutically acceptable salt thereof:

[0242]

[0243] When R 2 When is not hydrogen, the compound of formula (I) may exist as at least two diastereomers:

[0244]

[0245] For the avoidance of doubt, the general formula (I) and all subformulae encompass both individual diastereomers and mixtures of said diastereomers, said diastereomers being -CHR 2 -group. In one embodiment, the compound of Formula I is diastereomer 1A or its tautomer or solvate or pharmaceutically acceptable salt. In one embodiment, the compound of Formula I is diastereomer 1B or its tautomer or solvate or pharmaceutically acceptable salt.

[0246] In one embodiment, the compound is diastereomer 1A and R 2 Selected from:

[0247] iC 1-4 Alkyl, C 2-6Alkenyl, hydroxyl C 1-4 Alkyl, -(R x R y ) u -CO 2 H (e.g. -COOH, -CH 2 COOH, -CH 2 CH 2 -CO 2 H, -(CH(CH 3 ))-CO 2 H and -(C(CH 3 ) 2 -CO 2 H), -(CH 2 ) u -CO 2 C 1-4 Alkyl, and -(CH 2 ) u -CONR x R y ;or

[0248] ii.C 1-4 Alkyl, C 2-6 Alkenyl, and hydroxyl C 1-4 alkyl.

[0249] In one embodiment, the compound is diastereomer 1A and R 2 Selected from:

[0250] iC 1-4 Alkyl, C 2-6 Alkenyl, hydroxyl C 1-4 Alkyl, -(CH 2 ) u -CO 2 H, -(CH 2 ) u -CO 2 C 1-4 Alkyl, and -(CH 2 ) u -CONR x R y ;or

[0251] ii.C 1-4 Alkyl, C 2-6 Alkenyl, and hydroxyl C 1-4 alkyl.

[0252] In another embodiment, R 2 Selected from hydrogen and -(R x R y ) u -CO 2H (e.g. -COOH, -CH 2 COOH, -CH 2 CH 2 -CO 2 H, -(CH(CH 3 ))-CO 2 H and -(C(CH 3 ) 2 -CO 2 H).

[0253] In another embodiment, R 2 Selected from hydrogen and -(CH 2 ) u -CO 2 H (e.g. -CH 2 -CO 2 H).

[0254] In one embodiment, the compound is diastereomer 1A and R 2 Selected from:

[0255] i.-CH 3 、-CH 2 OH, -CH=CH 2 and -CH(OH)CH 2 OH; or

[0256] ii.C 1-4 Alkyl (e.g. -CH 3 or -CH 2 CH 3 );or

[0257] iii.-CH 3 and -CH 2 CH 3 .

[0258] In one embodiment, the compound is diastereomer 1B and R 2 Selected from:

[0259] iC 1-4 Alkyl, C 2-6 Alkenyl, hydroxyl C 1-4 Alkyl, -(R x R y ) u -CO 2 H (e.g. -COOH, -CH 2 COOH, -CH 2 CH 2 -CO 2 H, -(CH(CH 3 ))-CO 2H and -(C(CH 3 ) 2 -CO 2 H), -(CH 2 ) u -CO 2 C 1-4 Alkyl, and -(CH 2 ) u -CONR x R y ;or

[0260] ii.C 1-4 Alkyl, C 2-6 Alkenyl, and hydroxyl C 1-4 alkyl.

[0261] In one embodiment, the compound is diastereomer 1B and R 2 Selected from:

[0262] iC 1-4 Alkyl, C 2-6 Alkenyl, hydroxyl C 1-4 Alkyl, -(CH 2 ) u -CO 2 H, -(CH 2 ) u -CO 2 C 1-4 Alkyl, and -(CH 2 ) u -CONR x R y ;or

[0263] ii.C 1-4 Alkyl, C 2-6 Alkenyl, and hydroxyl C 1-4 alkyl.

[0264] In another embodiment, R 2 Selected from hydrogen and -(CH 2 ) u -CO 2 H (e.g. -CH 2 -CO 2 H).

[0265] In one embodiment, the compound is diastereomer 1B and R 2 Selected from:

[0266] i.-CH 3 、-CH 2 OH, -CH=CH 2 and -CH(OH)CH 2 OH; or

[0267] ii.C 1-4 Alkyl (e.g. -CH 3 or -CH 2 CH 3 );or

[0268] iii.-CH 3 and -CH 2 CH 3 .

[0269] In another embodiment, R 2 Selected from hydrogen and -(R x R y ) u -CO 2 H (e.g. -COOH, -CH 2 COOH, -CH 2 CH 2 -CO 2 H, -(CH(CH 3 ))-CO 2 H and -(C(CH 3 ) 2 -CO 2 H).

[0270] In one embodiment, R 2 Selected from C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, -(CH 2 ) u -CO 2 H, -(CH 2 ) u -CO 2 C 1-4 Alkyl, and -(CH 2 ) w -CONR x R y (especially -CH 2 -CO 2 H) and the compound is diastereomer 1A.

[0271] In one embodiment, R 2 Selected from C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, -(CH 2 ) u -CO 2 H, -(CH 2 ) u -CO 2 C 1-4 Alkyl, and -(CH 2 )u -CONR x R y (especially -CH 2 -CO 2 H) and the compound is diastereomer 1B.

[0272] In one embodiment, R 2 It is hydroxyl C 1-4 Alkyl (e.g. -CH 2 OH) and the compound is diastereomer 1A.

[0273] In one embodiment, R 2 Yes-(CH 2 ) u -CO 2 H (e.g. -CH 2 -CO 2 H) and the compound is diastereomer 1A.

[0274] In one embodiment, R 2 and the hydrogen on the carbon it is attached to is 2 H (i.e. deuterium).

[0275] R 3 and

[0276] R 3 is hydrogen or -(A) t -(CR x R y ) q -X;

[0277] s is selected from 0 and 1;

[0278] t is selected from 0 and 1;

[0279] q is selected from 0, 1 and 2;

[0280] When R 3 Yes - (A) t -(CR x R y ) q -X, then (i) at least one of s, t, and q is not 0; and (ii) when t is 0, then s is 1 and q is not 0;

[0281] A is for C 3-6 Cycloalkyl or heterocyclyl having 3 to 6 ring members, wherein the heterocyclyl contains one or more (e.g. 1, 2, or 3) heteroatoms selected from N, O, S and oxidized forms thereof;

[0282] X is selected from hydrogen, halogen, -CN, -OR 9 、-(CH2 ) v -CO 2 H, -(CH 2 ) v -CO 2 C 1-4 Alkyl, -S(O) d -R x , -C(=O)-C 1-4 Alkyl, -S(O) d -N(H) e (C 1-4 alkyl) 2-e 、-NR x R y 、-NHSO 2 R x 、-NR x COR y , and -C(=O)NR x R y ;

[0283] R 9 are independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, -(CH 2 ) k -OC 1-6 Alkyl, -(CH 2 ) k -O-(Hydroxy C 1-6 Alkyl), hydroxyl C 1-6 Alkoxy, -(CH 2 ) k -CO 2 C 1-6 Alkyl, -(CH 2 ) k -CO 2 H, -C 1-6 Alkyl-N(H) e (C 1-4 alkyl) 2-e 、-(CH 2 ) j -C 3-8 Cycloalkyl and -(CH 2 ) j -C 3-8 Cycloalkenyl;

[0284] R x and R y are independently selected from hydrogen, halogen, nitro, nitrile, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, Hydroxyl, Hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, -(CH 2 ) k -OC 1-6 Alkyl, hydroxyl C 1-6 Alkoxy, -COOC 1-6 Alkyl, -N(H) e (C 1-4 alkyl) 2-e , -C 1-6 Alkyl-N(H) e (C 1-4 alkyl) 2-e 、-(CH 2 ) k -C(=O)N(H) e (C 1-4 alkyl) 2-e , C 3-8 Cycloalkyl and C 3-8 Cycloalkenyl;

[0285] or R x Group and R y The groups together with the carbon or nitrogen atoms to which they are attached can be linked to form C 3-6 Cycloalkyl or a saturated heterocyclic group having 3 to 6 ring members, which may be optionally fused to an aromatic heterocyclic group having 3 to 5 ring members; or may be linked to form a =CH group;

[0286] j, d, and e are independently selected from 0, 1, and 2;

[0287] k is selected from 1 and 2; and

[0288] v is independently selected from 0 and 1.

[0289] In one embodiment, when t is 1, the group -(CR x R y ) q -X and the rest of the molecule are attached to the same carbon atom in the group A. In one embodiment, when t is 1, the group (CR x R y ) q -X and the rest of the molecule are attached to different carbon atoms in the A group.

[0290] In one embodiment, R 3 is hydrogen or -(A) t -(CR x R y ) q -X;

[0291] s is selected from 0 and 1;

[0292] t is selected from 0 and 1;

[0293] q is selected from 0, 1 and 2;

[0294] When R 3 Yes - (A) t -(CR x R y ) q -X, then (i) at least one of s, t, and q is not 0; and (ii) when t is 0, then s is 1 and q is not 0;

[0295] A is for C 3-6 Cycloalkyl or heterocyclyl having 3 to 6 ring members, wherein the heterocyclyl contains one or more (e.g. 1, 2, or 3) heteroatoms selected from N, O, S and oxidized forms thereof;

[0296] X is selected from hydrogen, halogen, -CN, -OR 9 、-(CH 2 ) v -CO 2 H, -(CH 2 ) v -CO 2 C 1-4 Alkyl, -S(O) d -R x , -C(=O)-C 1-4 Alkyl, -S(O) d -N(H) e (C 1-4 alkyl) 2-e 、-NR x R y 、-NHSO 2 R x 、-NR x COR y , and -C(=O)NR x R y ;

[0297] R 9 are independently selected from hydrogen and C 1-6 alkyl;

[0298] R x and R y are independently selected from hydrogen and C 1-6 alkyl;

[0299] d and e are independently selected from 0, 1 and 2;

[0300] v is independently selected from 0 and 1.

[0301] In one embodiment, R 3 is hydrogen or -(A) t -(CR x R y ) q -X;

[0302] s is selected from 0 and 1;

[0303] t is selected from 0 and 1;

[0304] q is selected from 0, 1 and 2;

[0305] When R 3 Yes - (A) t -(CR x R y ) q -X, then (i) at least one of s, t, and q is not 0; and (ii) when t is 0, then s is 1 and q is not 0;

[0306] A is for C 3-6 Cycloalkyl or heterocyclyl having 3 to 6 ring members, wherein the heterocyclyl contains one or more (e.g. 1, 2, or 3) heteroatoms selected from N, O, S and oxidized forms thereof;

[0307] X is selected from hydrogen, halogen, -CN, -OR 9 、-(CH 2 ) v -CO 2 H, -(CH 2 ) v -CO 2 C 1-4 Alkyl, -C(=O)-C 1-4 Alkyl, -NR x R y 、-NR x COR y , and -C(=O)NR x R y ;

[0308] R 9 are independently selected from hydrogen and C 1-6 alkyl;

[0309] R x and R y are independently selected from hydrogen and C 1-6 alkyl;

[0310] v is independently selected from 0 and 1.

[0311] In one embodiment, R 3 is hydrogen or -(A)t -(CR x R y ) q -X;

[0312] s is selected from 0 and 1;

[0313] t is selected from 0 and 1;

[0314] q is selected from 0, 1 and 2;

[0315] When R 3 Yes - (A) t -(CR x R y ) q -X, then (i) at least one of s, t, and q is not 0; and (ii) when t is 0, then s is 1 and q is not 0;

[0316] A is for C 3-6 Cycloalkyl or heterocyclyl having 3 to 6 ring members, wherein the heterocyclyl contains one or more (e.g. 1, 2, or 3) heteroatoms selected from N, O, S and oxidized forms thereof;

[0317] X is selected from hydrogen, halogen, -CN, -OR 9 、-NR x COR y , and -C(=O)NR x R y ;

[0318] R 9 are independently selected from hydrogen and C 1-6 alkyl;

[0319] R x and R y are independently selected from hydrogen and C 1-6 alkyl;

[0320] v is independently selected from 0 and 1.

[0321] In one embodiment, R 3 is hydrogen or -(A) t -(CR x R y ) q -X;

[0322] s is selected from 0 and 1;

[0323] t is selected from 0 and 1;

[0324] q is selected from 0, 1 and 2;

[0325] When R 3 Yes - (A)t -(CR x R y ) q -X, then (i) at least one of s, t, and q is not 0; and (ii) when t is 0, then s is 1 and q is not 0;

[0326] A is for C 3-6 Cycloalkyl or heterocyclyl having 3 to 6 ring members, wherein the heterocyclyl contains one or more (e.g. 1, 2, or 3) heteroatoms selected from N, O, S and oxidized forms thereof;

[0327] X is selected from hydrogen, halogen (such as fluorine), -OR 9 、-NR x COR y , and -C(=O)NR x R y ;

[0328] R 9 are independently selected from hydrogen and C 1-6 alkyl;

[0329] R x and R y are independently selected from hydrogen and C 1-6 alkyl;

[0330] v is independently selected from 0 and 1.

[0331] In one embodiment, R 3 is hydrogen and s is 1, i.e. the part -(CH 2 ) s R 3 Yes-CH 3 .

[0332] In one embodiment, R 3 is hydrogen and s is 0, i.e. the part -(CH 2 ) s R 3 Yes -H.

[0333] In one embodiment, t is 1 and A is C 3-6 Cycloalkyl or heterocyclyl having 3 to 6 ring members, wherein the heterocyclyl contains one or more (eg 1 or 2) heteroatoms selected from N, O, S and oxidized forms thereof.

[0334] In one embodiment, t is 1 and A is C 3-6 In one embodiment, A is C 3-5Cycloalkyl. For example, A is selected from cyclopropyl, cyclobutyl and cyclopentyl. In one embodiment, A is cyclopropyl. In one embodiment, A is cyclobutyl.

[0335] Specifically, t is 1 and A is cyclopropyl.

[0336] In one embodiment, t is 1 and A is a heterocyclyl having 3 to 6 ring members, wherein the heterocyclyl contains one or more (eg, 1, 2, or 3) heteroatoms selected from N, O, S and oxidized forms thereof.

[0337] In one embodiment, t is 1 and A is a heterocyclyl having 3 to 5 ring members, wherein the heterocyclyl contains one or more (eg, 1, 2, or 3) heteroatoms selected from N, O, S and oxidized forms thereof.

[0338] In one embodiment, t is 1 and A is an unsaturated heterocyclyl having 3 to 5 ring members, wherein the heterocyclyl contains one or more (e.g. 1, 2, or 3) heteroatoms selected from N, O, S and oxidized forms thereof, in particular O.

[0339] In one embodiment, t is 1 and A is a saturated heterocyclyl having 3 to 5 ring members, wherein the heterocyclyl contains one or more (e.g. 1, 2, or 3) heteroatoms selected from N, O, S and oxidized forms thereof, in particular O.

[0340] In one embodiment, t is 1 and A is a heterocyclyl selected from morpholinyl, piperidinyl (e.g., piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, and piperidin-4-yl), piperidonyl, pyrrolidinyl (e.g., pyrrolidin-1-yl, pyrrolidin-2-yl, and pyrrolidin-3-yl), pyrrolidinonyl, azetidinyl, oxetanyl, pyranyl (2H-pyran or 4H-pyran), dihydrothiophenyl, dihydropyranyl, dihydrofuranyl, dihydrothiazolyl, tetrahydrofuranyl (e.g., tetrahydrofuran-3-yl), tetrahydrothiophenyl, dihydropyranyl, dihydrofuranyl, dihydrothiazolyl, tetrahydrofuranyl (e.g., tetrahydrofuran-3-yl), tetrahydrothiophenyl, dihydropyranyl, dihydrofuranyl, dihydrothiazolyl, dihydrofuranyl, dihydrothiophenyl ... alkyl, Alkyl (e.g. alkyl-4-yl), imidazolinyl, imidazolidinone, oxazolinyl, thiazolinyl, pyrazolin-2-yl, pyrazolidinyl, piperazinonyl, piperazinyl, and N-alkylpiperazines such as N-methylpiperazinyl.

[0341] In one embodiment, t is 1 and A is a heterocyclyl selected from morpholinyl, piperidinyl (e.g., piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, and piperidin-4-yl), piperidonyl, pyrrolidinyl (e.g., pyrrolidin-1-yl, pyrrolidin-2-yl, and pyrrolidin-3-yl), pyrrolidinonyl, azetidinyl, oxetanyl, pyranyl (2H-pyran or 4H-pyran), dihydropyranyl, dihydrofuranyl, dihydrothiazolyl, tetrahydrofuranyl (e.g., tetrahydrofuran-3-yl), ... alkyl, Alkyl (e.g. alkyl-4-yl), imidazolinyl, imidazolidinone, oxazolinyl, pyrazolin-2-yl, pyrazolidinyl, piperazinonyl, piperazinyl, and N-alkylpiperazines such as N-methylpiperazinyl.

[0342] Specifically, t is 1 and A is a heterocyclyl group which is oxetanyl (eg, oxetan-3-yl).

[0343] Specifically, t is 1 and A is a heterocyclyl group which is tetrahydrofuranyl (eg, tetrahydrofuran-3-yl).

[0344] In one embodiment, X is hydrogen, s is 0 and q is 0, and R 3 is a heterocyclic group having 3 to 6 ring members, wherein the heterocyclic group contains one or more (e.g., 1, 2, or 3) heteroatoms selected from N, O, S, and oxidized forms thereof. Specifically, R 3 is tetrahydrofuranyl (eg tetrahydrofuran-3-yl).

[0345] In one embodiment, s is 0 and t is 1 and A is directly attached to the oxygen atom to which the isoindolinone is bound. In one embodiment, s is 1 and the cycloalkyl group is connected via a methylene group (i.e., -CH 2 -) is attached to the oxygen atom bound to the isoindolinone.

[0346] In one embodiment, A is tetrahydrofuranyl and X is hydrogen.

[0347] In one embodiment, A is selected from cyclopropyl, oxetanyl and tetrahydrofuranyl.

[0348] In one embodiment, q is 0. In one embodiment, q is 1. In one embodiment, q is 2.

[0349] In one embodiment, A is oxetanyl and X is fluoro.

[0350] When q is not 0, R x and R yis selected from hydrogen, halogen (eg fluorine), hydroxy and methyl, such as hydrogen and methyl, especially hydrogen.

[0351] In one embodiment, q is 1 and at least one R x and R y is hydrogen. In one embodiment, q is 2 and at least two R x and R y is hydrogen, for example, three R x and R y It's hydrogen.

[0352] In one embodiment, -(CR x R y ) q -Selected from -CH 2 -and-CH 2 CH 2 -.

[0353] In one embodiment, R x and R y Together they form a saturated heterocyclyl having 3 to 6 ring members.

[0354] In one embodiment, t is 0 and -(CR x R y ) q -Yes-CH 2 -. In one embodiment, t is 0, s is 0, -(CR x R y ) q -Yes-CH 2 - and X is hydroxyl.

[0355] In one embodiment, X is selected from -CN, -OH, -OC 1-4 Alkyl, -O-hydroxy C 1-4 Alkyl, -S(O) d -C 1-4 Alkyl, -C(=O)-C 1-4 Alkyl, -NR x R y 、-NR x COR y and -C(=O)NR x R y .

[0356] In one embodiment, X is selected from -CN, -OH, -O-CH 2 CH 2 OH, -S(O) d -C 1-4 Alkyl and -C(=O)NR x Ry (e.g. -C(=O)NH 2 or -C(=O)NH(CH 3 In one embodiment, X is selected from -CN, -OH, -C(=O)NH 2 or -C(=O)NH(CH 3 ).

[0357] In one embodiment, X is selected from hydrogen, halogen, -CN, -OR 9 , and -C(=O)NR x R y In another embodiment, X is selected from hydrogen, halogen, -CN, -OH, -OCH 3 , and -C(=O)NH 2 In another embodiment, X is selected from hydrogen, fluorine, -CN, -OH, and -C(=O)NH 2 .

[0358] In one embodiment, X is selected from hydrogen, fluorine, -CN, -OH and -C(=O)NH 2 In one embodiment, X is selected from hydrogen, -CN, -OH and -C(=O)NH 2 In one embodiment, X is selected from -CN, -OH and -C(=O)NH 2 .

[0359] In one embodiment, X is selected from -OH and -C(=O)NH 2 , for example -OH.

[0360] In one embodiment, X is -C(=O)NR x R y (e.g. -C(=O)NH 2 or -C(=O)NH(CH 3 )).

[0361] In one embodiment, R x and R y is hydrogen, halogen (such as fluorine), hydroxyl and methyl. In one embodiment, R x and R y In one embodiment, R x and R y Together they form a saturated heterocyclyl having 3 to 6 ring members.

[0362] In one embodiment, A is C 3-6Cycloalkyl (ie, g is 1, 2 or 3) and t is 1 and s is 0 or 1, and the compound of formula (I) is a compound of formula (If) or a tautomer or solvate or a pharmaceutically acceptable salt thereof:

[0363]

[0364] In one embodiment, A is C 3-6 Cycloalkyl (ie, g is 1, 2 or 3) and t is 1 and s is 1, and the compound of formula (I) is a compound of formula (Ig) or a tautomer or solvate or a pharmaceutically acceptable salt thereof:

[0365]

[0366] In one embodiment, A is C 3-6 Cycloalkyl (ie g is 1, 2 or 3) and t is 1 and s is 0, and the compound of formula (I) is a compound of formula (Ig') or a tautomer or solvate or a pharmaceutically acceptable salt thereof:

[0367]

[0368] In one embodiment, the compound of formula (I) is a compound of formula (Ig′) and g is 2.

[0369] In one embodiment, A is C 3-6 Cycloalkyl (ie, g is 1, 2 or 3) and t is 1 and s is 1, and the cycloalkyl is geminally disubstituted (ie, the group -(CR x R y ) q -X and -CH 2 -O-isoindolinone, both of which are attached to the same atom of the cycloalkyl group), and the compound of formula (I) is a compound of formula (Ih) or a tautomer or solvate or a pharmaceutically acceptable salt thereof:

[0370]

[0371] In one embodiment, A is cyclopropyl (ie, g is 1), t is 1 and s is 1. Thus, the cycloalkyl group is cyclopropyl and the compound of formula (I) is a compound of formula (Ii) or a tautomer or solvate or pharmaceutically acceptable salt thereof:

[0372]

[0373] In one embodiment, A is C 3-6cycloalkyl (ie, g is 1, 2 or 3), t is 1, s is 1 and X is hydroxy, and the compound of formula (I) is a compound of formula (Ij) or a tautomer or solvate or a pharmaceutically acceptable salt thereof:

[0374]

[0375] In one embodiment, A is C 3-6 Cycloalkyl (ie, g is 1, 2 or 3), t is 1, s is 1 and X is -C(=O)NH 2 , and the compound of formula (I) is a compound of formula (Ik) or a tautomer or solvate or a pharmaceutically acceptable salt thereof:

[0376]

[0377] In one embodiment, A is C 3-6 Cycloalkyl (ie, g is 1, 2 or 3), t is 1, s is 1 and X is -CN and the compound of formula (I) is a compound of formula (Ik') or a tautomer or solvate or a pharmaceutically acceptable salt thereof:

[0378]

[0379] In another embodiment, A is C 3-6 Cycloalkyl (ie, g is 1, 2 or 3), t is 1, s is 1 and R x and R y Is hydrogen (including 1 H and 2 H) and the compound of formula (I) is a compound of formula (IL) or a tautomer or solvate or a pharmaceutically acceptable salt thereof:

[0380]

[0381] In one embodiment, A is cyclopropyl or cyclobutyl (ie, g is 1 or 2), t is 1, s is 1 and X is hydroxy and the compound of formula (IL) is a compound of formula (Im) or a tautomer or solvate or pharmaceutically acceptable salt thereof:

[0382]

[0383] In one embodiment, g is 1 and the compound of formula (Im) is a compound of formula (Im') or a tautomer or solvate or pharmaceutically acceptable salt thereof:

[0384]

[0385] In one embodiment, A is C 3Cycloalkyl (ie, g is 1), t is 1, s is 1 and X is -C(=O)NH 2 And the compound of formula (I) is a compound of formula (In) or a tautomer or solvate or a pharmaceutically acceptable salt thereof:

[0386]

[0387] wherein q is 0 or 1. In one embodiment of compound (In), q is 0.

[0388] In one embodiment, A is C 3 Cycloalkyl (ie g is 1), t is 1, s is 1 and X is -CN and the compound of formula (I) is a compound of formula (In') or a tautomer or solvate or pharmaceutically acceptable salt thereof:

[0389]

[0390] wherein q is 0 or 1. In one embodiment of compound (In), q is 0.

[0391] In one embodiment of formula (I) and subformulae thereof, R 3 CR x R y The hydrogen in the )- group is 2 H (i.e., deuterium, D). In one embodiment, the group -CH 2 The hydrogen in -O is 2 H (i.e., deuterium, D). In one embodiment, -(CR x R y )-group and -CH 2 The hydrogen in the -O group is 2 H (i.e. deuterium, D).

[0392] In one embodiment, q is 0 or 1 and R x and R y It is hydrogen or deuterium.

[0393] In one embodiment, A is cyclopropyl (ie, g is 1), t is 1, s is 1, X is hydroxy and -(CR x R y )-group and -CH 2 The hydrogen in the -O group is 2 H (or D), and the compound of formula (I) is a compound of formula (Io) or a tautomer or solvate or a pharmaceutically acceptable salt thereof:

[0394]

[0395] In one embodiment, the compound of formula (I) is a compound of formula (Io') or (Io") or a tautomer or solvate or pharmaceutically acceptable salt thereof:

[0396]

[0397] In one embodiment, R 3 Yes-(CR x R y ) q -X and s is 1, t is 0 and q is 1 or 2, and the compound of formula (I) is a compound of formula (Ip):

[0398]

[0399] In one embodiment, R x and R y is H, and the compound of formula (Ip) is a compound of formula (Ip') or a tautomer or solvate or a pharmaceutically acceptable salt thereof:

[0400]

[0401] In one embodiment, A is C 3-6 Cycloalkyl or saturated heterocyclyl having 3 to 6 ring members, wherein t is 1, and s is 1, Y is independently selected from -CH 2 -, O, or SO 2 , i is 0 or 1, g is 1, 2, 3 or 4 and i+g is 1, 2, 3 or 4 and the compound of formula (I) is a compound of formula (Iq) or a tautomer or solvate or a pharmaceutically acceptable salt thereof:

[0402]

[0403] In one embodiment, the compound of formula (I) is a compound of formula (Iq') or a tautomer or solvate or pharmaceutically acceptable salt thereof:

[0404]

[0405] In one embodiment of the compound of formula (Iq'), q is 1 and R x , R y and X is hydrogen.

[0406] In one embodiment of the compound of formula (Iq'), q is 1, R x and R y is hydrogen, and X is hydroxyl.

[0407] In one embodiment of the compound of formula (Iq'), q is 1, Rx and R y is hydrogen, and X is fluorine.

[0408] In one embodiment of the compounds of formula (Iq'), q is 0. In one embodiment of the compounds of formula (Iq'), q is 0 and X is fluoro.

[0409] In one embodiment, q is 0 and X is fluoro and the compound of formula (Iq') is a compound of formula (Iq") or a tautomer or solvate or pharmaceutically acceptable salt thereof:

[0410]

[0411] In one embodiment of the compound of (Iq′) or the compound of (Iq″), g is 1, i is 1 and Y is O.

[0412] In one embodiment, g is 1, i is 1, Y is O, q is 0 and X is F and the compound of formula (Iq') is a compound of formula (Iq"') or a tautomer or solvate or pharmaceutically acceptable salt thereof:

[0413]

[0414] In one embodiment, i is 1 and Y is O or SO 2 , especially O. In one embodiment, the compound of formula (Iq) is a compound of formula (Iq"") or a tautomer or solvate or pharmaceutically acceptable salt thereof:

[0415]

[0416] In one embodiment, s is 0, t is 1, A is tetrahydrofuranyl, q is 0 and X is hydrogen. In one embodiment, R 3 is tetrahydrofuranyl and s is 0.

[0417] In one embodiment, -(CH 2 ) s R 3 Select from the following table (the point of attachment to oxygen is indicated by a dotted bond or a bond end marked with "*"):

[0418]

[0419]

[0420] In one embodiment, -(CH 2 ) s R 3 Select from the following table (the point of attachment to oxygen is indicated by a dotted bond or a bond end marked with "*"):

[0421]

[0422] In one embodiment, A is cyclopropyl, t is 1, s is 1, R x and R y is hydrogen and X is -OH.

[0423] In one embodiment, A is cyclopropyl, t is 1, s is 1, R x and R y is hydrogen and X is -CN.

[0424] In one embodiment, R 3 is hydrogen and s is 1. In one embodiment, X is hydrogen and s, t, and q are 0.

[0425] R 4 and a

[0426] a is 0, 1, 2 or 3. In other words, the phenyl group of isoindolin-1-one may have 0, 1, 2 or 3 substituents R 4 .

[0427] In one embodiment, a is 0 or 1. In another embodiment, a is 0. In another embodiment, a is 1.

[0428] When a is 2 or 3 (i.e. the phenyl group of isoindolin-1-one is replaced by more than one R 4 substituted), the substituent R 4 can be the same or different (i.e. independently selected from R 4 definition of ).

[0429] In one embodiment, a is 1 and the substituent R 4 is at the 4-position of isoindolin-1-one, and the compound of formula (I) is a compound of formula (Ir) or a tautomer or solvate or a pharmaceutically acceptable salt thereof:

[0430]

[0431] R 4 independently selected from halogen, nitrile, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy and halogenated C 1-4 Alkoxy.

[0432] In one embodiment, R 4 In one embodiment, R 4 In another embodiment, R 4 It's fluorine.

[0433] In one embodiment, a is 1, the substituent R 4 is at the 4-position of isoindolin-1-one, and R 4 is F and the compound of formula (I) is a compound of formula (Is) or a tautomer or solvate or a pharmaceutically acceptable salt thereof:

[0434]

[0435] In one embodiment, a is 0, and the compound of formula (I) is a compound of formula (It) or a tautomer or solvate or pharmaceutically acceptable salt thereof:

[0436]

[0437] In one embodiment, R 4 It is C 1-4 Alkyl (e.g. -CH 3 ), or halogen (such as F or Cl) and a is 1.

[0438] In one embodiment, a is 0 and R 4 Not present (i.e. hydrogen).

[0439] In one embodiment, a is 0 or 1 and R 4 is a halogen (eg, fluorine).

[0440] R 5 and m

[0441] m is 1 or 2. In other words, the phenyl group may have 1 or 2 substituents R 5 .

[0442] In one embodiment, m is 1 and the phenyl group has one substituent.

[0443] R 5 Attachment may be at the ortho (or adjacent), meta (or meta) or para (or para) position of the phenyl group, wherein the positions are defined relative to the point of attachment of the phenyl group to the 3-position of the isoindolin-1-one ring.

[0444] When m is 2 (i.e. the phenyl group is replaced by more than one R 5 When substituted), the substituent R 5 can be the same or different (i.e. independently selected from R 5 definition of ).

[0445] In one embodiment, m is 1 and the substituent R 4 is in the para position of the phenyl group, and the compound of formula (I) is a compound of formula (Iu) or a tautomer or solvate or a pharmaceutically acceptable salt thereof:

[0446]

[0447] R 5 independently selected from halogen, nitrile, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy and halogenated C 1-4 Alkoxy.

[0448] In one embodiment, R 5 Halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl or C 1-4 In another embodiment, R 5 is a halogen (eg chlorine).

[0449] In one embodiment, R 5 is a halogen (such as Cl or F), C 1-4 Alkyl (e.g. -CH 2 CH 3 ), nitrile, halogenated C 1-4 Alkyl (e.g. -CF 3 or -CF 2 CH 3 ), or halogenated C 1-4 Alkoxy (e.g. -OCF 3 ), and m is 1 or 2.

[0450] In one embodiment, m is 1 and R 5 Selected from halogen, nitrile, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy and halogenated C 1-4 Alkoxy.

[0451] In one embodiment, m=1 and R 5 is -Cl (e.g. p-Cl), -F (e.g. 4-F), -CN (e.g. p-CN), -CF 3 (For example, for CF 3 ),-OCF 3 (For example, for OCF 3 ), CF 2 CH 3 (For example, for CF 2 CH 3 ) or -CH 2 CH 3 (For example, for CH 2 CH 3 ), or m=2 and R 5 It is right F or interval F.

[0452] In one embodiment, m=1 and R 5 is -Cl (eg p-Cl).

[0453] R 6 and R 7

[0454] R 6 and R 7 are independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Hydroxyl, Hydroxyl C 1-6 Alkyl, -COOC 1-6 Alkyl, -(CH 2 ) j -OC 1-6 Alkyl, -(CH 2 ) j -O-(Hydroxy C 1-6 Alkyl), -C 1-6 Alkyl-NR x R y 、-(CR x R y ) p -CONR x R y 、-(CR x R y ) p -NR x COR y 、-(CR x R y ) p -O-CH 2 -CONR x R y , a heterocyclic group having 3 to 7 ring members, -CH 2 -heterocyclyl having 3 to 7 ring members, -CH 2 -O-heterocyclic group having 3 to 7 ring members, -CH 2 -NH-heterocyclic group having 3 to 7 ring members, -CH 2 -N(C 1-6 -C(=O)NH-heterocyclic group having 3 to 7 ring members, C 3-8 Cycloalkyl, -CH 2 -C 3-8 Cycloalkyl, -CH 2 -OC 3-8 Cycloalkyl, and C 3-8Cycloalkenyl, wherein the cycloalkyl, cycloalkenyl or heterocyclic group may be optionally substituted by one or more R z substituted with a group, and wherein in each case, the heterocyclyl contains one or more (e.g., 1, 2, or 3) heteroatoms selected from N, O, S, and oxidized forms thereof;

[0455] or the R 6 Group and R 7 The groups together with the carbon atoms to which they are attached can be linked to form C 3-6 Cycloalkyl or heterocyclyl having 3 to 6 ring members, wherein the heterocyclyl contains one or more (e.g., 1, 2, or 3) heteroatoms selected from N, O, S and oxidized forms thereof, and wherein the C 3-6 Cycloalkyl and heterocyclyl groups may be optionally substituted with one or more R z Group substitution;

[0456] R x and R y are independently selected from hydrogen, halogen, nitro, nitrile, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Hydroxyl, Hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, -(CH 2 ) k -OC 1-6 Alkyl, hydroxyl C 1-6 Alkoxy, -COOC 1-6 Alkyl, -N(H) e (C 1-4 alkyl) 2-e , -C 1-6 Alkyl-N(H) e (C 1-4 alkyl) 2-e 、-(CH 2 ) k -C(=O)N(H) e (C 1-4 alkyl) 2-e , C 3-8 Cycloalkyl and C 3-8 Cycloalkenyl;

[0457] or the R x Group and R y The groups together with the carbon or nitrogen atoms to which they are attached can be linked to form C 3-6 a cycloalkyl group or a saturated heterocyclic group having 3 to 6 ring members, which may be optionally condensed with an aromatic heterocyclic group having 3 to 5 ring members;

[0458] or when on a carbon atom, the R x Group and R y The groups can be linked together to form =CH 2 Group;

[0459] R z are independently selected from halogen, nitro, nitrile, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, =O, Hydroxyl, Hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, -(CH 2 ) k -OC 1-6 Alkyl, hydroxyl C 1-6 Alkoxy, -C(=O)C 1-6 Alkyl, -C(=O)C 1-6 Alkyl-OH, -C(=O)C 1-6 Alkyl-N(H) e (C 1-4 alkyl) 2-e 、-C(=O)N(H) e (C 1-4 alkyl) 2-e 、-(CH 2 ) r -CO 2 C 1-6 Alkyl, -(CH 2 ) r -CO 2 H, -N(H) e (C 1-4 alkyl) 2-e , -C 1-6 Alkyl-N(H) e (C 1-4 alkyl) 2-e , a heterocyclic group having 3 to 6 ring members, a -C(=O)C 1-4 Alkyl-substituted heterocyclic radical having 3 to 6 ring members, -C(=O)OC 1-4 Alkyl-substituted heterocyclic radical having 3 to 6 ring members, -C(=O)N(H) e (C 1-4 alkyl) 2-e substituted heterocyclic radical having 3 to 6 ring members, -C(=O) heterocyclic radical having 3 to 6 ring members, C 3-8 Cycloalkyl and C 3-8 Cycloalkenyl, where R 7 is pyridine, then R z No -NH2 ;

[0460] j, e, r and p are independently selected from 0, 1 and 2; and

[0461] k is selected from 1 and 2.

[0462] In one embodiment, R 6 and R 7 are independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Hydroxyl, Hydroxyl C 1-6 Alkyl, -COOC 1-6 Alkyl, -(CH 2 ) j -OC 1-6 Alkyl, -(CH 2 ) j -O-(Hydroxy C 1-6 Alkyl), -C 1-6 Alkyl-NR x R y 、-(CR x R y ) p -CONR x R y 、-(CR x R y ) p -NR x COR y 、-(CR x R y ) p -O-CH 2 -CONR x R y , a heterocyclic group having 3 to 7 ring members, -CH 2 -heterocyclyl having 3 to 7 ring members, -CH 2 -O-heterocyclic group having 3 to 7 ring members, -CH 2 -NH-heterocyclic group having 3 to 7 ring members, -CH 2 -N(C 1-6 -C(=O)NH-heterocyclic group having 3 to 7 ring members, C 3-8 Cycloalkyl, -CH 2 -C 3-8 Cycloalkyl, -CH 2 -OC 3-8 Cycloalkyl, and C 3-8Cycloalkenyl, wherein the cycloalkyl, cycloalkenyl or heterocyclic group may be optionally substituted by one or more R z substituted with a group, and wherein in each case, the heterocyclyl contains one or more (e.g., 1, 2, or 3) heteroatoms selected from N, O, S, and oxidized forms thereof;

[0463] In one embodiment, R 7 is a cycloalkyl, cycloalkenyl or heterocyclyl group, which is optionally substituted by one or more R z Substitution, the R z Selected from C 1-6 Alkyl (such as methyl), C 1-6 Alkoxy (eg, methoxy) and -C(=O)C 1-6 Alkyl (e.g. -C(=O)CH 3 ).

[0464] In one embodiment, R 7 is a cycloalkyl or cycloalkenyl group, which is optionally substituted by one or more R z Group substitution, where R z It's a hydroxyl group.

[0465] R 6 and R 7 Can be the same or different.

[0466] When R 6 and R 7 Differently, the compounds of formula (I) may exist as at least two diastereomers:

[0467]

[0468] For the avoidance of doubt, general formula (I) and all subformulae encompass both individual diastereomers and mixtures of said diastereomers, said diastereomers being -CR 6 R 7 The epimers at the OH group are related.

[0469] In one embodiment of the compound of formula (I), R 6 and R 7 are different and the compound is diastereomer 2A or a tautomer or solvate or a pharmaceutically acceptable salt thereof.

[0470] In one embodiment of the compound of formula (I), R 6 and R 7 are different and the compound is diastereomer 2B or a tautomer or solvate or a pharmaceutically acceptable salt thereof.

[0471] In one embodiment, R 6is methyl and the compound of formula (I) is a compound of formula (IV) or a tautomer or solvate or a pharmaceutically acceptable salt thereof:

[0472]

[0473] In one embodiment, R 6 is ethyl and the compound of formula (I) is a compound of formula (Iv') or a tautomer or solvate or a pharmaceutically acceptable salt thereof:

[0474]

[0475] In one embodiment, R 7 Selected from C 1-6 Alkyl or halogenated C 1-6 In one embodiment, R 7 It is C 3-6 Cycloalkyl (e.g. cyclopropyl, cyclobutyl or cyclohexyl), which is optionally substituted by one or more R z group (e.g. -OH).

[0476] In one embodiment, R 7 Selected from C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, -(CH 2 ) j -OC 1-6 Alkyl, -(CH 2 ) j -O-(Hydroxy C 1-6 Alkyl), -C 1-6 Alkyl-NR x R y (For example -C 1-6 Alkyl-N(H) e (C 1-4 alkyl) 2-e ),-(CR x R y ) p -NR x COR y , a heterocyclic group having 3 to 7 ring members, -CH 2 -heterocyclyl having 3 to 7 ring members, -CH 2 -NH-heterocyclic group having 3 to 7 ring members, -CH 2 -N(C 1-6 -C(=O)NH-heterocyclic group having 3 to 7 ring members, C 3-8 Cycloalkyl, and -CH 2 -C 3-8Cycloalkyl, wherein the cycloalkyl or heterocyclic group may be optionally substituted by one or more R z The heterocyclic group is substituted with a moiety and wherein in each case the heterocyclic group contains one or more (eg, 1, 2, or 3) heteroatoms selected from N, O, S and oxidized forms thereof.

[0477] In one embodiment, R 7 Selected from C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, -(CH 2 ) j -OC 1-6 Alkyl, -(CH 2 ) j -O-(Hydroxy C 1-6 Alkyl), -C 1-6 Alkyl-N(H) e (C 1-4 alkyl) 2-e , a heterocyclic group having 3 to 7 ring members, -CH 2 -heterocyclic group having 3 to 7 ring members, -C(=O)NH-heterocyclic group having 3 to 7 ring members, C 3-8 Cycloalkyl, and -CH 2 -C 3-8 Cycloalkyl, wherein the cycloalkyl or heterocyclic group may be optionally substituted by one or more R z The heterocyclic group is substituted with a moiety and wherein in each case the heterocyclic group contains one or more (eg, 1, 2, or 3) heteroatoms selected from N, O, S and oxidized forms thereof.

[0478] In one embodiment, R 7 is selected from a heterocyclic group having 3 to 7 ring members, -CH 2 -heterocyclic group having 3 to 7 ring members, -C(=O)NH-heterocyclic group having 3 to 7 ring members, C 3-8 Cycloalkyl, and -CH 2 -C 3-8 Cycloalkyl, wherein the cycloalkyl or heterocyclic group may be optionally substituted by one or more R z The heterocyclic group is substituted with a moiety and wherein in each case the heterocyclic group contains one or more (eg, 1, 2, or 3) heteroatoms selected from N, O, S and oxidized forms thereof.

[0479] In one embodiment, R 7 is selected from a heterocyclyl group having 3 to 7 ring members and -CH 2 - a heterocyclic group having 3 to 7 ring members, wherein the heterocyclic group may be optionally replaced by one or more R zThe heterocyclic group is substituted with a moiety and wherein in each case the heterocyclic group contains one or more (eg 1 or 2) heteroatoms selected from N, O, S and oxidized forms thereof.

[0480] In an embodiment, the heterocyclyl is saturated. 7 is a saturated heterocyclic group having 3 to 6 ring members or -CH 2 -(saturated heterocyclyl having 3 to 6 ring members), such as wherein the heterocyclyl is selected from oxetanyl, Alkyl, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, imidazolinyl, azetidinyl, thiomorpholinyl, such as alkyl, piperidinyl or piperazinyl.

[0481] In one embodiment, R 7 is selected from a saturated heterocyclic group having 3 to 6 ring members and -CH 2 - a saturated heterocyclic group having 3 to 6 ring members, wherein the heterocyclic group may be optionally replaced by one or more R z In one embodiment, R 7 is selected from a nitrogen-containing saturated heterocyclic group having 3 to 6 ring members and -CH 2 -(a nitrogen-containing saturated heterocyclic group having 3 to 6 ring members), wherein the heterocyclic group may be optionally replaced by one or more R z The heterocyclic group may optionally contain one or more (eg 1, 2, or 3) additional heteroatoms selected from N, O, S.

[0482] In one embodiment, R 7 is a nitrogen-containing saturated heterocyclic group having 3 to 7 ring members or -CH 2 -(a nitrogen-containing saturated heterocyclic group having 3 to 7 ring members), wherein the nitrogen-containing saturated heterocyclic group may be optionally replaced by one or more R z The nitrogen-containing saturated heterocyclic group is substituted with a group, and the nitrogen-containing saturated heterocyclic group may optionally contain one or more (e.g., 1, 2, or 3) additional heteroatoms selected from N, O, and S. In one embodiment, the nitrogen-containing saturated heterocyclic group having 3 to 7 ring members (e.g., 3 to 6 ring members) is selected from piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, imidazolinyl, azetidinyl, thiomorpholinyl, such as piperidinyl or piperazinyl.

[0483] In one embodiment, R 7 is a nitrogen-containing aromatic heterocyclic group having 3 to 6 ring members or -CH 2-(a nitrogen-containing aromatic heterocyclic group having 3 to 6 ring members), wherein the heterocyclic group may be optionally replaced by one or more R z The heterocyclic group may optionally contain one or more (eg 1, 2, or 3) additional heteroatoms selected from N, O, S.

[0484] In another embodiment, R 7 is a nitrogen-containing aromatic heterocyclic group having 3 to 6 ring members, wherein the heterocyclic group may be unsubstituted or substituted by one or more R z The group is substituted, the R z The group is selected, for example, from halogen (eg fluorine), C 1-6 Alkyl (such as methyl), C 1-6 Alkoxy (eg, methoxy), and -C(=O)C 1-6 Alkyl (e.g. -C(=O)CH 3 ).

[0485] In one embodiment, R 7 is an oxygen-containing aromatic heterocyclic group having 3 to 6 ring members or -CH 2 -(an oxygen-containing aromatic heterocyclic group having 3 to 6 ring members), wherein the heterocyclic group may be optionally replaced by one or more R z The heterocyclic group may optionally contain one or more (eg 1, 2, or 3) additional heteroatoms selected from N, O, S.

[0486] In another embodiment, R 7 is an oxygen-containing aromatic heterocyclic group having 3 to 6 ring members, wherein the heterocyclic group may be unsubstituted or substituted by one or more R z Group substitution, such as R z The group is selected from halogen (such as fluorine), C 1-6 Alkyl (such as methyl), C 1-6 Alkoxy (eg, methoxy), and -C(=O)C 1-6 Alkyl (e.g. -C(=O)CH 3 ).

[0487] In one embodiment, R 7 is selected from a heterocyclic group containing 5 or 6 ring members, which is optionally replaced by one or more R z replace.

[0488] In one embodiment, R 7 is selected from an aromatic heterocyclic group containing 5 ring members, which is optionally replaced by one or more R z In one embodiment, R 7is selected from an aromatic nitrogen-containing (e.g. diaza) heterocyclic group containing 5 ring members, which is optionally replaced by one or more R z In one embodiment, R 7 is pyrazolyl (eg, pyrazol-4-yl or pyrazol-3-yl).

[0489] In one embodiment, R 7 is selected from a saturated heterocyclic group containing 6 ring members, which is optionally substituted by one or more R z In one embodiment, R 7 is selected from a saturated oxygen-containing or nitrogen-containing heterocyclic group containing 6 ring members, which is optionally replaced by one or more R z replace.

[0490] In one embodiment, R 7 Selected from alkyl, piperidinyl, pyrazolyl or imidazolyl, which is optionally substituted by one or more R z In one embodiment, R 7 Selected from alkyl, piperidinyl, pyrazolyl or imidazolyl, which is optionally substituted by one or more R z Substitution, where R z Selected from halo (e.g. -F) or C 1-4 Alkyl (eg, methyl).

[0491] In one embodiment, R 7 Selected from alkyl (also known as tetrahydropyranyl) or piperidinyl, optionally substituted with one or more R z In one embodiment, R 7 Selected from alkyl or piperidinyl, which is unsubstituted or substituted by one or more R z Substitution, where R z Selected from halo (e.g. -F) or C 1-4 Alkyl (eg methyl), especially halo (eg -F).

[0492] In one embodiment, R 7 It is C 3-8 Cycloalkyl, such as C 3-6 Cycloalkyl (e.g. cyclobutyl or cyclohexyl), optionally substituted with one or more R z Substitution, for example, where R z In one embodiment, R 7 is cyclohexyl, which is optionally substituted with one or more hydroxyl groups. 7 is cyclohexyl, optionally substituted with one or more hydroxy groups, in trans stereochemistry (eg, trans-4-hydroxycyclohexane).

[0493] In one embodiment, R 7 Selected from -CH 2 -NH-heterocyclic groups having 3 to 7 ring members (e.g., -CH 2 -NH- alkyl) and -CH 2 -N(C 1-6 Alkyl)-heterocyclic group having 3 to 7 ring members (e.g. -CH 2 NCH 3 -(piperidinyl)), which is optionally substituted with one or more R z Groups (e.g., methyl, -COCH 3 )replace.

[0494] In one embodiment, R 7 Yes-(CR x R y ) p -CONR x R y or -C(=O)NH-heterocyclyl having 3 to 7 ring members. In one embodiment, R 7 is -C(=O)NH-heterocyclyl having 4 to 6 ring members (eg, piperidinyl, pyrazolyl, or azetidinyl).

[0495] In one embodiment, R 7 Yes-(CR x R y ) p -CONR x R y In one embodiment, R 7 Yes-(CR x R y ) p -CONH(C 1-4 alkyl), especially -(CO)NHCH 3 、-(CO)NHCH 2 CH 3 or -(CO)NH(CH(CH 3 ) 2 ).

[0496] In one embodiment, R 7 is a -C(=O)NH-heterocyclyl group having 3 to 7 ring members (e.g., -C(=O)NH-piperidinyl, -C(=O)NH-azetidinyl or -C(=O)NH-pyrazolyl), which is optionally substituted by one or more R z Groups (e.g., methyl, -COCH 3 )replace.

[0497] In one embodiment, R 7 Yes-C 1-6 Alkyl-NR x R y (For example -C 1-6 Alkyl-N(H) e (C 1-4 alkyl) 2-e In one embodiment, R 7 Yes-CH 2 NH 2 、-CH 2 NHCH 3 , or -CH 2 N(CH 3 ) 2 In one embodiment, R 7 Yes-C 1-6 Alkyl-NR x R y , where R x It is C 3-8 In one embodiment, R 7 Yes-C 1-2 Alkyl-NH-C 3-6 Cycloalkyl (e.g. -CH 2 -NH-cyclopropyl).

[0498] In one embodiment, R 7 Yes-C 1-6 Alkyl-NR x R y , where R x Group and R y The groups together with the nitrogen atoms to which they are attached can be linked to form C 3-6 In one embodiment, R x and R y Together they form a saturated heterocyclyl group having 3 to 6 ring members, for example piperazinyl.

[0499] In one embodiment, R 7 Yes-C 1-6 Alkyl-NR x R y , where R x Group and R y The groups, together with the nitrogen atoms to which they are attached, are linked to form C 3-6 cycloalkyl or a saturated heterocyclic group having 3 to 6 ring members, which may be optionally fused to an aromatic heterocyclic group having 3 to 5 ring members. 7 Yes-C 1-6 Alkyl-NRx R y , where R x Group and R y The radicals are linked together with the nitrogen atom to which they are attached to form a saturated heterocyclic radical having 3 to 6 ring members, which is fused to an aromatic heterocyclic radical having 3 to 5 ring members. z are independently selected from halogen, nitro, nitrile, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, =O, Hydroxyl, Hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, -(CH 2 ) k -OC 1-6 Alkyl, hydroxyl C 1-6 Alkoxy, -C(=O)C 1-6 Alkyl, -C(=O)C 1-6 Alkyl-OH, -C(=O)C 1-6 Alkyl-N(H) e (C 1-4 alkyl) 2-e 、-C(=O)N(H) e (C 1-4 alkyl) 2-e 、-(CH 2 ) r -CO 2 C 1-6 Alkyl, -(CH 2 ) r -CO 2 H, -N(H) e (C 1-4 alkyl) 2-e , -C 1-6 Alkyl-N(H) e (C 1-4 alkyl) 2-e , a heterocyclic group having 3 to 6 ring members, a -C(=O)C 1-4 Alkyl-substituted heterocyclic radical having 3 to 6 ring members, -C(=O)OC 1-4 Alkyl-substituted heterocyclic radical having 3 to 6 ring members, -C(=O)N(H) e (C 1-4 alkyl) 2-e substituted heterocyclic radical having 3 to 6 ring members, -C(=O) heterocyclic radical having 3 to 6 ring members, C 3-8 Cycloalkyl and C 3-8 Cycloalkenyl.

[0500] In one embodiment, Rz independently selected from halogen (e.g. fluorine), C 1-6 Alkyl (such as methyl), C 1-6 Alkoxy (eg, methoxy), and -C(=O)C 1-6 Alkyl (e.g. -C(=O)CH 3 ).

[0501] In one embodiment, R z Independently selected from C 1-6 Alkyl (such as methyl), C 1-6 Alkoxy (eg, methoxy), and -C(=O)C 1-6 Alkyl (e.g. -C(=O)CH 3 ).

[0502] In one embodiment, R 7 It is C 1-6 Alkyl (such as methyl or ethyl), halogenated C 1-6 Alkyl (e.g. trifluoromethyl), C 2-6 Alkenyl (e.g. C 2 Alkenyl), hydroxyl C 1-6 Alkyl (e.g. -CH 2 OH, -CH 2 CH 2 OH), -C 1-6 Alkyl-NR x R y (e.g. -CH 2 NH 2 、-CH 2 NHCH 3 、-CH 2 N(CH 3 ) 2 , or -CH 2 -NH-cyclopropyl), -(CR x R y ) p -CONR x R y (e.g. -(CO)NHCH 3 、-(CO)NHCH 2 CH 3 、-(CO)NHCH 2 CH 2 NH 2 or -(CO)NH(CH(CH 3 ) 2 ))、-(CH 2 ) j -OC 1-6 Alkyl (e.g. -CH 2 OCH 3、-CH 2 OCH 2 CH 3 or -CH 2 OCD 3 ),-(CR x R y ) p -NR x COR y (e.g. -CH 2 NHCOCH 3 ),-(CR x R y ) p -O-CH 2 -CONR x R y (e.g. -CH 2 -O-CH 2 CON(CH 3 ) 2 )、-(CH 2 ) j -O-(Hydroxy C 1-6 Alkyl) (e.g. -CH 2 -O-CH 2 CH 2 OH), -C(=O)NH-a heterocyclic group having 3 to 7 ring members, C 3-6 Cycloalkyl, heterocyclic group having 3 to 7 ring members (e.g. alkyl), or -CH 2 - a heterocyclic group having 3 to 7 ring members, wherein the cycloalkyl or heterocyclic group contains one or more (e.g. 1, 2, or 3) heteroatoms selected from N, O, S and oxidized forms and can be optionally replaced by one or more R z Group (e.g. selected from C 1-6 Alkyl (such as methyl), C 1-6 Alkoxy (eg, methoxy) and -C(=O)C 1-6 Alkyl (e.g. -C(=O)CH 3 In one embodiment, R 6 is methyl or ethyl and R 7 It is C 1-6 Alkyl (such as methyl), hydroxyl C 1-6 Alkyl, -C 1-6 Alkyl-NR x R y 、-(CR x R y ) p -CONR x R y 、-(CH 2 )j -OC 1-6 Alkyl, -(CR x R y ) p -NR x COR y 、-(CR x R y ) p -O-CH 2 -CONR x R y 、-(CH 2 ) j -O-(Hydroxy C 1-6 alkyl), heterocyclic groups having 3 to 7 ring members (e.g. alkyl), or -CH 2 - a heterocyclic group having 3 to 7 ring members, wherein the heterocyclic group contains one or more (e.g. 1, 2, or 3) heteroatoms selected from N, O, S and oxidized forms and can be optionally replaced by one or more R z The group is substituted, the R z The group is selected from C 1-6 Alkyl (such as methyl), C 1-6 Alkoxy (eg, methoxy) and -C(=O)C 1-6 Alkyl (e.g. -C(=O)CH 3 ).

[0503] In one embodiment, R 6 Selected from hydrogen, C 1-6 Alkyl (e.g. -CH 3 、-CH 2 CH 3 or -CH 2 CH 2 CH 3 ), C 2-6 Alkenyl (e.g. -CH=CH 2 ) and halogenated C 1-6 Alkyl (e.g. -CF 3 ).

[0504] In one embodiment, R 6 Selected from hydrogen or C 1-6 Alkyl (e.g. -CH 3 or -CH 2 CH 3 ).

[0505] In one embodiment, R 7 It is C 1-6 Alkyl (e.g. -CH 3 or -CH 2 CH3 ), hydroxyl C 1-6 Alkyl (e.g. -CH 2 OH), -C 1-6 Alkyl-NR x R y (e.g. -CH 2 N(CH 3 ) 2 ),-(CR x R y ) p -CONR x R y (e.g. -C(=O)N(CH 3 ) 2 or -C(=O)NHCH 3 or )、-(CH 2 ) j -OC 1-6 Alkyl (e.g. -CH 2 OCH 3 ), C 3-8 Cycloalkyl (e.g. cyclobutyl or cyclohexyl), heterocyclyl having 3 to 7 ring members, e.g.

[0506] (Connection points are represented by dashed keys):

[0507]

[0508] or -CH 2 - heterocyclyl groups having 3 to 7 ring members, for example

[0509] (Connection points are represented by dashed keys)

[0510]

[0511] When part R 7 When a heterocyclic group or a cycloalkyl group is included, the heterocyclic group may be optionally replaced by one or more R z The group is substituted, the R z The group is selected from C 1-6 Alkyl (e.g., methyl), hydroxy, halogen (e.g., fluorine), -C(=O)C 1-6 Alkyl (e.g. -C(=O)C(CH 3 ) 3 )、-(CH 2 ) r -CO 2 H (e.g. -CH 2 COOH or CH 2 CH 2 COOH) or -(CH 2 ) r-CO 2 C 1-6 Alkyl (e.g. CH 2 CH 2 COOCH 3 ).

[0512] In one embodiment, R 7 It is C 1-6 Alkyl (such as methyl or ethyl), halogenated C 1-6 Alkyl (e.g. trifluoromethyl), C 2-6 Alkenyl (e.g. C 2 Alkenyl), hydroxyl C 1-6 Alkyl (e.g. -CH 2 OH, -CH 2 CH 2 OH), -C 1-6 Alkyl-NR x R y (e.g. -CH 2 NH 2 、-CH 2 NHCH 3 、-CH 2 N(CH 3 ) 2 , or -CH 2 -NH-cyclopropyl), -(CR x R y ) p -CONR x R y (e.g. -(CO)NHCH 3 、-(CO)NHCH 2 CH 3 、-(CO)NHCH 2 CH 2 NH 2 or -(CO)NH(CH(CH 3 ) 2 ))、-(CH 2 ) j -OC 1-6 Alkyl (e.g. -CH 2 OCH 3 、-CH 2 OCH 2 CH 3 or -CH 2 OCD 3 ),-(CR x R y ) p -NR x COR y (e.g. -CH 2 NHCOCH3 ),-(CR x R y ) p -O-CH 2 -CONR x R y (e.g. -CH 2 -O-CH 2 CON(CH 3 ) 2 )、-(CH 2 ) j -O-(Hydroxy C 1-6 Alkyl) (e.g. -CH 2 -O-CH 2 CH 2 OH), -C(=O)NH-a heterocyclic group having 3 to 7 ring members, C 3-6 Cycloalkyl, heterocyclic group having 3 to 7 ring members (e.g. alkyl), or -CH 2 - a heterocyclic group having 3 to 7 ring members, wherein the cycloalkyl or heterocyclic group contains one or more (e.g. 1, 2, or 3) heteroatoms selected from N, O, S and oxidized forms and can be optionally replaced by one or more R z Group (e.g. selected from C 1-6 Alkyl (such as methyl), C 1-6 Alkoxy (eg, methoxy) and -C(=O)C 1-6 Alkyl (e.g. -C(=O)CH 3 In one embodiment, R 6 is methyl or ethyl and R 7 It is C 1-6 Alkyl (such as methyl), hydroxyl C 1-6 Alkyl, -C 1-6 Alkyl-NR x R y 、-(CR x R y ) p -CONR x R y 、-(CH 2 ) j -OC 1-6 Alkyl, -(CR x R y ) p -NR x COR y 、-(CR x R y ) p -O-CH 2 -CONRx R y 、-(CH 2 ) j -O-(Hydroxy C 1-6 alkyl), heterocyclic groups having 3 to 7 ring members (e.g. alkyl), or -CH 2 - a heterocyclic group having 3 to 7 ring members, wherein the heterocyclic group contains one or more (e.g. 1, 2, or 3) heteroatoms selected from N, O, S and oxidized forms and can be optionally replaced by one or more R z The group is substituted, the R z The group is selected from C 1-6 Alkyl (such as methyl), C 1-6 Alkoxy (eg, methoxy) and -C(=O)C 1-6 Alkyl (e.g. -C(=O)CH 3 ).

[0513] In one embodiment, R 6 Selected from hydrogen or C 1-6 Alkyl (e.g. -CH 3 or -CH 2 CH 3 ).

[0514] In one embodiment, R 7 It is C 1-6 Alkyl (e.g. -CH 3 or -CH 2 CH 3 ), hydroxyl C 1-6 Alkyl (e.g. -CH 2 OH), -C 1-6 Alkyl-NR x R y (e.g. -CH 2 N(CH 3 ) 2 ),-(CR x R y ) p -CONR x R y (e.g. -C(=O)N(CH 3 ) 2 or )、-(CH 2 ) j -OC 1-6 Alkyl (e.g. -CH 2 OCH 3 ), a heterocyclic group having 3 to 7 ring members, for example

[0515] (Connection points are represented by dashed keys):

[0516]

[0517] or -CH 2 - heterocyclyl groups having 3 to 7 ring members, for example

[0518] (Connection points are represented by dashed keys)

[0519]

[0520] When part R 7 When a heterocyclic group is included, the heterocyclic group may be optionally replaced by one or more R z The group is substituted, the R z The group is selected from C 1-6 Alkyl (eg, methyl).

[0521] In one embodiment of formula (I), R 7 is a heterocyclic group having 3 to 7 ring members, which is optionally replaced by one or more R z Group substitution, e.g.

[0522] (Connection points are represented by dashed keys)

[0523]

[0524] In one embodiment of formula (I), R 7 is a heterocyclic group having 3 to 7 ring members, which is optionally replaced by one or more R z Group substitution, e.g.

[0525] (Connection points are represented by dashed keys)

[0526]

[0527] In one embodiment, R 7 Yes-CH 2 - a heterocyclic group having 3 to 7 ring members, which is optionally replaced by one or more R z Group substitution, e.g.

[0528] (Connection points are represented by dashed keys)

[0529]

[0530] In one embodiment, R 7 Selected from:

[0531] (Connection points are represented by dashed keys):

[0532]

[0533] In one embodiment, R 7 Selected from:

[0534] (Connection points are represented by dashed keys):

[0535]

[0536]

[0537] In one embodiment, R 6 is hydrogen or C 1-6 In one embodiment, R 6 It is C 1-6 In one embodiment, R 6 is methyl or ethyl. In one embodiment, R 6 It is ethyl.

[0538] In one embodiment, R 6 It is C 1-6 alkyl (such as methyl or ethyl, for example methyl) and R 7 Selected from hydroxy C 1-6 Alkyl and -(CH 2 )-OC 1-6 Alkyl, in one embodiment, R 6 is methyl and R 7 Selected from methyl, -CH 2 -OH and -CH 2 -OCH 3 In one embodiment, R 6 is methyl and R 7 is methyl, ethyl or propyl. In one embodiment, R 6 is methyl and R 7 It's methyl.

[0539] In one embodiment, R 6 It is C 1-6 Alkyl or halogenated C 1-6 Alkyl (eg methyl, -monofluoromethyl, trifluoromethyl or ethyl).

[0540] In one embodiment, R 6 It is C 3-8 Cycloalkyl, such as C 3-6 Cycloalkyl (eg cyclopropyl).

[0541] In one embodiment, R 6 It is C 1-6 alkyl (such as methyl or ethyl, for example ethyl) and R 7 Selected from:

[0542] (Joining points are indicated by dashed bonds or bond ends marked with a "*"):

[0543]

[0544]

[0545] In one embodiment, R 6 It is C 1-6 alkyl (such as methyl or ethyl, for example ethyl) and R 7 Selected from:

[0546] (Joining points are indicated by dashed bonds or bond ends marked with a "*"):

[0547]

[0548] Specifically, R 7 yes:

[0549] (Connection points are represented by dashed keys):

[0550]

[0551] In one embodiment, R 6 It is C 1-6 alkyl (such as methyl or ethyl, for example methyl) and R 7 yes alkyl, and the compound of formula (I) is a compound of formula (Iw):

[0552]

[0553] In one embodiment of Formula (Iw), R z It is hydrogen or fluorine.

[0554] In one embodiment, R 7 is imidazolyl and the compound of formula (I) is a compound of formula (Ix) or a tautomer or solvate or a pharmaceutically acceptable salt thereof:

[0555]

[0556] In one embodiment, R 7 is N-methylpiperidinyl and the compound of formula (I) is a compound of formula (Ix') or a tautomer or solvate or a pharmaceutically acceptable salt thereof:

[0557]

[0558] In one embodiment, R 7is 4-fluoro-1-methylpiperidin-4-yl and the compound of formula (I) is a compound of formula (Ix") or a tautomer or solvate or a pharmaceutically acceptable salt thereof:

[0559]

[0560] In one embodiment, R 7 is pyrazolyl, which is optionally substituted by one or more R z In one embodiment, R 7 It is N-methylpyrazol-3-yl or N-methylpyrazol-4-yl.

[0561] In one embodiment, R 7 Selected from methyl, alkyl, pyrazolyl, imidazolyl, piperidinyl, and cyclohexyl, wherein the cycloalkyl and heterocyclic groups are optionally replaced by one or more R z groups (such as methyl, fluoro, or hydroxy).

[0562] In one embodiment, R 7 is selected from piperidinyl, which is optionally substituted by one or more R z groups (eg methyl, fluoro, or hydroxy, especially methyl and fluoro).

[0563] In one embodiment, the compound of formula (I) is a compound of formula (Ix) and R 6 It is C 1-4 alkyl.

[0564] In one embodiment, R 6 It is C 1-6 Alkyl (e.g. -CH 3 、-CH 2 CH 3 or -CH 2 CH 2 CH 3 , such as methyl or ethyl, for example ethyl) and R 7 is a heterocyclic group having 3 to 7 ring members, which is optionally replaced by one or more R z Group substitution.

[0565] In one embodiment, R 6 It is C 1-6 Alkyl (e.g. -CH 3 、-CH 2 CH 3 or -CH 2 CH 2 CH 3 , such as methyl or ethyl, for example ethyl) and R 7is an imidazolyl group, which is optionally substituted with one or more R z Group substitution (for example, methylimidazolyl).

[0566] In one embodiment, R 6 It is C 1-6 Alkyl (e.g. -CH 3 、-CH 2 CH 3 or -CH 2 CH 2 CH 3 , such as methyl or ethyl, for example ethyl) and R 7 is piperidinyl, which is optionally substituted by one or more R z Group substitution (e.g., methylpiperidinyl).

[0567] In one embodiment, R 6 It is C 1-6 Alkyl (e.g. -CH 3 、-CH 2 CH 3 or -CH 2 CH 2 CH 3 , such as methyl or ethyl, for example ethyl) and R 7 It is C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, methoxy C 1-4 Alkyl, heterocyclic radical having 5 or 6 ring members or C 3-6 Cycloalkyl, wherein the heterocyclic group or C 3-6 The cycloalkyl group is optionally substituted with one or more R z (eg, methyl, halogen (eg, fluorine), C(=O)Me, or -OH).

[0568] In one embodiment, R 6 It is C 1-6 Alkyl (e.g. -CH 3 、-CH 2 CH 3 or -CH 2 CH 2 CH 3 , such as methyl or ethyl, for example ethyl) and R 7 is methyl, ethyl, hydroxymethyl, hydroxyethyl, methoxymethyl, piperidinyl, alkyl, imidazolyl, pyrazolyl, cyclobutyl, cyclohexyl, which is optionally substituted by one or more R z (eg, methyl, halogen (eg, fluorine), C(=O)Me, or -OH).

[0569] In one embodiment, R 6 and R7 These two are the same. In one embodiment, R 6 and R 7 Both are methyl, and the compound of formula (I) is a compound of formula (Iy) or a tautomer or solvate or a pharmaceutically acceptable salt thereof:

[0570]

[0571] In one embodiment, the group -CR 6 R 7 OH is not -C(CH 3 ) 2 OH.

[0572] In one embodiment, R 7 Select from the group consisting of:

[0573] (Connection points are represented by dashed keys)

[0574]

[0575]

[0576] In one embodiment, R 7 Select from the group consisting of:

[0577] (Connection points are represented by dashed keys)

[0578]

[0579] In one embodiment, R z are independently selected from halogen, nitro, nitrile, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, =O, Hydroxyl, Hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, -(CH 2 ) k -OC 1-6 Alkyl, hydroxyl C 1-6 Alkoxy, -C(=O)C 1-6 Alkyl, -C(=O)C 1-6 Alkyl-OH, -C(=O)C 1-6 Alkyl-N(H) e (C 1-4 alkyl) 2-e 、-C(=O)N(H) e (C 1-4 alkyl) 2-e 、-(CH 2) k -CO 2 C 1-6 Alkyl, -(CH 2 ) r -CO 2 H, -NH(C 1-4 Alkyl), -N(C 1-4 alkyl) 2 , -C 1-6 Alkyl-N(H) e (C 1-4 alkyl) 2-e , a heterocyclic group having 3 to 6 ring members, a -C(=O)C 1-4 Alkyl-substituted heterocyclic radical having 3 to 6 ring members, -C(=O)OC 1-4 Alkyl-substituted heterocyclic radical having 3 to 6 ring members, -C(=O)N(H) e (C 1-4 alkyl) 2-e substituted heterocyclic radical having 3 to 6 ring members, -C(=O) heterocyclic radical having 3 to 6 ring members, C 3-8 Cycloalkyl and C 3-8 Cycloalkenyl.

[0580] In another embodiment, R z are independently selected from halogen, nitro, nitrile, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, =O, Hydroxyl, Hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, -(CH 2 ) k -OC 1-6 Alkyl, hydroxyl C 1-6 Alkoxy, -C(=O)C 1-6 Alkyl, -C(=O)C 1-6 Alkyl-OH, -C(=O)C 1-6 Alkyl-N(H) e (C 1-4 alkyl) 2-e 、-C(=O)N(H) e (C 1-4 alkyl) 2-e 、-(CH 2 ) r -CO 2 C 1-6 Alkyl, -(CH 2 ) r -CO 2 H, -C 1-6Alkyl-N(H) e (C 1-4 alkyl) 2-e , a heterocyclic group having 3 to 6 ring members, a -C(=O)C 1-4 Alkyl-substituted heterocyclic radical having 3 to 6 ring members, -C(=O)OC 1-4 Alkyl-substituted heterocyclic radical having 3 to 6 ring members, -C(=O)N(H) e (C 1-4 alkyl) 2-e substituted heterocyclic radical having 3 to 6 ring members, -C(=O) heterocyclic radical having 3 to 6 ring members, C 3-8 Cycloalkyl and C 3-8 Cycloalkenyl.

[0581] In another embodiment, when R 7 When it contains a saturated heterocyclic group, R z are independently selected from halogen, nitro, nitrile, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, =O, Hydroxyl, Hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, -(CH 2 ) k -OC 1-6 Alkyl, hydroxyl C 1-6 Alkoxy, -C(=O)C 1-6 Alkyl, -C(=O)C 1-6 Alkyl-OH, -C(=O)C 1-6 Alkyl-N(H) e (C 1-4 alkyl) 2-e 、-C(=O)N(H) e (C 1-4 alkyl) 2-e 、-(CH 2 ) r -CO 2 C 1-6 Alkyl, -(CH 2 ) r -CO 2 H, -N(H) e (C 1-4 alkyl) 2-e , -C 1-6 Alkyl-N(H) e (C 1-4 alkyl) 2-e , a heterocyclic group having 3 to 6 ring members, a -C(=O)C 1-4Alkyl-substituted heterocyclic radical having 3 to 6 ring members, -C(=O)OC 1-4 Alkyl-substituted heterocyclic radical having 3 to 6 ring members, -C(=O)N(H) e (C 1-4 alkyl) 2-e substituted heterocyclic radical having 3 to 6 ring members, -C(=O) heterocyclic radical having 3 to 6 ring members, C 3-8 Cycloalkyl and C 3-8 Cycloalkenyl.

[0582] Sub

[0583] In one embodiment, the compound of formula (I) is a compound of formula (II) or a tautomer or solvate or pharmaceutically acceptable salt thereof:

[0584]

[0585] Where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , a, m and s are as defined herein.

[0586] In one embodiment, R 1 is chloro, nitrile, methyl or methoxy. 1 is hydroxyl or hydroxyl C 1-4 Alkyl (eg hydroxy).

[0587] In one embodiment, R 1 Yes 0,1 (CR x R y ) v COOH (e.g. -COOH, -CH 2 COOH, -OCH 2 COOH or -C(CH 3 ) 2 COOH).

[0588] In another embodiment, R 1 is chlorine or nitrile and the compound of formula (II) is a compound of formula (IIa) or (IIb) or a tautomer or solvate or a pharmaceutically acceptable salt thereof:

[0589]

[0590] Where R 2 , R3 , R 4 , R 5 , R 7 , m and s are as defined herein. In one embodiment, R 1 Yes-SO 2 -R x Specifically, R x Yes-SO 2 -C 1-4 Alkyl (e.g. -SO 2 -CH 3 ) or -SO 2 - a heterocyclic group having 5 to 6 ring members (e.g., -SO 2 -morpholinyl, usually -SO 2 -(1-morpholinyl)). In another embodiment, in one embodiment, R 1 is hydroxyl or hydroxyl C 1-4 Alkyl (e.g. -CH 2 OH or -OH).

[0591] In one embodiment, R 6 is methyl or ethyl, and the compound of formula (I) is a compound of formula (IIIa) or (IIIb) or a tautomer or solvate or a pharmaceutically acceptable salt thereof:

[0592]

[0593]

[0594] Where R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , a, m and s are as defined herein.

[0595] In one embodiment, a is 1 and the compound of formula (I) is a compound of formula (IVa) or a tautomer or solvate or pharmaceutically acceptable salt thereof:

[0596]

[0597] Where R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , a, m and s are as defined herein.

[0598] In one embodiment, s is 0 and the compound of formula (I) is a compound of formula (IVb) or a tautomer or solvate or pharmaceutically acceptable salt thereof:

[0599]

[0600] Where R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , a, m and s are as defined herein.

[0601] In one embodiment, R 4 is F and the compound of formula (IVa) is a compound of formula (V) or a tautomer or solvate or a pharmaceutically acceptable salt thereof:

[0602]

[0603] Where R 1 , R 2 , R 3 , R 5 , R 7 , m and s are as defined herein.

[0604] In one embodiment, m is 1 and the substituent R 4 is at the 4-position of the phenyl group, and the compound of formula (I) is a compound of formula (VI) or a tautomer or solvate or a pharmaceutically acceptable salt thereof:

[0605]

[0606] In one embodiment, R 5 is chloro and the compound of formula (VI) is a compound of formula (VIa) or a tautomer or solvate or a pharmaceutically acceptable salt thereof:

[0607]

[0608] In one embodiment, A is C 3-6 Cycloalkyl (g is 1, 2 or 3) and t is 1, and the compound of formula (VI) is a compound of formula (VII) or a tautomer or solvate or a pharmaceutically acceptable salt thereof:

[0609]

[0610] In one embodiment, A is C 3-6 Cycloalkyl (g is 1, 2 or 3) and t is 1, and the cycloalkyl is geminally disubstituted (i.e., the group -(CRx R y )-X and CH 2 A group (where s is 1) or an oxygen atom (where s is 0) both of which are attached to the same atom of the cycloalkyl group), and the compound of formula (VII) is a compound of formula (VIIa) or a tautomer or solvate or a pharmaceutically acceptable salt thereof:

[0611]

[0612] In one embodiment, g is 1, and thus the cycloalkyl is cyclopropyl and the compound of formula (VIIa) is a compound of formula (VIIb) or a tautomer or solvate or pharmaceutically acceptable salt thereof:

[0613]

[0614] In one embodiment, s is 1, and the compound of formula (VIIb) is a compound of formula (VIIc) or a tautomer or solvate or pharmaceutically acceptable salt thereof:

[0615]

[0616] In one embodiment, R x and R y Is hydrogen (including 1 H and 2 H) and q is 1 and the compound of formula (VIIc) is a compound of formula (VIId) or a tautomer or solvate or a pharmaceutically acceptable salt thereof:

[0617]

[0618] In one embodiment, the compound of formula (VIId) is a compound of (VIId') or a tautomer or solvate or pharmaceutically acceptable salt thereof:

[0619]

[0620] In one embodiment, the compound of formula (VIId) is a compound of (VIId') and X is hydroxy.

[0621] In one embodiment, X is hydroxyl and the compound of formula (VIIId) is a compound of formula (VIle) or a tautomer or solvate or pharmaceutically acceptable salt thereof:

[0622]

[0623] In one embodiment, X is -C(=O)NH 2And the compound of formula (VlIe) is a compound of formula (VIle') or a tautomer or solvate or a pharmaceutically acceptable salt thereof:

[0624]

[0625] wherein q is 0 or 1, in particular q is 0.

[0626] In one embodiment, X is -CN and the compound of formula (Vlld) is a compound of formula (Ville") or a tautomer or solvate or pharmaceutically acceptable salt thereof:

[0627]

[0628] wherein q is 0 or 1, in particular q is 0.

[0629] In one embodiment, R 3 is methyl, and the compound of formula (VI) is a compound of formula (VIIf) or a tautomer or solvate or a pharmaceutically acceptable salt thereof:

[0630]

[0631] In one embodiment of Formula (VIIa-e'), R 6 In one embodiment of Formula (VIIa-e'), R 6 It is ethyl.

[0632] In one embodiment of Formula (VIIe") or Formula (VIIf), R 6 In one embodiment of Formula (VIIe") or Formula (VIIf), R 6 It is ethyl.

[0633] In one embodiment of Formula (VIIe") or Formula (VIIf), R 6 In one embodiment of Formula (VIIe") or Formula (VIIf), R 6 It is ethyl.

[0634] In one embodiment of the compound of Formula (VIIa-e'), R 7 Selected from methyl, alkyl, pyrazolyl, imidazolyl, piperidinyl, and cyclohexyl, wherein the cycloalkyl and heterocyclic groups are optionally replaced by one or more R z groups (such as methyl, fluoro, or hydroxy).

[0635] In one embodiment of the compound of Formula (VIIa-e'), R 7 Selected from Alkyl and methyl.

[0636] In one embodiment of the compound of Formula (VIIe") or Formula (VIIf), R 7 Selected from methyl, alkyl, pyrazolyl, imidazolyl, piperidinyl, and cyclohexyl, wherein the cycloalkyl and heterocyclic groups are optionally replaced by one or more R z groups (such as methyl, fluoro, or hydroxy).

[0637] In one embodiment of the compound of Formula (VIIe") or Formula (VIIf), R 7 Selected from Alkyl and methyl.

[0638] In one embodiment of the compound of Formula (VIIa-f), R 7 is selected from piperidinyl, which is optionally substituted by one or more R z groups (such as methyl, fluoro, or hydroxy).

[0639] In another embodiment, the compound of formula (I) is a compound of formula (a) or a tautomer or solvate or pharmaceutically acceptable salt thereof:

[0640]

[0641] Where R 1 is chlorine or nitrile, when s is 1, then X is hydroxyl or when s is 0, then X is -C(=O)NH 2 .

[0642] In another embodiment, the compound of formula (I) is a compound of formula (a') or a tautomer or solvate or pharmaceutically acceptable salt thereof:

[0643]

[0644] Where R 1 is chloro or nitrile, when s is 1, then X is hydroxy or when s is 0, then X is -CN.

[0645] In another embodiment, the compound of formula (I) is a compound of formula (a") or a tautomer or solvate or pharmaceutically acceptable salt thereof:

[0646]

[0647] Where R 1 is chlorine or nitrile, when s is 1, then X is hydroxyl or when s is 0, then X is -C(=O)NH 2 .

[0648] In another embodiment, the compound of formula (I) is a compound of formula (a') or a tautomer or solvate or pharmaceutically acceptable salt thereof:

[0649]

[0650] Where R 1 is chloro or nitrile, when s is 1, then X is hydroxy or when s is 0, then X is -CN.

[0651] In one embodiment of the compound of formula (a), R 7 Selected from methyl, alkyl, pyrazolyl, imidazolyl, piperidinyl, and cyclohexyl, wherein the cycloalkyl and heterocyclic groups are optionally replaced by one or more R z groups (such as methyl, fluoro, or hydroxy).

[0652] In one embodiment of the compound of formula (a), R 7 yes Alkyl or methyl.

[0653] In one embodiment of the compound of formula (a), R 7 is piperidinyl, which is optionally substituted by C 1-6 Alkyl (eg methyl) and / or halo (eg fluorine) substitution.

[0654] In one embodiment of the compound of Formula (a'), Formula (a") or Formula (a'"), R 7 Selected from methyl, alkyl, pyrazolyl, imidazolyl, piperidinyl, and cyclohexyl, wherein the cycloalkyl and heterocyclic groups are optionally replaced by one or more R z groups (such as methyl, fluoro, or hydroxy).

[0655] In one embodiment of the compound of Formula (a'), Formula (a") or Formula (a'"), R 7 yes Alkyl or methyl.

[0656] In one embodiment of the compound of Formula (a'), Formula (a") or Formula (a'"), R 7 is piperidinyl, which is optionally substituted by C 1-6 Alkyl (eg methyl) and / or halo (eg fluorine) substitution.

[0657] In one embodiment, A is a heterocyclyl having 3 to 6 ring members, wherein the heterocyclyl contains one or more (e.g., 1, 2, or 3) heteroatoms selected from N, O, S and oxidized forms thereof (t is 1; g is 1, 2, 3 or 4; Z represents N, O, S and oxidized forms thereof; i is 1, 2, or 3; and i+g=2, 3, 4 or 5), and the compound of formula (VI) is a compound of formula (b) or a tautomer or solvate or a pharmaceutically acceptable salt thereof:

[0658]

[0659] In one embodiment, Y is O and i is 1 and the compound of formula (b) is a compound of formula (ba) or a tautomer or solvate or pharmaceutically acceptable salt thereof:

[0660]

[0661] In one embodiment, s is 0, g is 2, q is 0 and X is hydrogen, and the compound of formula (b) is a compound of formula (bb) or a tautomer or solvate or pharmaceutically acceptable salt thereof:

[0662]

[0663] In one embodiment, s is 0, g is 1, Y is O and i is 1 and the compound of formula (b) is a compound of formula (bc) or a tautomer or solvate or pharmaceutically acceptable salt thereof:

[0664]

[0665] In one embodiment, the compound of formula (bc) is that compound wherein q is 0 and X is fluorine.

[0666] In another embodiment, the compound of formula (I) is a compound of formula (c) or a tautomer or solvate or pharmaceutically acceptable salt thereof:

[0667]

[0668] Where R 1 is chlorine or nitrile, s is 1 and X is hydroxy or s is 0 and X is -C(=O)NH 2 .

[0669] In another embodiment, the compound of formula (I) is a compound of formula (c') or a tautomer or solvate or pharmaceutically acceptable salt thereof:

[0670]

[0671] Where R1 is chloro or nitrile, s is 1 and X is hydroxy or s is 0 and X is -CN.

[0672] In another embodiment, the compound of formula (I) is a compound of formula (c") or a tautomer or solvate or pharmaceutically acceptable salt thereof:

[0673]

[0674] Where R 1 is chlorine or nitrile, s is 1 and X is hydroxy or s is 0 and X is -C(=O)NH 2 .

[0675] In another embodiment, the compound of formula (I) is a compound of formula (c'") or a tautomer or solvate or pharmaceutically acceptable salt thereof:

[0676]

[0677] Where R 1 is chloro or nitrile, s is 1 and X is hydroxy or s is 0 and X is -CN.

[0678] In one embodiment of the compound of formula (c), R 7 Selected from methyl, alkyl, pyrazolyl, imidazolyl, piperidinyl, and cyclohexyl, wherein the cycloalkyl and heterocyclic groups are optionally replaced by one or more R z groups (such as methyl, fluoro, or hydroxy).

[0679] In one embodiment of the compound of formula (c), R 7 yes Alkyl or methyl.

[0680] In one embodiment of the compound of formula (c), R 7 is piperidinyl, which is optionally substituted by C 1-6 Alkyl (eg methyl) and / or halo (eg fluorine) substitution.

[0681] In one embodiment of the compound of formula (c'), formula (c") or formula (c'"), R 7 Selected from methyl, alkyl, pyrazolyl, imidazolyl, piperidinyl, and cyclohexyl, wherein the cycloalkyl and heterocyclic groups are optionally replaced by one or more R z groups (such as methyl, fluoro, or hydroxy).

[0682] In one embodiment of the compound of formula (c'), formula (c") or formula (c'"), R 7 yes Alkyl or methyl.

[0683] In one embodiment of the compound of formula (c'), formula (c") or formula (c'"), R 7 is piperidinyl, which is optionally substituted by C 1-6 Alkyl (eg methyl) and / or halo (eg fluorine) substitution.

[0684] In another embodiment of the above subformula, R 2 Selected from hydrogen and -(R x R y ) u -CO 2 H (e.g. -COOH, -CH 2 COOH, -CH 2 CH 2 -CO 2 H, -(CH(CH 3 ))-CO 2 H and -(C(CH 3 ) 2 -CO 2 H).

[0685] In another embodiment of the above subformula, R 2 Selected from -(CH(CH 3 ))-CO 2 H and -(C(CH 3 ) 2 -CO 2 H).

[0686] In another embodiment, R 2 Selected from -(CH(CH 3 ))-CO 2 H and -(C(CH 3 ) 2 -CO 2 H)(e.g. or -(C(CH 3 ) 2 -CO 2 H).

[0687] In one embodiment, the present invention provides a compound of formula (I) or a tautomer or solvate or pharmaceutically acceptable salt thereof, wherein:

[0688] R 1 are independently selected from hydroxy, halogen, nitro, nitrile, C 1-4 Alkyl, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 2-6 Alkenyl, C1-4 Alkoxy, halogenated C 1-4 Alkoxy, and C 2-4 Alkynyl;

[0689] R 2 Selected from hydrogen, C 1-4 Alkyl, C 2-6 Alkenyl, hydroxyl C 1-4 Alkyl and -CH 2 CO 2 H;

[0690] R 3 is hydrogen or -(A) t -(CR x R y ) q -X;

[0691] s and t are independently selected from 0 and 1;

[0692] q is selected from 0, 1 and 2;

[0693] When R 3 Yes - (A) t -(CR x R y ) q -X, then (i) at least one of s, t, and q is not 0; and (ii) when t is 0, then s is 1 and q is not 0;

[0694] A is for C 3-6 Cycloalkyl or heterocyclyl having 3 to 6 ring members, wherein the heterocyclyl contains one or more (e.g. 1, 2, or 3) heteroatoms selected from N, O, S and oxidized forms thereof;

[0695] X is selected from hydrogen, halogen, -CN, -OR 9 、-(CH 2 ) v -CO 2 H, -(CH 2 ) v -CO 2 C 1-4 Alkyl, -C(=O)-C 1-4 Alkyl, -NR x R y 、-NHSO 2 R x 、-NR x COR y , and -C(=O)NR x R y ;

[0696] R 4 and R5 independently selected from halogen, nitrile, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy and halogenated C 1-4 Alkoxy;

[0697] R 6 and R 7 are independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Hydroxyl, Hydroxyl C 1-6 Alkyl, -COOC 1-6 Alkyl, heterocyclic group having 3 to 7 ring members, -CH 2 -heterocyclyl having 3 to 7 ring members, -CH 2 -O-heterocyclic group having 3 to 7 ring members, -CH 2 -NH-heterocyclic group having 3 to 7 ring members, -CH 2 -N(C 1-6 -C(=O)NH-heterocyclic group having 3 to 7 ring members, C 3-8 Cycloalkyl, -CH 2 -C 3-8 Cycloalkyl, -CH 2 -OC 3-8 Cycloalkyl, and C 3-8 Cycloalkenyl, wherein the cycloalkyl, cycloalkenyl or heterocyclic group may be optionally substituted by one or more R z substituted with a group, and wherein in each case, the heterocyclyl contains one or more (e.g., 1, 2, or 3) heteroatoms selected from N, O, S, and oxidized forms thereof;

[0698] R 9 Selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, -(CH 2 ) k -OC 1-6 Alkyl, -(CH 2 ) k -O-(Hydroxy C 1-6 Alkyl), hydroxyl C 1-6 Alkoxy, -(CH 2 ) k -CO 2 C 1-6 Alkyl, -(CH 2 ) k -CO2 H, -C 1-6 Alkyl-N(H) e (C 1-4 alkyl) 2-e 、-(CH 2 ) j -C 3-8 Cycloalkyl and -(CH 2 ) j -C 3-8 Cycloalkenyl;

[0699] R x and R y are independently selected from hydrogen, halogen, nitro, nitrile, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Hydroxyl, Hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, -(CH 2 ) k -OC 1-6 Alkyl, hydroxyl C 1-6 Alkoxy, -COOC 1-6 Alkyl, -N(H) e (C 1-4 alkyl) 2-e , -C 1-6 Alkyl-N(H) e (C 1-4 alkyl) 2-e 、-(CH 2 ) k -C(=O)N(H) e (C 1-4 alkyl) 2-e , C 3-8 Cycloalkyl and C 3-8 Cycloalkenyl;

[0700] R z are independently selected from halogen, nitro, nitrile, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, =O, Hydroxyl, Hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, -(CH 2 ) k -OC 1-6 Alkyl, hydroxyl C 1-6 Alkoxy, -C(=O)C 1-6 Alkyl, -C(=O)C 1-6 Alkyl-OH, -C(=O)C 1-6Alkyl-N(H) e (C 1-4 alkyl) 2-e 、-C(=O)N(H) e (C 1-4 alkyl) 2-e 、-(CH 2 ) r -CO 2 C 1-6 Alkyl, -(CH 2 ) r -CO 2 H, -N(H) e (C 1-4 alkyl) 2-e , -C 1-6 Alkyl-N(H) e (C 1-4 alkyl) 2-e , a heterocyclic group having 3 to 6 ring members, a -C(=O)C 1-4 Alkyl-substituted heterocyclic radical having 3 to 6 ring members, -C(=O)OC 1-4 Alkyl-substituted heterocyclic radical having 3 to 6 ring members, -C(=O)N(H) e (C 1-4 alkyl) 2-e substituted heterocyclic radical having 3 to 6 ring members, -C(=O) heterocyclic radical having 3 to 6 ring members, C 3-8 Cycloalkyl and C 3-8 Cycloalkenyl;

[0701] n, e, r and j are independently selected from 0, 1 and 2;

[0702] k and m are independently selected from 1 and 2; and

[0703] v and a are independently selected from 0 and 1.

[0704] In one embodiment, the present invention provides a compound of formula (I) or a tautomer or solvate or pharmaceutically acceptable salt thereof, wherein:

[0705] R 1 are independently selected from hydroxy, halogen, nitro, nitrile and C 1-4 alkyl;

[0706] R 2 Selected from hydrogen, C 1-4 Alkyl, C 2-6 Alkenyl, hydroxyl C 1-4 Alkyl and -CH 2 CO 2 H;

[0707] R3 is hydrogen or -(A) t -(CR x R y ) q -X;

[0708] s and t are independently selected from 0 and 1;

[0709] q is selected from 0, 1 and 2;

[0710] When R 3 Yes - (A) t -(CR x R y ) q -X, then (i) at least one of s, t, and q is not 0; and (ii) when t is 0, then s is 1 and q is not 0;

[0711] A is for C 3-6 Cycloalkyl or heterocyclyl having 3 to 6 ring members, wherein the heterocyclyl contains one or more (e.g. 1, 2, or 3) heteroatoms selected from N, O, S and oxidized forms thereof;

[0712] X is selected from hydrogen, halogen, -CN, -OR 9 、-(CH 2 ) v -CO 2 H, -(CH 2 ) v -CO 2 C 1-4 Alkyl, -C(=O)-C 1-4 Alkyl, -NR x R y 、-NHSO 2 R x 、-NR x COR y , and -C(=O)NR x R y ;

[0713] R 4 and R 5 independently selected from halogen, nitrile and C 1-4 alkyl;

[0714] R 6 Selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl;

[0715] R 7 Selected from hydrogen, C 1-6Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Hydroxyl, Hydroxyl C 1-6 Alkyl, -COOC 1-6 alkyl, heterocyclic radical having 3 to 7 ring members, -CH 2 -heterocyclyl having 3 to 7 ring members, -CH 2 -O-heterocyclic group having 3 to 7 ring members, -CH 2 -NH-heterocyclic group having 3 to 7 ring members, -CH 2 -N(C 1-6 -C(=O)NH-heterocyclic group having 3 to 7 ring members, C 3-8 Cycloalkyl, -CH 2 -C 3-8 Cycloalkyl, -CH 2 -OC 3-8 Cycloalkyl, and C 3-8 Cycloalkenyl, wherein the cycloalkyl, cycloalkenyl or heterocyclic group may be optionally substituted by one or more R z substituted with a group, and wherein in each case, the heterocyclyl contains one or more (e.g., 1, 2, or 3) heteroatoms selected from N, O, S, and oxidized forms thereof;

[0716] R 9 Selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, -(CH 2 ) k -OC 1-6 Alkyl, -(CH 2 ) k -O-(Hydroxy C 1-6 Alkyl), hydroxyl C 1-6 Alkoxy, -(CH 2 ) k -CO 2 C 1-6 Alkyl, -(CH 2 ) k -CO 2 H, -C 1-6 Alkyl-N(H) e (C 1-4 alkyl) 2-e 、-(CH 2 )jC 3-8 Cycloalkyl and -(CH 2 ) j -C 3-8 Cycloalkenyl;

[0717] R x and R y are independently selected from hydrogen, halogen, nitro, nitrile, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Hydroxyl, Hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, -(CH 2 ) k -OC 1-6 Alkyl, hydroxyl C 1-6 Alkoxy, -COOC 1-6 Alkyl, -N(H) e (C 1-4 alkyl) 2-e , -C 1-6 Alkyl-N(H) e (C 1-4 alkyl) 2-e 、-(CH 2 ) k -C(=O)N(H) e (C 1-4 alkyl) 2-e , C 3-8 Cycloalkyl and C 3-8 Cycloalkenyl;

[0718] R z are independently selected from halogen, nitro, nitrile, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, =O, Hydroxyl, Hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, -(CH 2 ) k -OC 1-6 Alkyl, hydroxyl C 1-6 Alkoxy, -C(=O)C 1-6 Alkyl, -C(=O)C 1-6 Alkyl-OH, -C(=O)C 1-6 Alkyl-N(H) e (C 1-4 alkyl) 2-e 、-C(=O)N(H) e (C 1-4 alkyl) 2-e 、-(CH 2 ) r -CO 2 C 1-6 Alkyl, -(CH2 ) r -CO 2 H, -N(H) e (C 1-4 alkyl) 2-e , -C 1-6 Alkyl-N(H) e (C 1-4 alkyl) 2-e , a heterocyclic group having 3 to 6 ring members, a -C(=O)C 1-4 Alkyl-substituted heterocyclic radical having 3 to 6 ring members, -C(=O)OC 1-4 Alkyl-substituted heterocyclic radical having 3 to 6 ring members, -C(=O)N(H) e (C 1-4 alkyl) 2-e substituted heterocyclic radical having 3 to 6 ring members, -C(=O) heterocyclic radical having 3 to 6 ring members, C 3-8 Cycloalkyl and C 3-8 Cycloalkenyl;

[0719] n, e, r and j are independently selected from 0, 1 and 2;

[0720] k and m are independently selected from 1 and 2; and

[0721] v and a are independently selected from 0 and 1.

[0722] In one embodiment, the present invention provides a compound of formula (I) or a tautomer or solvate or pharmaceutically acceptable salt thereof, wherein:

[0723] R 1 are independently selected from hydroxy, halogen, nitro, nitrile and C 1-4 alkyl;

[0724] R 2 Selected from hydrogen, C 1-4 Alkyl, C 2-6 Alkenyl, hydroxyl C 1-4 Alkyl and -CH 2 CO 2 H;

[0725] R 3 is hydrogen or -(A) t -(CR x R y ) q -X;

[0726] s and t are independently selected from 0 and 1;

[0727] q is selected from 0, 1 and 2;

[0728] When R 3 Yes - (A) t -(CR x R y ) q -X, then (i) at least one of s, t, and q is not 0; and (ii) when t is 0, then s is 1 and q is not 0;

[0729] A is a heterocyclyl having 3 to 6 ring members, wherein the heterocyclyl contains one or more (e.g., 1, 2, or 3) heteroatoms selected from N, O, S, and oxidized forms thereof;

[0730] X is selected from hydrogen, halogen, -CN and -OR 9 ;

[0731] R 4 and R 5 independently selected from halogen, nitrile and C 1-4 alkyl;

[0732] R 6 Selected from hydrogen and C 1-6 alkyl;

[0733] R 7 is selected from a heterocyclic group having 3 to 7 ring members, -CH 2 - a heterocyclic group having 3 to 7 ring members, C 3-8 Cycloalkyl, and -CH 2 -C 3-8 Cycloalkyl, wherein the cycloalkyl or heterocyclic group may be optionally substituted by one or more R z substituted with a group, and wherein in each case, the heterocyclyl contains one or more (e.g., 1, 2, or 3) heteroatoms selected from N, O, S, and oxidized forms thereof;

[0734] R 9 Selected from hydrogen and C 1-6 alkyl;

[0735] R x and R y are independently selected from hydrogen and C 1-6 alkyl;

[0736] R z are independently selected from halogen, nitro, nitrile, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, Hydroxyl, Hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, -C(=O)C 1-6 Alkyl, and -N(H) e (C 1-4alkyl) 2-e ;

[0737] n and e are independently selected from 0, 1 and 2;

[0738] m is selected from 1 and 2; and

[0739] a is selected from 0 and 1.

[0740] In one embodiment, the present invention provides a compound of formula (I) or a tautomer or solvate or pharmaceutically acceptable salt thereof, wherein:

[0741] R 1 independently selected from halogen, hydroxyl and nitrile;

[0742] R 2 Selected from hydrogen, C 1-4 Alkyl and -CH 2 CO 2 H;

[0743] R 3 Yes - (A) t -(CR x R y ) q -X;

[0744] A is a heterocyclyl having 3 to 6 ring members, wherein the heterocyclyl contains one or more (e.g., 1, 2, or 3) heteroatoms selected from N, O, S, and oxidized forms thereof;

[0745] s and t are independently selected from 0 and 1;

[0746] q is selected from 0, 1 and 2;

[0747] wherein (i) at least one of s, t, and q is not 0; and (ii) when t is 0, then s is 1 and q is not 0;

[0748] X is selected from hydrogen, halogen or -OR 9 ;

[0749] R 4 and R 5 independently selected from halogen;

[0750] R 6 Selected from hydrogen and C 1-6 alkyl;

[0751] R 7 is selected from a heterocyclic group having 3 to 7 ring members, -CH 2 - a heterocyclic group having 3 to 7 ring members, C 3-8 Cycloalkyl, and -CH 2 -C3-8 Cycloalkyl, wherein the cycloalkyl, cycloalkenyl or heterocyclyl may be optionally substituted by one or more R z substituted with a group, and wherein in each case, the heterocyclyl contains one or more (e.g., 1, 2, or 3) heteroatoms selected from N, O, S, and oxidized forms thereof;

[0752] R 9 Selected from hydrogen and C 1-6 alkyl;

[0753] R x and R y are independently selected from hydrogen and C 1-6 alkyl;

[0754] R z independently selected from halogen, nitro, nitrile, and C 1-6 alkyl;

[0755] n is 1 and m is 1; and

[0756] a is selected from 0 and 1.

[0757] In one embodiment, the present invention provides a compound of formula (I) or a tautomer or solvate or pharmaceutically acceptable salt thereof, wherein:

[0758] R 1 independently selected from halogen, hydroxyl and nitrile;

[0759] R 2 Selected from hydrogen, C 1-4 Alkyl and -CH 2 CO 2 H;

[0760] R 3 Yes - (A) t -(CR x R y ) q -X;

[0761] A is a heterocyclyl having 3 to 6 ring members, wherein the heterocyclyl contains one or more (e.g., 1, 2, or 3) heteroatoms selected from N, O, S, and oxidized forms thereof;

[0762] s and t are independently selected from 0 and 1;

[0763] q is selected from 0, 1 and 2;

[0764] wherein (i) at least one of s, t, and q is not 0; and (ii) when t is 0, then s is 1 and q is not 0;

[0765] X is selected from hydrogen, halogen and -OR9 ;

[0766] R 4 and R 5 independently selected from halogen;

[0767] R 6 Selected from hydrogen and C 1-6 alkyl;

[0768] R 7 is a heterocyclic group having 3 to 7 ring members, which is optionally replaced by one or more R z Group substitution;

[0769] R 9 Selected from hydrogen and C 1-6 alkyl;

[0770] R x and R y are independently selected from hydrogen and C 1-6 alkyl;

[0771] R z independently selected from halogen and C 1-6 Alkyl; and

[0772] n is 1 and m is 1; and

[0773] a is 1.

[0774] In one embodiment, the present invention provides a compound of formula (I) or a tautomer or solvate or pharmaceutically acceptable salt thereof, wherein:

[0775] R 1 is a halogen (e.g. Cl), C 1-4 Alkynyl (e.g. -C≡CH), nitrile, hydroxyl C 1-4 Alkyl (e.g. CH 2 OH), -O 0,1 (CR x R y ) v COOH (e.g. -COOH, -CH 2 COOH, -OCH 2 COOH or -C(CH 3 ) 2 COOH)、-S(O) d -C 1-4 Alkyl (e.g. SCH 3 、SOCH 3 , or SO 2 CH 3 ),-SO 2 -(1-morpholinyl) or -P(=O)(R x )2 (e.g. -P(=O)(CH 3 ) 2 );

[0776] n is 1 or 2;

[0777] R 2 It is hydrogen, C 1-4 Alkyl (e.g. -CH 3 ), hydroxyl C 1-4 Alkyl (e.g. CH 2 OH) or -(CH 2 ) u COOH (e.g. -CH 2 COOH, -CH 2 CH 2 -CO 2 H or -(CH(CH 3 ))-CO 2 H);

[0778] Part-(CH 2 ) s R 3 Selected from:

[0779] (The point of attachment to the oxygen is indicated by a dotted bond or by the end of a bond indicated by an *):

[0780]

[0781]

[0782] R 4 is a halogen (e.g. F);

[0783] a is 0 or 1;

[0784] R 5 is a halogen (e.g. Cl);

[0785] m is 1;

[0786] R 6 is hydrogen or C 1-6 Alkyl (e.g. -CH 3 or -CH 2 CH 3 );

[0787] R 7 It is C 1-6 Alkyl (e.g. -CH 3 or -CH 2 CH 3 ), hydroxyl C 1-6 Alkyl (e.g. -CH 2 OH), -C 1-6 Alkyl-NRx R y (e.g. -CH 2 N(CH 3 ) 2 ),-(CR x R y ) p -CONR x R y (e.g. -C(=O)N(CH 3 ) 2 or -C(=O)NHCH 3 or )、-(CH 2 ) j -OC 1-6 Alkyl (e.g. -CH 2 OCH 3 ), C 3-8 Cycloalkyl (e.g. cyclobutyl or cyclohexyl), heterocyclyl having 3 to 7 ring members, e.g.

[0788] (Connection points are represented by dashed keys)

[0789]

[0790]

[0791] or -CH 2 - heterocyclyl groups having 3 to 7 ring members, for example

[0792] (Connection points are represented by dashed keys)

[0793]

[0794] When part R 7 When a heterocyclic group or a cycloalkyl group is included, the heterocyclic group may be optionally replaced by one or more R z The group is substituted, the R z The group is selected from C 1-6 Alkyl (e.g., methyl), hydroxy, halogen (e.g., fluorine), -C(=O)C 1-6 Alkyl (e.g. -C(=O)C(CH 3 ) 3 )、-(CH 2 ) r -CO 2 H (e.g. -CH 2 COOH or CH 2 CH 2 COOH) or -(CH 2 ) r -CO 2 C 1-6Alkyl (e.g. CH 2 CH 2 COOCH 3 ).

[0795] In one embodiment, the present invention provides a compound of formula (I) or a tautomer or solvate or pharmaceutically acceptable salt thereof, wherein:

[0796] R 1 is a halogen (e.g. Cl), C 1-4 Alkynyl (e.g. -C≡CH), nitrile, hydroxyl C 1-4 Alkyl (e.g. CH 2 OH), -(CH 2 ) v COOH (e.g. -COOH), -S(O) d -C 1-4 Alkyl (e.g. SCH 3 、SOCH 3 , or SO 2 CH 3 ),-SO 2 -(1-morpholinyl) or -P(=O)(R x ) 2 (e.g. -P(=O)(CH 3 ) 2 );

[0797] n is 1 or 2;

[0798] R 2 It is hydrogen, C 1-4 Alkyl (e.g. -CH 3 ), hydroxyl C 1-4 Alkyl (e.g. CH 2 OH) or -(CH 2 ) u COOH (e.g. -CH 2 COOH);

[0799] Part-(CH 2 ) s R 3 Selected from:

[0800] (The point of attachment to the oxygen is indicated by a dotted bond or by the end of a bond indicated by an *):

[0801]

[0802]

[0803] R 4 is a halogen (e.g. F);

[0804] a is 0 or 1;

[0805] R 5 is a halogen (e.g. Cl);

[0806] m is 1;

[0807] R 6 is hydrogen or C 1-6 Alkyl (e.g. -CH 3 or -CH 2 CH 3 );

[0808] R 7 It is C 1-6 Alkyl (e.g. -CH 3 ), hydroxyl C 1-6 Alkyl (e.g. -CH 2 OH), -(CH 2 ) j -OC 1-6 Alkyl (e.g. -CH 2 OCH 3 ),-C 1-6 Alkyl-NR x R y (e.g. -CH 2 N(CH 3 ) 2 ),-(CR x R y ) p -CONR x R y (e.g. -C(=O)N(CH 3 ) 2 or -C(=O)NHCH 3 or ), a heterocyclic group having 3 to 7 ring members, for example

[0809] (Connection points are represented by dashed keys)

[0810]

[0811] or -CH 2 - heterocyclyl groups having 3 to 7 ring members, for example

[0812] (Connection points are represented by dashed keys)

[0813]

[0814] When R 7 When a heterocyclic group is included, the heterocyclic group may be optionally replaced by one or more R z The group is substituted, the R z The group is selected from C 1-6Alkyl (eg, methyl).

[0815] In one embodiment of formula (I), R 7 is a heterocyclic group having 3 to 7 ring members, for example

[0816] (Connection points are represented by dashed keys)

[0817]

[0818]

[0819] In one embodiment of the chemical formula, when R 7 When a heterocyclic group is included, the heterocyclic group may be a heterocyclic group having 3 to 7 ring members, which is optionally substituted by one or more R z Group substitution, e.g.

[0820] (Connection points are represented by dashed keys)

[0821]

[0822] or -CH 2 - a heterocyclic group having 3 to 7 ring members, which is optionally replaced by one or more R z Group substitution, e.g.

[0823] (Connection points are represented by dashed keys)

[0824]

[0825] In one embodiment of the chemical formula, when R 7 When a heterocyclic group is included, the heterocyclic group may be a heterocyclic group having 3 to 7 ring members, which is optionally substituted by one or more R z Group substitution, e.g.

[0826] (Connection points are represented by dashed keys)

[0827]

[0828] or -CH 2 - a heterocyclic group having 3 to 7 ring members, which is optionally replaced by one or more R z Group substitution, e.g.

[0829] (Connection points are represented by dashed keys)

[0830]

[0831] In one embodiment, the present invention provides a compound of formula (I) or a tautomer or solvate or pharmaceutically acceptable salt thereof, wherein:

[0832] R 1 is -Cl, -CN, -OH or -OCH 3 ;

[0833] n is 1;

[0834] R 2 It is hydrogen;

[0835] R 3 is hydrogen or -(A) t -(CR x R y ) q -X;

[0836] s is 0 or 1, and t is 1;

[0837] A is selected from cyclopropyl, oxetanyl and tetrahydrofuranyl;

[0838] X is selected from hydrogen, fluorine, -CN, -OH and -C(=O)NH 2 ;

[0839] q is 0 or 1 and R x and R y is hydrogen or deuterium;

[0840] a is 0 or 1 and R 4 is a halogen (e.g. fluorine);

[0841] R 5 is a halogen (e.g. Cl);

[0842] m is 1;

[0843] R 6 It is C 1-4 Alkyl (e.g., methyl or ethyl);

[0844] R 7 It is C 1-4 Alkyl (such as methyl or ethyl), hydroxyl C 1-4 Alkyl (e.g. hydroxymethyl or hydroxyethyl), methoxy 1-4 Alkyl (e.g. methoxymethyl), heterocyclic group having 5 or 6 ring members (e.g. piperidinyl, alkyl, imidazolyl or pyrazolyl) or C 3-6 Cycloalkyl (e.g. cyclobutyl or cyclohexyl), wherein the heterocyclic group having 5 or 6 ring members and C 3-6 The cycloalkyl group may be optionally substituted by one or two R z The group is substituted, the R z The groups are independently selected from methyl, halogen (eg, fluorine), -C(=O)Me, and -OH.

[0845] In one embodiment, the present invention provides a compound of formula (I) or a tautomer or solvate or pharmaceutically acceptable salt thereof, wherein:

[0846] R 1 is -Cl, -CN, -OH or -OCH 3 ;

[0847] n is 1;

[0848] R 2 is hydrogen or -(CH 2 ) u -CO 2 H, wherein u is independently selected from 0 and 1;

[0849] R 3 is hydrogen and s is 1 or R 3 Yes - (A) t -(CR x R y ) q -X and t is 1 and q is 1;

[0850] A is selected from cyclopropyl;

[0851] X is -OH;

[0852] R x and R y is hydrogen or deuterium;

[0853] a is 0 or 1 and R 4 is a halogen (e.g. fluorine);

[0854] R 5 is a halogen (e.g. Cl);

[0855] m is 1;

[0856] R 6 It is C 1-4 Alkyl (e.g., methyl or ethyl);

[0857] R 7 It is C 1-4 Alkyl (such as methyl or ethyl), hydroxyl C 1-4 Alkyl (e.g. hydroxymethyl or hydroxyethyl), methoxy 1-4 Alkyl (e.g. methoxymethyl), heterocyclic group having 5 or 6 ring members (e.g. piperidinyl, alkyl, imidazolyl or pyrazolyl) or C 3-6 Cycloalkyl (e.g., cyclobutyl or cyclohexyl);

[0858] wherein the heterocyclic group having 5 or 6 ring members and C 3-6 The cycloalkyl group may be optionally substituted by one or two Rz The group is substituted, the R z The groups are independently selected from methyl, halogen (eg, fluorine), -C(=O)Me, and -OH.

[0859] In one embodiment, the present invention provides a compound of formula (I) or a tautomer or solvate or pharmaceutically acceptable salt thereof, wherein:

[0860] R 1 is halogen (e.g. Cl) or nitrile;

[0861] n is 1;

[0862] R 2 is hydrogen or -(CH 2 ) u COOH (e.g. -CH 2 COOH);

[0863] R 3 is hydrogen and s is 1 or R 3 Yes - (A) t -(CR x R y ) q -X and t is 1 and q is 1;

[0864] A is selected from cyclopropyl;

[0865] X is -OH;

[0866] R x and R y is hydrogen or deuterium (e.g. hydrogen);

[0867] R 4 is a halogen (e.g. F);

[0868] a is 0 or 1;

[0869] R 5 is a halogen (e.g. Cl);

[0870] m is 1;

[0871] R 6 is hydrogen or C 1-6 Alkyl (e.g. -CH 3 or -CH 2 CH 3 );

[0872] R 7 It is C 1-4 Alkyl (such as methyl), hydroxyl C 1-4 Alkyl (e.g. hydroxymethyl), methoxy 1-4Alkyl (e.g. methoxymethyl), heterocyclic group having 5 or 6 ring members (e.g. piperidinyl, alkyl, imidazolyl or pyrazolyl);

[0873] wherein the heterocyclic group having 5 or 6 ring members may be optionally replaced by one or two R z The group is substituted, the R z The groups are independently selected from C 1-4 Alkyl (eg, methyl).

[0874] In one embodiment, the present invention provides a compound of formula (I) or a tautomer or solvate or pharmaceutically acceptable salt thereof, wherein:

[0875] R 1 is halogen (e.g. Cl), nitrile, O 0,1 (CR x R y ) v COOH (e.g. -COOH, -CH 2 COOH, -OCH 2 COOH or -C(CH 3 ) 2 COOH);

[0876] n is 1 or 2;

[0877] R 2 Selected from hydrogen and -(R x R y ) u -CO 2 H (e.g. -COOH, -CH 2 COOH, -CH 2 CH 2 -CO 2 H, -(CH(CH 3 ))-CO 2 H and -(C(CH 3 ) 2 -CO 2 H).

[0878] R 3 is hydrogen and s is 1;

[0879] R 4 is a halogen (e.g. F);

[0880] R 5 is a halogen (e.g. Cl);

[0881] m is 1;

[0882] R 6 is hydrogen or C 1-6Alkyl (e.g. -CH 3 or -CH 2 CH 3 );

[0883] R 7 It is C 1-4 Alkyl (such as methyl), hydroxyl C 1-4 Alkyl (e.g. hydroxymethyl), methoxy 1-4 Alkyl (e.g. methoxymethyl), heterocyclic group having 5 or 6 ring members (e.g. piperidinyl, alkyl, imidazolyl or pyrazolyl);

[0884] wherein the heterocyclic group having 5 or 6 ring members may be optionally replaced by one or two R z The group is substituted, the R z The groups are independently selected from C 1-4 Alkyl (eg, methyl).

[0885] In one embodiment, the present invention provides a compound of formula (I), which is one of Examples 1-137 or selected from Examples 1-137 or their tautomers, N-oxides, pharmaceutically acceptable salts or solvates.

[0886] In one embodiment, the present invention provides a compound of formula (I), which is one of Examples 1-97 or selected from Examples 1-97 or their tautomers, N-oxides, pharmaceutically acceptable salts or solvates.

[0887] In one embodiment, the present invention provides a compound of formula (I), which is selected from the following compounds, or their tautomers, N-oxides, pharmaceutically acceptable salts or solvates:

[0888] 4-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(1-methyl-1H-imidazol-4-yl)propyl]-1-{[1-(hydroxymethyl)cyclopropyl]methoxy}-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzonitrile; and

[0889] (3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-( [(4-(((((((((((((((((((((((- ...

[0890] In one embodiment, the present invention provides a compound of formula (I), which is diastereomer 2A and is selected from the following compounds, or tautomers, N-oxides, pharmaceutically acceptable salts or solvates thereof:

[0891] 4-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(1-methyl-1H-imidazol-4-yl)propyl]-1-{[1-(hydroxymethyl)cyclopropyl]methoxy}-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzonitrile; and

[0892] (3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-( [(4-(((((((((((((((((((((((- ...

[0893] In one embodiment, the present invention provides a compound of formula (I), which is diastereomer 2B and is selected from the following compounds, or tautomers, N-oxides, pharmaceutically acceptable salts or solvates thereof:

[0894] 4-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(1-methyl-1H-imidazol-4-yl)propyl]-1-{[1-(hydroxymethyl)cyclopropyl]methoxy}-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzonitrile; and

[0895] (3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-( [(4-(((((((((((((((((((((((- ...

[0896] In one embodiment, the invention provides a compound of formula (I), which is 2-(5-chloro-2-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(

[0047] The compound of the present invention is 1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}phenyl)-2-methylpropanoic acid, or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof.

[0897] In one embodiment, the present invention provides a compound of formula (I), which is (2S, 3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(

[0043] The compound of the present invention is 1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]-2-methylpropanoic acid, or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof.

[0898] For the avoidance of doubt, it should be understood that every general and specific embodiment and example for one substituent may be combined with one or more, and in particular every general and specific embodiment and example for all other substituents as defined herein, and that all such embodiments are encompassed by the present application.

[0899] Salts, solvates, tautomers, isomers, N-oxides, esters, prodrugs and isotopes

[0900] Reference to compounds of formula (I), subgroups thereof (e.g. formulas I(c), I(f), I(g), I(g'), I(h), I(i), I(j), I(k), I(L), I(m), I(m'), I(n), I(o), I(o'), I(o"), I(p), I(p '), I(q), I(q'), I(q"), I(q"'), I(q""), I(r), I(s), I(t), I(u), I(v), I(v'), I(w), I(x), I(x'), I(y), (II), (IIa), (IIb), (II When the invention relates to a compound of the present invention, it also includes its ionic forms, salts, solvates, isomers (including geometric isomers and stereochemical isomers unless otherwise stated), tautomers, N-oxides, esters, prodrugs, isotopes and protected forms, for example, as described below. In one embodiment, the compounds of formula (I), subgroups thereof (e.g., formula I(c), I(f), I(g), I(g'), I(h), I(i), I(j), I(k), I(L), I(m), I(m'), I(n), I(o), I(o'), I(o"), I(p), I(p'), I(q), I(q'), I(q"), I(q'"), I(q")"), I(r), I(s ), I(t), I(u), I(v), I(v'), I(w), I(x), I(x'), I(y), (II), (IIa), (IIb), (IIIa), (IIIb), (IVa), (IVb), (V), (VI), (Via), (VII), (VIIa), (VIIb), (VIIc), (VIId), (VIId'), (VIIe), (VIIe'), (a), (b), (ba), (bb), (bc) or (c)) and any embodiment, also includes its salts, tautomers or solvates.

[0901] Salt

[0902] Many compounds of formula (I) can exist in the form of salts, for example acid addition salts, or in some cases, salts of organic and inorganic bases, such as carboxylates, sulfonates and phosphates. All such salts are within the scope of the present invention, and when referring to compounds of formula (I), the salt forms of the compounds are included.

[0903] The salts of the present invention can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods, such as those described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (ed.), Camille G. Wermuth (ed.), ISBN: 3-90639-026-8, hardcover, 388 pages, August 2002. Generally, such salts can be prepared by reacting the free acid or free base forms of these compounds with the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is used.

[0904] Acid addition salts (mono or di-salts) can be formed with a variety of inorganic and organic acids. Examples of acid addition salts include mono or di-salts formed with an acid selected from the group consisting of acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid (e.g., L-ascorbic acid), L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, butyric acid, (+) camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, glucuronic acid (e.g., D-glucuronic acid), glutamic acid (e.g., L-glutamic acid), α-ketoglutaric acid, glycolic acid , hippuric acid, hydrohalic acid (e.g., hydrobromic acid, hydrochloric acid, hydroiodic acid), isethionic acid, lactic acid (e.g., (+)-L-lactic acid, (±)-DL-lactic acid), lactobionic acid, maleic acid, malic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, pyruvic acid, L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid and valeric acid, as well as acylated amino acids and cation exchange resins.

[0905] A specific group of salts consists of salts formed from acetic acid, hydrochloric acid, hydroiodic acid, phosphoric acid, nitric acid, sulfuric acid, citric acid, lactic acid, succinic acid, maleic acid, malic acid, isethionic acid, fumaric acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid (mesylate), ethanesulfonic acid, naphthylsulfonic acid, valeric acid, acetic acid, propionic acid, butyric acid, malonic acid, glucuronic acid and lactobionic acid. A specific salt is the hydrochloride salt.

[0906] In one embodiment, the compound is a tris(hydroxymethyl)aminomethane (TRIS) salt.

[0907] If the compound is anionic or has a functional group that can be anionic (e.g., -COOH can be -COO - ), then it can form a salt with an organic base or an inorganic base to produce a suitable cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions, such as Li + 、Na + and K + ; Alkaline earth metal cations, such as Ca 2+ and Mg 2+ ; and other cations, such as Al 3+ or Zn + Examples of suitable organic cations include, but are not limited to, ammonium ions (i.e., NH 4 + ) and substituted ammonium ions (e.g. NH 3 R + NH 2 R 2 + 、NHR 3 + NR 4 + ). Some examples of suitable substituted ammonium ions are those derived from methylamine, ethylamine, diethylamine, propylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, and amino acids such as lysine and arginine. Common examples of quaternary ammonium ions are N(CH 3 ) 4 + .

[0908] Where compounds of formula (I) contain amine functional groups, these can be reacted with alkylating agents to form quaternary ammonium salts, for example according to methods known to those skilled in the art. Such quaternary ammonium compounds are within the scope of formula (I).

[0909] The compounds of the present invention may exist as mono- or di-salts, depending on the pKa of the acid forming the salt.

[0910] The salt forms of the compounds of the present invention are generally pharmaceutically acceptable salts, and examples of pharmaceutically acceptable salts are discussed in Berge et al., 1977, "Pharmaceutically Acceptable Salts", J. Pharm. Sci., Vol. 66, pp. 1-19. However, salts that are not pharmaceutically acceptable may also be prepared as intermediate forms, which may then be converted into pharmaceutically acceptable salts. Such non-pharmaceutically acceptable salt forms that may be useful, for example, in the purification or isolation of the compounds of the present invention also form part of the present invention.

[0911] In one embodiment of the invention, a pharmaceutical composition is provided, comprising a solution (e.g., an aqueous solution) containing a compound of formula (I) as described herein, and subgroups and examples thereof, in salt form at a concentration of greater than 10 mg / ml, typically greater than 15 mg / ml and typically greater than 20 mg / ml.

[0912] N-oxides

[0913] Compounds of formula (I) containing an amine functional group may also form N-oxides. Reference herein to compounds of formula (I) containing an amine functional group also includes N-oxides.

[0914] In case the compound contains several amine functional groups, one, or more than one nitrogen atom may be oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of tertiary amines or nitrogen atoms of nitrogen-containing heterocyclic groups.

[0915] N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid), see, e.g., Advanced Organic Chemistry, Jerry March, 4th edition, Wiley Interscience, pp. More specifically, N-oxides can be prepared by the procedure of LW Deady (Syn. Comm. 1977, 7, 509-514), wherein the amine compound is reacted with meta-chloroperbenzoic acid (MCPBA), for example, in an inert solvent such as dichloromethane.

[0916] In one embodiment of the invention, the compound is an N-oxide, for example from R 6 Group or R 7 A nitrogen atom on a radical, for example pyridine N-oxide.

[0917] Geometric isomers and tautomers

[0918] Compounds of formula (I) can exist in many different geometric isomers and tautomeric forms, and when referring to compounds of formula (I), all such forms are included. For the avoidance of doubt, where a compound can exist in one of several geometric isomers or tautomeric forms and only one is specifically described or shown, all other forms are still encompassed by formula (I).

[0919] For example, certain heteroaromatic rings can exist in two tautomeric forms, as shown below, A and B. For simplicity, a chemical formula may illustrate one form, but the formula should be considered to encompass both tautomeric forms.

[0920]

[0921] Other examples of tautomeric forms include, for example, the keto form, the enol form, and the enolate form, as in, for example, the following tautomeric pairs: keto / enol (shown below), imine / enamine, amide / iminoalcohol, amidine / enediamine, nitroso / oxime, thione / enethiol, and nitro / acid nitro.

[0922]

[0923] Stereoisomers

[0924] Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms.

[0925] Stereocentres are shown in the usual manner, using either 'cut' or 'solid' wedge lines.

[0926]

[0927] Where a compound is described as a mixture of two diastereomers / epimers, the configuration of a stereocenter is not specified and is represented by a straight line.

[0928] Unless the context requires otherwise, where compounds of formula (I) contain one or more chiral centers and can exist in the form of two or more optical isomers, reference to compounds of formula (I) includes all optical isomeric forms thereof (e.g., enantiomers, epimers and diastereomers), as individual optical isomers, or as mixtures of two or more optical isomers (e.g., racemic mixtures or scalemic mixtures).

[0929] Optical isomers can be characterized and identified by their optical rotation (i.e., as + and - isomers, or d and l isomers) or they can be characterized according to their absolute stereochemistry using the "R and S" nomenclature developed by Cahn, Ingold, and Prelog, see Advanced Organic Chemistry, Jerry March, 4th edition, John Wiley & Sons, New York, 1992, pp. 109-114, and see also Cahn, Ingold, and Prelog, Angew. Chem. Int. Ed. Engl., 1966, 5, 385-415.

[0930] Optical isomers may be separated by a number of techniques including chiral chromatography (chromatography on a chiral support), and such techniques are well known to those skilled in the art.

[0931] As an alternative to chiral chromatography, optical isomers can be separated by forming diastereomeric salts with chiral acids such as (+)-tartaric acid, (-)-pyroglutamic acid, (-)-ditoluoyl-L-tartaric acid, (+)-mandelic acid, (-)-malic acid, and (-)-camphorsulfonic acid; separating the diastereomers by preferential crystallization; and then dissociating the salts to give the individual enantiomers of the free base.

[0932] Alternatively, enantiomeric separation may be achieved by covalently attaching an enantiomerically pure chiral auxiliary to the compound and then separating the diastereomers using conventional methods such as chromatography, followed by cleavage of the covalent bond to produce the appropriate enantiomerically pure product.

[0933] In the case where the compound of formula (I) exists as two or more optical isomeric forms, one enantiomer of a pair of enantiomers may exhibit advantages over the other enantiomer, such as advantages in biological activity. Therefore, in some cases, it may be desirable to use only one of a pair of enantiomers or only one of multiple diastereomers as a therapeutic agent.

[0934] Therefore, the present invention provides compositions containing compounds of formula (I) having one or more chiral centers, wherein at least 55% (e.g., at least 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%) of the compounds of formula (I) exist as single optical isomers (e.g., enantiomers or diastereomers). In a general embodiment, 99% or more (e.g., substantially all) of the total amount of the compounds of formula (I) can exist as single optical isomers (e.g., enantiomers or diastereomers).

[0935] Compounds containing double bonds may have E-type (heterolateral) or Z-type (same side) stereochemistry at the double bond. Substituents on divalent cyclic or (partially) saturated groups may have cis-configuration or trans-configuration. The terms cis and trans when used herein are based on the nomenclature of Chemical Abstracts (J. Org. Chem. 1970, 35 (9), 2849-2867) and refer to the position of the substituent on the ring portion.

[0936] Of particular interest are those compounds of formula (I) that are stereochemically pure. When a compound of formula (I) is, for example, designated as the R-form, this means that the compound is substantially free of the S-isomer. If a compound of formula (I) is, for example, designated as the E-form, this means that the compound is substantially free of the Z-isomer. The terms cis, trans, R-form, S-form, E-form and Z-form are well known to those skilled in the art.

[0937] Isotope variation

[0938] The present invention includes all pharmaceutically acceptable isotopically labeled compounds of the present invention, i.e., compounds of formula (I), wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.

[0939] Examples of isotopes suitable for inclusion in the compounds of the present invention include isotopes of hydrogen such as 2 H(D) and 3 H(T); isotopes of carbon, such as 11 C. 13 C and 14 C; isotopes of chlorine, such as 36 Cl; isotopes of fluorine, such as 18 F; isotopes of iodine, such as 123 I. 125 I and 131 I; isotopes of nitrogen, such as 13 N and 15 N; isotopes of oxygen, such as 15 O. 17 O and 18 O; isotopes of phosphorus, such as 32 P; and sulfur isotopes, such as 35 S.

[0940] Certain isotopically labeled compounds of formula (I), for example those containing radioactive isotopes, can be used in drug and / or substrate tissue distribution studies. Compounds of formula (I) can also have valuable diagnostic properties because they can be used to detect or identify the formation of complexes between labeled compounds and other molecules, peptides, proteins, enzymes or receptors. The detection or identification methods can use compounds labeled with labeling agents such as radioactive isotopes, enzymes, fluorescent materials, luminescent materials (e.g., luminol, luminol derivatives, fluorescein, aequorin and luciferase), etc. The radioactive isotope tritium, i.e. 3 H(T), and carbon-14, i.e. 14 C are particularly useful for this purpose in view of their ease of incorporation and readily available means of detection.

[0941] Using heavier isotopes, such as deuterium, 2 H(D) substitution may offer certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and may therefore be useful in some settings.

[0942] Specifically, each time hydrogen is mentioned in this application, it should be understood to cover 1 H and 2 H, whether hydrogen is explicitly defined or is implicitly present to satisfy the valence of the relevant atom (especially carbon).

[0943] Using positron emitting isotopes, such as 11 C. 18 F. 15 O and 13 N substitutions may be useful in positron emission tomography (PET) studies for examining target occupancy.

[0944] Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples and preparations, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.

[0945] ester

[0946] Esters of compounds of formula (I) bearing carboxylic acid or hydroxyl groups, such as carboxylic acid esters, acyloxy esters and phosphate esters are also encompassed by formula (I). Examples of esters are compounds containing the group -C(=O)OR, wherein R is an ester substituent, such as C 1-7 Alkyl, C 3-12 Heterocyclic group, or C 5-12 Aryl, usually C 1-6 Specific examples of ester groups include, but are not limited to, -C(=O)OCH 3、-C(=O)OCH 2 CH 3 、-C(=O)OC(CH 3 ) 3 , and -C(=O)OPh. Examples of acyloxy (reverse ester) groups are represented by -OC(=O)R, where R is an acyloxy substituent, such as C 1-6 Alkyl, C 3-12 Heterocyclic group, or C 5-12 Aryl, usually C 1-6 Specific examples of acyloxy include, but are not limited to, -OC(=O)CH 3 (acetoxy), -OC(=O)CH 2 CH 3 、-OC(=O)C(CH 3 ) 3 , -OC(=O)Ph, and -OC(=O)CH 2 Ph. Examples of phosphates are those derived from phosphoric acid.

[0947] In one embodiment of the present invention, formula (I) includes within its scope esters of compounds of formula (I) with carboxylic acid groups or hydroxyl groups. In another embodiment of the present invention, formula (I) does not include within its scope esters of compounds of formula (I) with carboxylic acid groups or hydroxyl groups.

[0948] Solvates and crystalline forms

[0949] Formula (I) also encompasses any polymorphs of the compound, as well as solvates such as hydrates, alcoholates, and the like.

[0950] The compounds of the present invention can, for example, form solvates with water (i.e., hydrates) or common organic solvents. As used herein, the term "solvate" means the physical association of the compounds of the present invention with one or more solvent molecules. This physical association involves varying degrees of ionic bonding and covalent bonding, including hydrogen bonding. In some cases, the solvate will be able to separate, such as when one or more solvent molecules are incorporated into the lattice of a crystalline solid. The term "solvate" is intended to encompass both solution phase solvates and separable solvates. Non-limiting examples of suitable solvates include combinations of the compounds of the present invention with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid or ethanolamine, etc. The compounds of the present invention can exert their biological effects when they are in solution.

[0951] Solvates are well known in medicinal chemistry. They may be important for the process of preparing a substance (e.g., with respect to their purification), the storage of the substance (e.g., its stability), and the ease with which the substance can be handled and are often formed as part of the separation or purification stage of a chemical synthesis. One skilled in the art can determine by standard and long-standing techniques whether a hydrate or other solvate has been formed by the separation or purification conditions used to prepare a given compound. Examples of such techniques include thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray crystallography (e.g., single crystal X-ray crystallography or X-ray powder diffraction), and solid-state NMR (SS-NMR, also known as magic angle spinning NMR or MAS-NMR). Such techniques are part of the standard analytical toolkit of a skilled chemist, as are NMR, IR, HPLC, and MS.

[0952] Alternatively, one skilled in the art can intentionally form a solvate using crystallization conditions that include the amount of solvent desired for a particular solvate. Afterwards, standard methods described herein can be used to determine whether a solvate has been formed.

[0953] Furthermore, the compounds of the present invention may have one or more polymorphs or amorphous crystalline forms and are thus intended to be included within the scope of the present invention.

[0954] Complex

[0955] Formula (I) also includes within its scope complexes of the compounds (e.g. inclusion complexes or clathrates with compounds such as cyclodextrins, or complexes with metals). Inclusion complexes, clathrates and metal complexes can be formed by methods known to those skilled in the art.

[0956] Prodrug

[0957] Formula (I) also encompasses any prodrugs of the compounds of formula (I). "Prodrug" means any compound that is converted, for example, in vivo into a biologically active compound of formula (I).

[0958] For example, some prodrugs are esters of active compounds (e.g., physiologically acceptable metabolically unstable esters). During metabolism, the ester group (-C(=O)OR) is cleaved to produce the active drug. Such esters can be formed by esterifying any of the carboxylic acid groups (-C(=O)OH) in the parent compound, for example, with pre-protection of any other reactive groups present in the parent compound, followed by deprotection if necessary.

[0959] Examples of such metabolically labile esters include those of the formula -C(=O)OR, wherein R is:

[0960] C 1-7 Alkyl (e.g., -Me, -Et, -nPr, -iPr, -nBu, -sBu, -iBu, -tBu);

[0961] C 1-7 aminoalkyl (eg, aminoethyl; 2-(N,N-diethylamino)ethyl; 2-(4-(morpholin-1-yl))ethyl); and acyloxy-C 1-7 Alkyl (e.g., acyloxymethyl; acyloxyethyl; pivaloyloxymethyl; acetoxymethyl; 1-acetoxyethyl; 1-(1-methoxy-1-methyl)ethyl-carbonyloxyethyl; 1-(benzoyloxy)ethyl; isopropoxy-carbonyloxymethyl; 1-isopropoxy-carbonyloxyethyl; cyclohexyl-carbonyloxymethyl; 1-cyclohexyl-carbonyloxyethyl; cyclohexyloxy-carbonyloxymethyl; 1-cyclohexyloxy-carbonyloxyethyl; (4- Alkyloxy)carbonyloxymethyl; 1-(4- Alkyloxy)carbonyloxyethyl; (4- alkyl)carbonyloxymethyl; and 1-(4-tetrahydropyranyl)carbonyloxyethyl).

[0962] In addition, some prodrugs are enzymatically activated to produce an active compound or a compound that produces an active compound upon further chemical reaction (e.g., as in antigen-directed enzyme prodrug therapy (ADEPT), gene-directed enzyme prodrug therapy (GDEPT), and ligand-directed enzyme prodrug therapy (LIDEPT), etc.). For example, a prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative. In one embodiment, Formula (I) does not include within its scope prodrugs of compounds of Formula (I).

[0963] Process for preparing compounds of formula (I)

[0964] In this section, as in all other sections of this application, unless the context indicates otherwise, reference to formula (I) also includes all other subformulae thereof as defined herein (e.g., formulas I(c), I(f), I(g), I(g'), I(h), I(i), I(j), I(k), I(L), I(m), I(m'), I(n), I(o), I(o'), I(o"), I(p), I(p'), I(q), I(q'), I(q"), I(q'"), I(q")"), I(c), I(f), I(g), I(g'), I(h), I(i), I(j), I(k), I(L), I(m), I(m'), I(n), I(o), I(o'), I(o"), I(p), I(p'), I(q), I(q'), I(q"), I(q")"), I(c), I(f), I(g), I(g'), I(h), I(i), I(j), I(k), I(L), I(m), I(m'), I(n), I(o), I(o'), I(o"), r), I(s), I(t), I(u), I(v), I(v'), I(w), I(x), I(x'), I(y), (II), (IIa), (IIb), (IIIa), (IIIb), (IVa), (IVb), (V), (V 1), (Via), (VII), (VIIa), (VIIb), (VIIc), (VIId), (VIId'), (VIIe), (VIIe'), (a), (b), (ba), (bb), (bc) or (c)) and examples.

[0965] The compounds of formula (I) can be prepared according to synthetic methods known to those skilled in the art.

[0966] According to another aspect of the present invention, there is provided a method for preparing a compound of formula (I) or a tautomer, stereoisomer, N-oxide, pharmaceutically acceptable salt, or solvate thereof, the method comprising:

[0967] According to another aspect of the present invention, there is provided a method for preparing a compound of formula (I) as defined above, the method comprising:

[0968] (a) reacting a compound of formula (XV) with a compound of formula R 7 M (wherein M is a metal), such as an organometallic reagent of formula R 7 Grignard reagent reaction of MgBr:

[0969]

[0970] Where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , a, s, m and n are as defined herein;

[0971] (b) interconverting a compound of formula (I) or a protected derivative thereof into another compound of formula (I) or a protected derivative thereof; and / or

[0972] (c) deprotecting a protected derivative of a compound of formula (I); and / or

[0973] (d) providing a compound of formula (I) and forming a pharmaceutically acceptable salt of said compound.

[0974] The required intermediates are either commercially available, known in the literature, prepared by methods analogous to those in the literature or by methods analogous to those described in the experimental procedures of the examples below. Other compounds may be prepared by functional group interconversions using methods well known in the art.

[0975] The general synthetic route for preparing the key intermediate compound of Formula XV is shown in the following scheme.

[0976]

[0977] Exemplary reagents and conditions for Scheme 1: a) NaOH, H 2 O, CHCl 3 , 85℃; A) AcOH, room temperature; B) Pb(OAc) 4 , THF, 0℃; C) NaClO 2 , H 2 NSO 3 H, CH 3 CN、H 2 O, room temperature; D) i) SOCl 2 , DMF, THF; ii) amine, i-Pr 2 EtN, THF; E)i)SOCl 2 , DMF, THF; ii) R 3 (CH 2 ) S -OH, K 2 CO 3 ,THF;F)InBr 3 , R 3 (CH 2 ) S -OH, DCE, 85°C; separation and isolation of the 3(R) enantiomer can be achieved at this stage by chiral HPLC.

[0978] In Scheme 1, R 1 , R 2 , R 3 , R 4 and R 5 As described herein and W represents a leaving group such as, for example, halo, for example bromo; or a carbonyl such as, for example, acetyl.

[0979] N-Aroylhydrazone (XI) can be prepared by condensing benzaldehyde (IX) with benzoylhydrazide (X). 4 The reaction produces the aldehyde (XII), which undergoes Pinnick oxidation to give the acid (XIII). The appropriate benzylamine can then be used to provide the 3-hydroxyisoindolinone (XIV), and thionyl chloride or InBr can be used to convert the 3-hydroxyisoindolinone (XIV) into 3-hydroxyisoindolinone (XIV). 3 and appropriate alcohols are added containing R 3 of the side chain.

[0980] The intermediate of formula (XV) can be used as a raw material for synthesizing R 3 Position, R 6 Location and R 7 The starting point of the compound of the present invention having different functional groups at the position.

[0981] Scheme 2 below shows the methods for introducing various R starting from an intermediate of formula (XVI), which is a compound of formula (XV) wherein W is Br. 6 Part of the exemplary procedure.

[0982]

[0983] Exemplary reagents and conditions for Scheme 2: G) (i) toluene, 1,4-dimethoxybenzene, Alkane, LiCl, tributyl(1-ethoxyvinyl)tin, Pd(PPh 3 ) 4 (ii) HCl, H 2 O / THF; H)MeMgCl, in ZnCl 2 and / or LaCl 3 -2LiCl, THF. Separation and isolation of the 3(R) enantiomer can be achieved at any stage by chiral HPLC.

[0984] Bromide (XVI) can be prepared by using, for example, 1,4-dibromo Alkane, LiCl, tributyl(1-ethoxyvinyl)tin, Pd(PPh 3 ) 4 This is converted to the methyl ketone (XVII) and further converted to the alcohol XVIII by reaction with a methyl Grignard reagent.

[0985] Where R 6 and R 7 Compounds where R is hydrogen can also be prepared according to general synthetic scheme 3. 3 Where hydroxyl groups are present, these may be protected during synthesis using standard protecting groups (eg TBDMS, TBDPS). Deprotection may be carried out using standard conditions (eg TBAF).

[0986]

[0987] Exemplary reagents and conditions for Scheme 3: I) HCOOLi·H 2 O、Ac 2 O、Et 3 N, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, Pd(OAc) 2 ,DMF; J)LiBH 4 , THF.

[0988] Where R 6 and R 7 Compounds of formula (XVIII) first shown in Scheme 2 which are methyl can also be prepared according to General Synthetic Scheme 4.

[0989] In Scheme 4, according to Procedure F (InBr 3 and R 3 (CH 2 ) s -OH) to prepare an intermediate of formula (XXIV) from an intermediate of formula (XXIII). The intermediate of formula (XXIV) is then converted into a compound of formula (XVIII) by a Grignard reaction.

[0990]

[0991] Exemplary reagents and conditions: F) InBr 3 , R 3 (CH 2 ) S -OH, DCE, 85℃; H) MeMgCl, ZnCl 2 , THF, 0° C. Separation and isolation of the 3(R) enantiomer can be achieved in stage F or H by chiral HPLC.

[0992] Compounds of general formula XXX can also be prepared according to Scheme 5 and Scheme 6.

[0993]

[0994] Exemplary reagents and conditions: L) nBuLi, Het-CHO, THF, -78°C; M) MnO 2 , MeCN, or I 2 , KI, K 2 CO 3 ; D) i) SOCl 2 , DMF, THF; ii) amine, i-Pr 2 EtN, THF or HATU, amine, DIPEA, DMF; E) i) SOCl2 , DMF, THF; ii) R 3 (CH 2 ) S -OH, K 2 CO 3 ,THF;F)InBr 3 , R 3 (CH 2 ) S -OH, DCE, 85℃; N)R 7 MgX, in ZnCl 2 and / or LaCl 3 -2LiCl, THF or Al(R 7 ) 3 , THF or EtLi, ZnEt 2 In stages E, F and N, the separation of enantiomers and / or diastereomers can be achieved by chiral HPLC and / or achiral HPLC.

[0995] Intermediate XIII (where W is Br) is reacted with nBuLi and an appropriate aldehyde to afford alcohol XXVI. 2 or I 2 The alcohol XXVI is oxidized to the corresponding ketone (XXVII) by using KI. The intermediate XXVII is then converted to the 3-hydroxyisoindolinone XXIX following Procedure D and Procedure E (or F) described above.

[0996] The intermediate of formula XXIX can be used as a synthesizer of R in formula I 7 The starting point of the compound of the present invention having different functional groups at the position.

[0997] Alternatively, introducing R earlier in the synthesis 7 Substituents are as shown in Scheme 6. Intermediates of Formula XXVII can be reacted with organometallic reagents to give tertiary alcohols (XXXI) which are then converted to final compounds of Formula I following Procedure D and Procedure E (or F) (Scheme 6).

[0998]

[0999] Exemplary reagents and conditions: N)R 7 MgX, in ZnCl 2 and / or LaCl 3 -2LiCl, THF or Al(R 7 ) 3 , THF or EtLi, ZnEt 2 , in the presence of THF; D) i) SOCl 2, DMF, THF; ii) amine, i-Pr 2 EtN, THF or HATU, amine, DIPEA, DMF; E) i) SOCl 2 , DMF, THF; ii) R 3 (CH 2 ) S -OH, K 2 CO 3 ,THF;F)InBr 3 , R 3 (CH 2 ) S -OH, DCE, 85° C. In stages N and E / F, separation of enantiomers and / or diastereomers can be achieved by chiral HPLC and / or achiral HPLC.

[1000] Compounds of formula XVI (first shown in Scheme 2) can also be used to prepare compounds of formula XXIX using the methods outlined in Scheme 7. In this case, XVI can be converted to a suitable boronate ester using, for example, Miyaura conditions. This is then reacted in the presence of carbon monoxide, a suitable catalyst such as Pd(dppf)Cl 2 ) and a solvent such as toluene or anisole, by treating the boronate with an appropriate heterocyclic iodide (or heterocyclic bromide).

[1001] Alternatively, carbon monoxide, a suitable catalyst [such as Pd(dppf)Cl 2 ] and a solvent (such as DMF) in the presence of a suitable heterocyclic stannane to treat a compound of formula XVI to obtain a compound of formula XXIX (Scheme 7). The separation and isolation of the 3(R) intermediate can be achieved at any stage using chiral HPLC. The compound of formula XXIX can then be carried forward to a compound of formula XXX (as shown in Scheme 5).

[1002]

[1003] Compounds of formula XVI can also be used to prepare compounds of formula XXIX using the methods outlined in Scheme 8. In this case, compounds of formula XVI can be used to prepare Weinreb amide derivatives using N,O-dimethylhydroxylamine hydrochloride in the presence of carbon monoxide and a suitable palladium catalyst (e.g., Xantphos G3 catalyst). Weinreb amide can then be reacted with an appropriate metallated heterocycle (e.g., the product of 4-bromo-1-methyl-1H-pyrazole and nBuLi in THF) to obtain compounds of formula XXIX (Scheme 8). The separation and isolation of the 3(R) intermediate can be achieved at any stage using chiral HPLC. Compounds of formula XXIX can then be carried out to compounds of formula XXX (as shown in Scheme 5).

[1004]

[1005] It will be appreciated that certain compounds may exist in different diastereomeric and / or enantiomeric forms and that methods for their preparation may utilize enantiomerically pure synthetic precursors.

[1006] Alternatively, racemic precursors may be used and the mixture of diastereomers produced in these processes may be separated by methods known to those skilled in the art, for example using achiral or chiral preparative chromatography or resolution using diastereomeric derivatives: for example crystallization of salts formed with an enantiomerically pure acid such as L-tartaric acid (or an enantiomerically pure base such as (1R)-1-phenylethan-1-amine); or separation of the enantiomers by covalently attaching an enantiomerically pure chiral auxiliary to the compound to form diastereomeric derivatives followed by separation using conventional methods such as chiral or achiral chromatography. The covalent bonds are then cleaved to produce the appropriate enantiomerically pure product.

[1007] A wide range of well-known functional group interconversions are known to those skilled in the art for converting precursor compounds into compounds of formula I and are described in Advanced Organic Chemistry, Jerry March, 4th edition, John Wiley & Sons, 1992. For example, possible metal-catalyzed functionalizations, such as the use of organotin reagents (Stille reaction), Grignard reagents and reactions with nitrogen nucleophiles are described in 'Palladium Reagents and Catalysts' [Jiro Tsuji, Wiley, ISBN 0-470-85032-9] and in Handbook of OrganoPalladium Chemistry for Organic Synthesis [Volume 1, Ei-ichi Negishi, ed., Wiley, ISBN 0-471-31506-0].

[1008] If appropriate, one or more reactions known to those skilled in the art are carried out after or before the reactions previously described below and in the appropriate order to achieve the necessary substitutions defined above to obtain other compounds of formula (I). Non-limiting examples of these reactions where conditions can be found in the literature include:

[1009] Protection of reactive functional groups;

[1010] Deprotection of reactive functional groups;

[1011] Halogenation;

[1012] Dehalogenation;

[1013] Dealkylation;

[1014] Alkylation or arylation of amines, anilines, alcohols, and phenols;

[1015] Mitsunobu reaction on hydroxyl groups;

[1016] Cycloaddition reactions on appropriate groups;

[1017] Reduction of nitro groups, esters, cyano groups, and aldehydes;

[1018] Transition metal-catalyzed coupling reactions;

[1019] Acylation;

[1020] Sulfonylation / introduction of sulfonyl groups;

[1021] saponification / hydrolysis of ester groups;

[1022] Amidation or transesterification of ester groups;

[1023] Esterification or amidation of carboxyl groups;

[1024] Halogen exchange;

[1025] nucleophilic substitution with amines, thiols, or alcohols;

[1026] Reductive amination;

[1027] Oxime formation on carbonyl and hydroxylamine groups;

[1028] S-oxidation;

[1029] N-oxidation;

[1030] Salinization.

[1031] It should be understood that certain compounds such as formula (I), I(c), I(f), I(g), I(g'), I(h), I(i), I(j), I(k), I(L), I(m), I(m'), I(n), I(o), I(o'), I( o”), I(p), I(p’), I(q), I(q’), I(q”), I(q”’), I(q””), I(r), I(s), I(t), I(u), I(v), I(v’), I(w), I(x), I(x’), I( The compounds of (a), (b), (ba), (bb), (bc) or (c) may exist in different diastereomeric and / or enantiomeric forms and the methods for their preparation may utilize enantiomerically pure synthetic precursors.

[1032] Alternatively, racemic precursors may be used and the mixture of diastereomers produced in these processes may be separated by methods known to those skilled in the art, for example using achiral or chiral preparative chromatography or resolution using diastereomeric derivatives: for example crystallization of salts formed with enantiomerically pure acids such as L-tartaric acid; or by covalently attaching an enantiomerically pure chiral auxiliary to the compound to form diastereomeric derivatives followed by enantiomer separation using conventional methods such as chiral chromatography. The above covalent bonds are then cleaved to produce the appropriate enantiomerically pure product.

[1033] Some of the required intermediates are commercially available, known in the literature, prepared by methods analogous to those in the literature, or prepared by methods analogous to those described in the experimental procedures of the examples below. Other compounds can be prepared by functional group interconversion using methods well known in the art.

[1034] In another embodiment, the invention provides a novel intermediate. In one embodiment, the invention provides novel intermediates of (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XIX), (XX), (XXI), (XXIII) and (XXIV).

[1035] Protecting Group

[1036] In many of the reactions described herein, it may be necessary to protect one or more groups to prevent reactions at undesirable locations on the molecule. Examples of protecting groups and methods for protecting and deprotecting functional groups can be found in Protective Groups in Organic Synthesis (T. Green and P. Wuts; 3rd ed.; John Wiley & Sons, 1999).

[1037] In particular, the compounds may be synthesized in protected form and the protecting groups removed to produce compounds of formula (I).

[1038] Hydroxyl groups may be protected, for example, as ethers (—OR) or esters (—OC(═O)R), such as tert-butyl ether; tetrahydropyranyl (THP) ether; anisole, diphenylmethyl (diphenylmethyl) ether, or triphenylmethyl (triphenylmethyl) ether; trimethylsilyl ether or tert-butyldimethylsilyl ether; or acetyl esters (—OC(═O)CH 3 ).

[1039] Aldehyde or ketone groups can be protected as acetals (R-CH(OR) 2 ) or ketal (R 2 C(OR) 2 ), wherein the carbonyl group (>C=O) is treated with, for example, a primary alcohol. The aldehyde or keto group is readily regenerated by hydrolysis using a large excess of water in the presence of an acid.

[1040] Amine groups can be protected as amides (-NRCO-R) or carbamates (-NRCO-OR), for example, methyl amide (-NHCO-CH 3 ); benzyl carbamate (-NHCO-OCH 2 C6 H 5 , -NH-Cbz or NH-Z); tert-butyl carbamate (-NHCO-OC(CH 3 ) 3 , -NH-Boc); 2-biphenyl-2-propyl carbamate (-NHCO-OC(CH 3 ) 2 C 6 H 4 C 6 H 5 , -NH-Bpoc), 9-fluorenylmethyl carbamate (-NH-Fmoc), 6-nitroveratryl carbamate (-NH-Nvoc), 2-trimethylsilylethyl carbamate (-NH-Teoc), 2,2,2-trichloroethyl carbamate (-NH-Troc), allyl carbamate (-NH-Alloc), or 2-(phenylsulfonyl)ethyl carbamate (-NH-Psec).

[1041] Other protecting groups for amines, such as cyclic amines and heterocyclic NH groups include toluenesulfonyl (tosyl) and methanesulfonyl (mesyl), benzyl (such as p-methoxybenzyl (PMB)) and tetrahydropyranyl (THP).

[1042] The carboxylic acid group can be protected as an ester, for example: 1-7 Alkyl ester (eg methyl ester; tert-butyl ester); C 1-7 Haloalkyl esters (e.g. 1-7 trihaloalkyl ester); triC 1-7 Alkylsilyl-C 1-7 Alkyl ester; or C 5-20 Aryl-C 1-7 Alkyl esters (e.g., benzyl ester; nitrobenzyl ester; p-methoxybenzyl ester). Thiol groups can be protected as, for example, thioethers (-SR), for example, benzyl thioether; acetamidomethyl ether (-S-CH 2 NHC(=O)CH 3 ).

[1043] Isolation and purification of the compounds of the present invention

[1044] The compounds of the present invention can be isolated and purified according to standard techniques well known to those skilled in the art and examples of such methods include chromatographic techniques such as column chromatography (e.g. flash chromatography) and HPLC. One technique that is particularly useful in purifying the compounds is preparative liquid chromatography using mass spectrometry as a means of detecting the purified compounds emerging from the chromatographic column.

[1045] Preparative LC-MS is a standard and effective method for purifying small organic molecules, such as compounds described herein. The methods for liquid chromatography (LC) and mass spectrometry (MS) can be modified to provide better separation of crude material and improved detection of samples by MS. Optimization of preparative gradient LC methods will involve changing the column, volatile eluents and modifiers, and gradients. Methods for optimizing preparative LC-MS methods and then using them to purify compounds are well known in the art. Such methods are described in Rosentreter U, Huber U.; Optimal fraction collecting in preparative LC / MS; J Comb Chem.; 2004; 6(2), 159-64; and Leister W, Strauss K, Wisnoski D, Zhao Z, Lindsley C., Development of a custom high-throughput preparative liquid chromatography / mass spectrometer platform for the preparative purification and analytical analysis of compound libraries; J Comb Chem.; 2003; 5(3); 322-9. Examples of such systems for purifying compounds via preparative LC-MS are described below in the Examples section of this application (under the heading "Mass-directed purification LC-MS system").

[1046] The method of recrystallization of the compound of formula (I) and its salt can be carried out by methods known to those skilled in the art, see for example (P. Heinrich Stahl (ed.), Camille G. Wermuth (ed.), ISBN: 3-90639-026-8, "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", Chapter 8, Wiley-VCH Publishing House). When directly separated from the reaction mixture, the product obtained from the organic reaction is rarely pure. If the compound (or its salt) is solid, it can be purified and / or crystallized by recrystallization from a suitable solvent. A good recrystallization solvent should dissolve an appropriate amount of the substance to be purified at high temperatures, but only dissolve a small amount of the substance at lower temperatures. It should easily dissolve impurities or not dissolve at all at low temperatures. Finally, the solvent should be easily removed from the purified product. This usually means that it has a relatively low boiling point and the skilled person will know the recrystallization solvent for a specific substance, or if this information is not available, test several solvents. In order to obtain a good yield of purified material, a minimum amount of hot solvent is used to dissolve all impure materials. In practice, 3%-5% more solvent than necessary is used to make the solution unsaturated. If the impure compound contains impurities that are insoluble in the solvent, then it can be removed by filtering and then the solution is crystallized. In addition, if the impure compound contains traces of colored substances that are not native to the compound, then it can be removed by adding a small amount of decolorizing agent, such as activated carbon, to the hot solution, filtering the solution, and then crystallizing the solution. Usually, when the solution is cooled, crystallization occurs spontaneously. If not, crystallization can be induced by cooling the solution to below room temperature or by adding a single crystal (seed) of a pure substance. Recrystallization and / or yield can also be optimized by using an antisolvent or a cosolvent. In this case, the compound is dissolved in a suitable solvent at high temperature, filtered, and then another solvent in which the desired compound has a low solubility is added to help crystallization. Then vacuum filtration is usually used to separate the crystals, the crystals are washed, and then dried, such as in an oven or via dehydration.

[1047] Other examples of methods for purification include sublimation, which includes a heating step under vacuum, for example using a cold finger, and crystallization from the melt (Crystallization Technology Handbook, 2nd edition, edited by A. Mersmann, 2001).

[1048] Biological effects

[1049] It is contemplated that the compounds of the present invention will be useful in medicine or therapy. The compounds of the present invention, its subgroups and embodiments have been shown to inhibit the interaction of p53 and MDM2. Such inhibition causes cell proliferation arrest and apoptosis, which may be useful in preventing or treating disease states or conditions described herein, such as the diseases and conditions described below and the diseases and conditions described in the "Background of the Invention" section above, in which p53 and MDM2 play a role. Thus, for example, it is contemplated that the compounds of the present invention may be useful in alleviating cancer or reducing the incidence of cancer.

[1050] The compounds of the invention may be useful for treating the adult population.The compounds of the invention may be useful for treating the pediatric population.

[1051] The compounds of the present invention have been shown to be good inhibitors of the formation of the MDM2-p53 complex. Antagonist compounds of formula (I) are able to bind to MDM2 and exhibit efficacy against MDM2. The efficacy of the compounds of the present invention against MDM2 / p53 has been determined using the assay protocols described herein and other methods known in the art. More specifically, the compounds of formula (I) and its subgroups have affinity for MDM2 / p53.

[1052] Certain compounds of the present invention have an IC of less than 0.1 μM, particularly less than 0.01 μM or 0.001 μM. 50 Those that are worth it.

[1053] MDM2 / p53 function has been implicated in many diseases because it plays a role in multiple processes, such as vascular remodeling and anti-angiogenic processes, as well as regulation of metabolic pathways, and tumorigenesis. Due to the affinity of the compound to MDM2, it is expected that the compound may prove useful in treating or preventing a variety of diseases or conditions, including autoimmune conditions; diabetes; chronic inflammatory diseases, such as lupus nephritis, systemic lupus erythematosus (SLE), autoimmune-mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, autoimmune diabetes, eczema, hypersensitivity reactions, asthma, COPD, rhinitis, and upper respiratory tract diseases; hyperkeratosis, such as autosomal recessive congenital ichthyosis (ARCI); kidney disease, These include glomerular disorders, chronic kidney disease (CKD), nephritis, podocyte loss, glomerulosclerosis, proteinuria, and progressive renal disease; cardiovascular diseases, such as cardiac hypertrophy, restenosis, arrhythmias, atherosclerosis; myocardial infarction, vascular injury, stroke, and reperfusion injury associated with ischemic injury; vascular proliferative diseases; ocular diseases, such as age-related macular degeneration, particularly the wet form of age-related macular degeneration; ischemic proliferative retinopathy, such as retinopathy of prematurity (ROP) and diabetic retinopathy; and hemangiomas.

[1054] Due to their affinity for MDM2, it is expected that the compounds may prove useful in treating or preventing proliferative disorders, such as cancer.

[1055] Examples of cancers (and their benign counterparts) that may be treated (or inhibited) include, but are not limited to, tumors of epithelial origin (various types of adenomas and carcinomas, including adenocarcinomas, squamous carcinomas, transitional cell carcinomas, and other carcinomas), such as bladder cancer and urinary tract cancer, breast cancer, gastrointestinal cancer (including esophageal cancer, stomach / gastric cancer, small intestine cancer, colon cancer, intestinal cancer, colorectal cancer, rectal cancer, and anal cancer), liver cancer (hepatocellular carcinoma), gallbladder cancer and biliary system cancer, exocrine pancreatic cancer, kidney cancer (e.g., renal cell carcinoma), lung cancer (e.g., adenocarcinoma, small cell lung cancer, non-small cell lung cancer, bronchioloalveolar carcinoma, and mesothelioma), head and neck cancer (e.g., tongue cancer, buccal cancer, laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, tonsil cancer, salivary gland cancer, nasal cancer, and paranasal cancer). antrum, ovarian cancer, fallopian tube cancer, peritoneal cancer, vaginal cancer, vulvar cancer, penis cancer, testicular cancer, cervical cancer, myometrial cancer, endometrial cancer, thyroid cancer (e.g., follicular thyroid cancer), brain cancer, adrenal cancer, prostate cancer, skin cancer, and adnexal cancer (e.g., melanoma, basal cell carcinoma, squamous cell carcinoma, keratoacanthoma, dysplastic nevus); hematologic malignancies (i.e., leukemias, lymphomas) and premalignant hematologic disorders and borderline malignancies, including hematologic malignancies and related conditions of the lymphoid lineage (e.g., acute lymphocytic leukemia [ALL], chronic lymphocytic leukemia [CLL], B-cell lymphomas, such as diffuse large B-cell lymphoma [DLBCL], follicular lymphoma, Burkitt's lymphoma (Burkitt's lymphoma, mantle cell lymphoma, T-cell lymphoma and leukemia, natural killer [NK] cell lymphoma, Hodgkin's lymphoma, hairy cell leukemia, monoclonal gammopathy of undetermined significance, plasmacytoma, multiple myeloma, and post-transplant lymphoproliferative disorder), as well as hematologic malignancies and myeloid-related conditions (e.g., acute myeloid leukemia [AML], chronic myeloid leukemia [CML], chronic myelomonocytic leukemia [CMML], hypereosinophilic syndrome, myeloproliferative disorders such as polycythemia vera, essential thrombocythemia and primary myelofibrosis, myeloproliferative syndrome, myelodysplastic syndrome, and promyelocytic leukemia); tumors of mesenchymal origin, such as sarcomas of soft tissue, bone, or cartilage, such as osteosarcoma, fibrosarcoma, chondrosarcoma, rhabdomyosarcoma, leiomyosarcoma, liposarcoma, angiosarcoma, Kaposi's sarcoma, sarcoma), Ewing's sarcoma, synovial sarcoma, epithelioid sarcoma, gastrointestinal stromal tumors, benign and malignant histiocytomas, and dermatofibrosarcoma protuberans; tumors of the central or peripheral nervous system (e.g., astrocytomas (e.g., gliomas), neuromas and glioblastomas, meningiomas, ependymomas, pinealomas, and schwannomas);Endocrine tumors (e.g., pituitary tumors, adrenal tumors, islet cell tumors, parathyroid tumors, carcinoid tumors, and medullary thyroid carcinoma); ocular and adnexal tumors (e.g., retinoblastoma); germ cell and trophoblastic tumors (e.g., teratoma, seminoma, dysgerminoma, hydatidiform mole, and choriocarcinoma); and pediatric and embryonal tumors (e.g., medulloblastoma, neuroblastoma, Wilms tumor, and primitive neuroectodermal tumor); or congenital or other syndromes that predispose patients to malignancy (e.g., xeroderma pigmentosum).

[1056] The growth of cells is a tightly controlled function. Cancer is a condition of abnormal cell growth that occurs when cells replicate (increase in number), grow uncontrollably (become larger) and / or experience reduced cell death caused by apoptosis (programmed cell death), necrosis, or anoikis in an uncontrolled manner. In one embodiment, abnormal cell growth is selected from uncontrolled cell proliferation, excessive cell growth, or reduced programmed cell death. Specifically, the condition or disease of abnormal cell growth is cancer.

[1057] Thus, in one embodiment, in the pharmaceutical composition, use or method of the invention for treating a disease or condition involving abnormal cell growth (i.e. uncontrolled and / or rapid cell growth), the disease or condition involving abnormal cell growth is cancer.

[1058] Many diseases are characterized by persistent and dysregulated angiogenesis. Chronic proliferative diseases are often accompanied by significant angiogenesis, which can lead to or maintain an inflammatory and / or proliferative state, or which can cause tissue destruction via invasive proliferation of blood vessels. Tumor growth and metastasis have been found to be angiogenesis-dependent. The compounds of the present invention may therefore be useful in preventing and disrupting the initiation of tumor angiogenesis.

[1059] Angiogenesis is generally used to describe the generation of new or replacement blood vessels, or angiogenesis. It is a necessary and physiological normal process for establishing a vascular system in the embryo. Angiogenesis generally does not occur in most normal adult tissues, with the exception of ovulation, menstruation, and wound healing. However, many diseases are characterized by sustained and unregulated angiogenesis. For example, in arthritis, new capillaries invade the joints and destroy cartilage. In diabetes (and in many different eye diseases), new blood vessels invade the macula or retina or other eye structures and may cause blindness. The process of atherosclerosis has been associated with angiogenesis. It has been found that tumor growth and metastasis are angiogenesis-dependent. The compounds may be beneficial in treating diseases such as cancer and metastasis, eye diseases, arthritis, and hemangiomas.

[1060] Therefore, the compounds of the present invention may be useful in treating metastasis and metastatic cancer. Metastasis or metastatic disease is the spread of disease from one organ or part to another non-adjacent organ or part. Cancers that can be treated by the compounds of the present invention include primary tumors (i.e. cancer cells at the starting site), local invasion (cancer cells that penetrate and infiltrate surrounding normal tissues in a local area) and metastatic (or secondary) tumors, i.e. tumors formed by malignant cells that have been circulated to other parts and tissues in the body via the bloodstream (hematogenous spread) or via lymphatic vessels or through the body cavity (implantation). Specifically, the compounds of the present invention may be useful in treating metastasis and metastatic cancer.

[1061] In one embodiment, the hematological malignancy is a leukemia. In another embodiment, the hematological malignancy is a lymphoma. In one embodiment, the cancer is AML. In another embodiment, the cancer is CLL.

[1062] In one embodiment, the compounds of the invention are used to prevent or treat leukemias, such as acute or chronic leukemias, in particular acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), or chronic myeloid leukemia (CML). In one embodiment, the compounds of the invention are used to prevent or treat lymphomas, such as acute or chronic lymphomas, in particular Burkitt's lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma or diffuse large B-cell lymphoma.

[1063] In one embodiment, the compounds of the invention are used to prevent or treat acute myeloid leukemia (AML) or acute lymphocytic leukemia (ALL).

[1064] One embodiment includes a compound of the invention for use in preventing or treating cancer in a patient selected from a subpopulation having p53 wild-type or having MDM2 amplified cancer.

[1065] The cancer may be a cancer that is sensitive to treatment with an MDM2 inhibitor. The cancer may be a cancer that overexpresses MDM2. The cancer may be a p53 wild-type cancer.

[1066] Particular cancers include those with MDM2 amplification and / or MDM2 overexpression, such as hepatocellular carcinoma, lung cancer, sarcoma, osteosarcoma, and Hodgkin's disease.

[1067] Particular cancers include those with wild-type p53. Particular cancers include those cancer cells with wild-type p53, particularly but not limited to if MDM2 is highly expressed.

[1068] In one embodiment, the cancer is a p53 functional tumor. In one embodiment, the disease to be treated is a p53 functional solid and hematological malignancy. In another embodiment, the patient to be treated has a p53 mutant tumor, such as an AML patient with a p53 mutant tumor.

[1069] In one embodiment, the cancer is a brain tumor, such as a glioma or a neuroblastoma.

[1070] In one embodiment, the cancer is skin cancer, such as melanoma.

[1071] In one embodiment, the cancer is lung cancer, such as mesothelioma. In one embodiment, the mesothelioma is malignant peritoneal mesothelioma or malignant pleural mesothelioma.

[1072] In one embodiment, the cancer is a gastrointestinal cancer, such as GIST, gastric cancer, colorectal cancer, or intestinal cancer.

[1073] In one embodiment, the cancer is osteosarcoma.

[1074] In one embodiment, the cancer is liposarcoma.

[1075] In one embodiment, the cancer is Ewing's sarcoma.

[1076] In one embodiment, the cancer is liposarcoma, soft tissue sarcoma, osteosarcoma, esophageal cancer, and certain pediatric malignancies, including B-cell malignancies.

[1077] In one embodiment, the cancer is colorectal cancer, breast cancer, lung cancer, and brain cancer.

[1078] In one embodiment, the cancer is a pediatric cancer.

[1079] Whether a particular cancer is a cancer that is sensitive to an MDM2 inhibitor can be determined by methods as described in the section entitled "Diagnostic Methods."

[1080] Another aspect provides the use of a compound for the manufacture of a medicament for the treatment of a disease or condition as described herein, particularly cancer.

[1081] Some cancers are resistant to the treatment of specific drugs. This may be because the type of tumor (the most common epithelial malignancies are chemoresistant in nature and the prostate is relatively resistant to currently available chemotherapy regimens or radiotherapy regimens) or resistance can occur spontaneously with disease progression or due to treatment. In this regard, when prostate is mentioned, it includes prostate or castration-resistant prostate that is resistant to androgen therapy, particularly abiraterone (abiraterone) or enzalutamide (enzalutamide). Similarly, when multiple myeloma is mentioned, multiple myeloma or refractory multiple myeloma that are insensitive to bortezomib (bortezomib) are included and chronic myeloid leukemia is mentioned, including imatinib (imitanib) insensitive chronic myeloid leukemia and refractory chronic myeloid leukemia. In this regard, reference to mesothelioma includes mesothelioma that is resistant to topoisomerase poisons, alkylating agents, anti-tubulin agents, antifolates, platinum compounds and radiation therapy, in particular cisplatin-resistant mesothelioma.

[1082] The compounds may also be useful in treating tumor growth, pathogenesis, resistance to chemotherapy and radiation therapy by sensitizing cells to chemotherapy and as antimetastatic agents.

[1083] All types of therapeutic anticancer interventions necessarily increase the stress imposed on target tumor cells. MDM2 / p53 inhibitors represent a class of chemotherapeutic agents with the potential to: (i) sensitize malignant cells to anticancer drugs and / or treatments; (ii) alleviate or reduce the incidence of resistance to anticancer drugs and / or treatments; (iii) reverse resistance to anticancer drugs and / or treatments; (iv) enhance the activity of anticancer drugs and / or treatments; (v) delay or prevent the onset of resistance to anticancer drugs and / or treatments.

[1084] In one embodiment, the invention provides a compound for use in treating a disease or condition mediated by MDM2. In another embodiment, the disease or condition mediated by MDM2 is a cancer characterized by overexpression and / or increased activity of MDM2, or high copy number of MDM2 and / or wild-type p53.

[1085] Another aspect provides the use of a compound for the manufacture of a medicament for the treatment of a disease or condition as described herein, particularly cancer.

[1086] In one embodiment, a compound for preventing or treating a disease or condition mediated by MDM2 / p53 is provided. In one embodiment, a compound for inhibiting the interaction between MDM2 protein and p53 is provided.

[1087] In one embodiment, there is provided a pharmaceutical composition comprising an effective amount of at least one compound as defined herein. In another aspect of the invention, there is provided a compound as defined herein.

[1088] In one embodiment, there is provided a method for preventing or treating cancer, said method comprising the step of administering to a mammal a medicament comprising at least one compound as defined.

[1089] Diagnostic Methods

[1090] Prior to administering a compound of formula (I), a patient may be screened to determine whether the disease or condition the patient suffers from or may suffer from is one that would be susceptible to treatment with a compound that inhibits Mdm2 / p53. The term 'patient' includes human and veterinary subjects, such as primates, particularly human patients.

[1091] For example, a biological sample taken from a patient can be analyzed to determine whether the condition or disease, such as cancer, that the patient is suffering from or may be suffering from is a condition or disease characterized by a genetic abnormality or abnormal protein expression that results in upregulated levels of MDM2 or upregulated biochemical pathways downstream of MDM2 / p53.

[1092] Examples of such abnormalities are activation or sensitization of MDM2, loss or inhibition of regulatory pathways affecting MDM2 expression, upregulation of receptors or their ligands, cytogenetic aberrations, or the presence of mutant variants of said receptors or ligands. Tumors with upregulation of MDM2 / p53, particularly overexpression of MDM2 or displaying wild-type p53, may be particularly sensitive to MDM2 / p53 inhibitors. For example, amplification of MDM2 and / or loss of its negative regulators (such as p14ARF) have been identified in a variety of cancers, as discussed in the introduction.

[1093] The term up-regulation includes elevated expression or overexpression, including gene amplification (i.e., multiple gene copies), cytogenetic aberrations, and increased expression caused by transcriptional or post-translational effects. Therefore, the patient can be subjected to diagnostic testing to detect characteristic markers of MDM2 upregulation. The term diagnosis includes screening. By markers, we include genetic markers, including, for example, measuring DNA composition to identify the presence of mutations in p53 or the amplification of MDM2 or the absence (loss) of p14ARF. The term marker also includes markers that are characteristic of MDM2 / p53 upregulation, including protein levels, protein states, and mRNA levels of the above-mentioned proteins. Gene amplification includes the acquisition of greater than 7 copies, and 2 to 7 copies.

[1094] Diagnostic tests and screening are typically performed on a biological sample (i.e., body tissue or fluid) selected from a tumor biopsy sample, a blood sample (isolation and enrichment of exfoliated tumor cells), cerebrospinal fluid, plasma, serum, saliva, stool biopsy, sputum, chromosome analysis, pleural fluid, peritoneal fluid, buccal smear, skin biopsy, or urine.

[1095] Methods for identifying and analyzing cytogenetic aberrations, genetic amplification, mutations, and protein upregulation are known to those skilled in the art. Screening methods may include, but are not limited to, standard methods, such as DNA sequence analysis, reverse transcriptase polymerase chain reaction (RT-PCR), RNA sequencing (RNAseq), nanochain hybridization approaching RNA nCounter assays or in situ hybridization, such as fluorescence in situ hybridization (FISH) or allele-specific polymerase chain reaction (PCR) by conventional Sanger or next generation sequencing methods.

[1096] In screening by RT-PCR, by generating a cDNA copy of mRNA, the level of mRNA in the tumor is assessed by PCR amplification of cDNA. The method of PCR amplification, the selection of primers and the conditions for amplification are known to those skilled in the art. Nucleic acid manipulation and PCR are performed by standard methods, such as Ausubel, FM et al., (2004) "Current Protocols in Molecular Biology", John Wiley & Sons; or Innis, MA et al., (1990) "PCR Protocols: a guide to methods and applications", Academic Press, San Diego. Reactions and operations involving nucleic acid technology are also described in Sambrook et al., (2001), 3rd edition, "Molecular Cloning: A Laboratory Manual", Cold Spring Harbor Laboratory Press. Alternatively, commercially available kits for RT-PCR (e.g., Roche Molecular Biochemicals) or methods such as those described in U.S. Pat. Nos. 4,666,828, 4,683,202, 4,801,531, 5,192,659, 5,272,057, 5,882,864, and 6,218,529 may be used, and the U.S. Pat. Nos. 4,683,202, 4,801,531, 5,192,659, 5,272,057, 5,882,864, and 6,218,529 are incorporated herein by reference. An example of an in situ hybridization technique for assessing mRNA expression would be fluorescence in situ hybridization (FISH) (see Angerer (1987) Meth. Enzymol., 152:649).

[1097] In general, in situ hybridization includes the following major steps: (1) fixing the tissue to be analyzed; (2) subjecting the sample to a pre-hybridization treatment to increase the accessibility of the target nucleic acid and reduce non-specific binding; (3) hybridizing the mixture of nucleic acids to nucleic acids in the biological structure or tissue; (4) washing after hybridization to remove nucleic acid fragments that did not bind during hybridization; and (5) detecting the hybridized nucleic acid fragments. Probes used in such applications are usually labeled, for example, with a radioisotope or a fluorescent reporter gene. Certain probes are long enough to enable specific hybridization with one or more target nucleic acids under stringent conditions, for example, from about 50, 100, or 200 nucleotides to about 1000 or more nucleotides. Standard methods for performing FISH are described in Ausubel, FM et al., eds., (2004) Current Protocols in Molecular Biology, John Wiley & Sons, Inc., and in Fluorescence In Situ Hybridization: Technical Overview, John MS Bartlett, Molecular Diagnosis of Cancer, Methods and Protocols, 2nd ed.; ISBN: 1-59259-760-2; March 2004, pp. 077-088; in the series: Methods in Molecular Medicine.

[1098] Methods for gene expression profiling are described by (DePrimo et al. (2003), BMC Cancer, 3:3). Briefly, the protocol is as follows: (dT)24 oligomers are used to initiate first-strand cDNA synthesis from polyadenylated mRNA, followed by random hexamer primers to synthesize second-strand cDNA from total RNA to synthesize double-stranded cDNA. The double-stranded cDNA is used as a template to perform in vitro transcription of cRNA using biotinylated ribonucleotides. According to the protocol described by Affymetrix (Santa Clara, CA, USA), cRNA is chemically fragmented and then hybridized overnight with gene-specific oligonucleotide probes on human genome arrays. Alternatively, single nucleotide polymorphism (SNP) arrays (a type of DNA microarray) can be used to detect polymorphisms within a population.

[1099] Alternatively, the protein product expressed from the mRNA can be determined by immunohistochemistry of tumor samples, solid phase immunoassays performed with microtiter plates, Western blotting, two-dimensional SDS-polyacrylamide gel electrophoresis, ELISA, flow cytometry, and other methods known in the art for detecting specific proteins, such as capillary electrophoresis. Detection methods will include the use of site-specific antibodies. Those skilled in the art will recognize that in the present case, all such well-known techniques can be used to detect upregulation of MDM2 and p53, detection of variants or mutants of MDM2 or p53, or loss of negative regulators of MDM2.

[1100] Abnormal levels of proteins such as MDM2 or p53 can be measured using standard protein assays, such as those described herein. Protein levels can also be measured by using assays such as those from Chemicon International to detect elevated levels or overexpression in tissue samples, such as tumor tissues. The protein of interest will be immunoprecipitated from the sample lysate and its level measured. Assays also include the use of labels.

[1101] In other words, p53 and MDM2 overexpression can be measured by tumor biopsy.

[1102] Methods used to assess gene copy changes include techniques commonly used in cytogenetic laboratories, such as MLPA (multiplex ligation-dependent probe amplification), multiplex PCR methods that detect abnormal copy number, or other PCR techniques that can detect gene amplification, gain, and deletion.

[1103] Extra-functional assays may also be utilized where appropriate, such as measuring circulating leukemic cells in cancer patients to assess responses to challenge with MDM2 / p53 inhibitors.

[1104] Therefore, all of these techniques can also be used to identify tumors that are particularly suitable for treatment with the compounds of the present invention.

[1105] Thus, in another aspect of the invention, encompassed is the use of a compound according to the invention for the manufacture of a medicament for treating or preventing a disease state or condition in a patient who has been screened and has been identified as having, or being at risk of, a disease or condition that would be susceptible to treatment with an MDM2 / p53 inhibitor.

[1106] Another aspect of the invention includes compounds of the invention for use in preventing or treating cancer in a patient selected from a subpopulation having MDM2 amplification.

[1107] Another aspect of the invention includes compounds of the invention for use in preventing or treating cancer in a patient selected from a subpopulation having wild-type p53.

[1108] Another aspect of the invention includes compounds of the invention for use in preventing or treating cancer in a patient with a loss of a negative regulator of MDM2, such as pl4ARF.

[1109] MRI assays of vascular normalization (eg, using MRI gradient echo, spin echo, and contrast enhancement to measure blood volume, relative vessel size, and vascular permeability) in combination with circulating biomarkers can also be used to identify patients suitable for treatment with the compounds of the invention.

[1110] Accordingly, another aspect of the invention is a method for diagnosing and treating a disease state or condition mediated by MDM2 / p53, the method comprising (i) screening a patient to determine whether the disease or condition from which the patient is suffering or may be suffering is one that would be sensitive to treatment with an MDM2 / p53 inhibitor; and (ii) where the disease or condition from the patient is indicated to be so sensitive, thereafter administering to the patient a compound of formula (I) and subgroups or embodiments thereof as defined herein.

[1111] Advantages of the compounds of the present invention

[1112] The compounds of formula (I) have many advantages over prior art compounds. The compounds of the present invention may have specific advantages in one or more of the following aspects:

[1113] (i) Superior performance;

[1114] (ii) Superior in vivo efficacy;

[1115] (iii) superior PK;

[1116] (iv) Superior metabolic stability;

[1117] (v) excellent oral bioavailability; and

[1118] (vi) Excellent physiological and chemical properties.

[1119] Superior Potency and In Vivo Effectiveness

[1120] The compounds of formula (I) have increased affinity for MDM2, in particular increased cellular potency against cell lines known to be sensitive to MDM2 antagonists.

[1121] Enhanced target engagement is a highly desirable property for a drug compound as it allows for lower doses of the drug and a good separation between MDM2 activity and toxic effects (the 'therapeutic window').

[1122] The compounds of formula (I) have increased cellular potency and / or increased selectivity for wild-type p53 cell lines relative to mutant p53 cell lines. Due to the increased potency against MDM2, the compounds of the present invention may have increased in vivo efficacy in cancer cell lines and in vivo models. In addition, the compounds show selectivity for MDM2 over MDMX, despite the close sequence, structural and functional similarities between these genetic paralogs.

[1123] Superior PK and metabolic stability

[1124] Compounds of formula (I) may have favorable ADMET properties, such as better metabolic stability (e.g., as determined using mouse liver microsomes), better P450 profiles, short half-lives, and / or beneficial clearance rates (e.g., low or high clearance rates). It has also been found that many compounds of formula (I) have improved PK profiles.

[1125] These characteristics can give more drugs in the systemic circulation can be used to reach the appropriate site of action to play its therapeutic advantage. The drug concentration that plays a pharmacological role in tumors increases, potentially improving efficacy, which allows the reduction of the dose to be administered. Therefore, the compound of formula (I) should show a reduced dosage requirement and should be easier to prepare and use.

[1126] This results in a good separation between MDM2 activity and toxic effects ('therapeutic window').Many compounds of formula (I) have a reduction in Cmax required for efficacy (due to better MDM2 potency and / or PK).

[1127] Excellent oral bioavailability

[1128] Potentially, the compounds of the invention have physiochemical properties suitable for oral exposure (oral exposure or AUC). Specifically, the compounds of formula (I) may exhibit increased oral bioavailability or increased reproducibility of oral absorption. Oral bioavailability may be defined as the ratio (F) of the plasma exposure of a compound when administered by the oral route to the plasma exposure of the compound when administered by the intravenous (iv) route, expressed as a percentage.

[1129] Compounds having an oral bioavailability (F value) of greater than 10%, 20% or 30%, more particularly greater than 40%, are particularly advantageous because they can be administered orally rather than, or as well as, parenterally.

[1130] Excellent physiological and chemical properties

[1131] The compounds of formula (I) may have advantageous physiochemical properties, in particular chemical stability under acidic conditions and reduced lipophilicity.

[1132] Lipophilicity can be measured using the partition coefficient (logP) or distribution coefficient (logD). The partition coefficient is the ratio of the concentration of the unionized compound between two immiscible phases (n-octanol and water) under equilibrium, and the distribution coefficient is the ratio of the sum of the concentrations of all forms of the compound (ionized plus unionized) in each of the two phases. High lipophilicity is associated with poor drug-like properties, such as low water solubility, poor pharmacokinetic properties (low oral bioavailability), undesirable drug metabolism, and high indiscriminacy. Compounds with optimal lipophilicity may have a greater chance of success in drug development. However, due to the lipophilic nature of the target involved, it may be challenging to achieve a reduced logP (or calculated logP, clogP) while maintaining an acceptable level of efficacy in inhibiting protein-protein interactions (PPI).

[1133] Pharmaceutical preparations

[1134] While it is possible for the active compound to be administered alone, it will generally be presented as a pharmaceutical composition (eg, formulation).

[1135] Therefore, the present invention also provides pharmaceutical compositions as defined above, and methods for preparing pharmaceutical compositions, said pharmaceutical compositions comprising (e.g., mixed with) at least one compound of formula (I) (and subgroups thereof as defined herein), and one or more pharmaceutically acceptable excipients and optionally other therapeutic or prophylactic agents as described herein.

[1136] One or more pharmaceutically acceptable excipients can be selected from, for example, carriers (for example, solid, liquid or semisolid carriers), adjuvants, diluents, fillers or extenders, granulating agents, coating agents, release control agents, adhesives, disintegrants, lubricants, preservatives, antioxidants, buffers, suspending agents, thickeners, flavoring agents, sweeteners, taste masking agents, stabilizers or any other excipients conventionally used in pharmaceutical compositions. Examples of excipients for various types of pharmaceutical compositions are described in more detail below.

[1137] The term "pharmaceutically acceptable" as used herein relates to compounds, materials, compositions and / or dosage forms that are suitable for use in contact with the tissues of subjects (e.g., human subjects) without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment. Each excipient must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation.

[1138] Pharmaceutical compositions containing compounds of formula (I) can be formulated according to known techniques, see, for example, Remington's Pharmaceutical Sciences (Mack Publishing Company, Easton, PA, USA).

[1139] The pharmaceutical composition can be in any form suitable for oral, parenteral, topical, intranasal, intrabronchial, sublingual, ophthalmic, auricular, rectal, intravaginal, or transdermal administration. Where the compositions are intended for parenteral administration, they can be formulated for intravenous, intramuscular, intraperitoneal, subcutaneous administration or for direct delivery to a target organ or target tissue by injection, infusion or other delivery means. The delivery can be by push, short-term infusion or longer-term infusion and can be delivered via passive delivery or via utilizing a suitable infusion pump or syringe driver.

[1140] Pharmaceutical preparations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions, which may contain antioxidants, buffers, bacteriostats, cosolvents, surfactants, organic solvent mixtures, cyclodextrin complexing agents, emulsifiers (for forming and stabilizing emulsion preparations), liposome components for forming liposomes, gellable polymers for forming polymer gels, lyoprotectants, and combinations of agents, in particular, for stabilizing the active ingredient in soluble form and making the preparation isotonic with the blood of the intended recipient. Pharmaceutical preparations for parenteral administration may also take the form of aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents (RG Strickly, Solubilizing Excipients in Oral and Injectable Formulations, Pharmaceutical Research, Vol. 21(2) 2004, pp. 201-230).

[1141] The formulation can be present in unit dose or multi-dose containers, such as sealed ampoules, vials and pre-filled syringes, and can be stored in freeze-dried (lyophilized) conditions, thereby only requiring the addition of a sterile liquid carrier, such as water for injection, prior to use. In one embodiment, the formulation is provided as an active pharmaceutical ingredient in a bottle for subsequent reconstitution with an appropriate diluent.

[1142] The pharmaceutical formulation can be prepared by lyophilizing the compound of formula (I) or a subgroup thereof. Lyophilization refers to the process of freeze-drying a composition. Freeze-drying and lyophilization are therefore used herein as synonyms.

[1143] Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets.

[1144] The pharmaceutical composition of the present invention for parenteral injection can also include pharmaceutically acceptable sterile aqueous or non-aqueous solution, dispersion, suspension or emulsion, and for recovering into sterile injectable solution or the sterile powder of dispersion before use.The example of suitable aqueous and non-aqueous carrier, diluent, solvent or vehicle includes water, ethanol, polyol (such as glycerol, propylene glycol, Polyethylene Glycol etc.), carboxymethyl cellulose and its suitable mixture, vegetable oil (such as sunflower seed oil, safflower oil, corn oil or olive oil) and injectable organic ester, such as ethyl oleate.Can for example by using thickening material such as lecithin, by maintaining required granularity and by using surfactant to maintain suitable fluidity in the case of dispersion.

[1145] Compositions of the present invention may also contain adjuvants, such as preservatives, wetting agents, emulsifiers, and dispersants. Prevention of microbial action may be ensured by including various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, etc. It may also be desirable to include tonicity agents, such as sugar, sodium chloride, etc. The absorption of injectable drug forms may be extended by including delayed absorption agents such as aluminum monostearate and gelatin.

[1146] In a typical embodiment of the present invention, the pharmaceutical composition is in a form suitable for intravenous administration, such as intravenous administration by injection or infusion. For intravenous administration, the solution can be given as is, or can be injected into an infusion bag (containing a pharmaceutically acceptable excipient, such as 0.9% saline or 5% dextrose) before administration.

[1147] In another exemplary embodiment, the pharmaceutical composition is in a form suitable for subcutaneous (sc) administration.

[1148] Suitable pharmaceutical dosage forms for oral administration include tablets (coated or uncoated), capsules (hard shell or soft shell), caplets, pills, lozenges, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, wafers or patches, such as buccal patches.

[1149] Therefore, tablet compositions can contain a unit dose of active compound and an inert diluent or carrier, such as a sugar or sugar alcohol, such as lactose, sucrose, sorbitol or mannitol; and / or a non-sugar derived diluent, such as sodium carbonate, calcium phosphate, calcium carbonate, or cellulose or its derivatives, such as microcrystalline cellulose (MCC), methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, and starch, such as corn starch. Tablets can also contain standard ingredients such as the following: binders and granulators, such as polyvinyl pyrrolidone; disintegrants (e.g., swellable cross-linked polymers, such as cross-linked carboxymethyl cellulose); lubricants (e.g., stearates); preservatives (e.g., parabens); antioxidants (e.g., BHT); buffers (e.g., phosphate or citrate buffer); and effervescent agents, such as citrate / bicarbonate mixtures. These excipients are well known and do not need to be discussed in detail herein.

[1150] Tablets may be designed to release the drug upon contact with gastric fluid (immediate release tablets) or in a controlled manner over a longer period of time or in a specific area of ​​the gastrointestinal tract (controlled release tablets).

[1151] Capsule formulations may be of hard or soft gelatin variety and may contain the active ingredient in solid, semisolid, or liquid form. Gelatin capsules may be formed from animal gelatin or its synthetic or plant-derived equivalents.

[1152] Solid dosage forms (e.g., tablets, capsules, etc.) may be coated or uncoated. Coatings may serve as protective films (e.g., polymers, waxes, or varnishes) or as mechanisms for controlling drug release or for aesthetic or identification purposes. Coatings (e.g., Eudragit TM Type polymers) can be designed to release the active ingredient at a desired location in the gastrointestinal tract. Thus, the coating can be selected to degrade under certain pH conditions in the gastrointestinal tract, thereby selectively releasing the compound in the stomach or in the ileum, duodenum, jejunum or colon.

[1153] Instead of coating or in addition to coating, the drug can be present in a solid matrix, the solid matrix includes a release control agent, such as a release delay agent, which can be suitable for releasing the compound in a controlled manner in the gastrointestinal tract. Alternatively, the drug can be present in a polymer coating, such as a polymethacrylate polymer coating, which can be suitable for selectively releasing the compound under conditions of acidity or alkalinity that vary in the gastrointestinal tract. Alternatively, the matrix material or the release delay coating can be in the form of an erodible polymer (such as a maleic anhydride polymer), which is substantially continuously eroded when the dosage form passes through the gastrointestinal tract. In another alternative, the coating can be designed to disintegrate under the action of microorganisms in the intestinal tract. As another alternative, the active compound can be formulated in a osmotic controlled delivery system that provides the release of the compound. Osmotic release and other delayed release or sustained release formulations (such as formulations based on ion exchange resins) can be prepared according to methods known to those skilled in the art.

[1154] The compound of formula (I) can be formulated with a carrier and applied in the form of nanoparticles, and the increased surface area of ​​the nanoparticles contributes to their absorption. In addition, nanoparticles provide the possibility of penetrating directly into cells. Nanoparticle drug delivery systems are described in "Nanoparticle Technology for Drug Delivery", compiled by Ram B Gupta and Uday B. Kompella, Informa Healthcare, ISBN9781574448573, published for the 13th time in March 2006. Nanoparticles for drug delivery are also described in J. Control. Release, 2003, 91 (1-2), 167-172; and Sinha et al., Mol. Cancer Ther. August 1, (2006) 5, 1909.

[1155] The pharmaceutical composition generally comprises about 1% (w / w) to about 95% active ingredient and 99% (w / w) to 5% (w / w) of a pharmaceutically acceptable excipient or a combination of excipients. Generally, the composition comprises about 20% (w / w) to about 90% (w / w) of an active ingredient and 80% (w / w) to 10% of a pharmaceutically acceptable excipient or a combination of excipients. The pharmaceutical composition comprises about 1% to about 95%, generally about 20% to about 90% of an active ingredient. The pharmaceutical composition according to the present invention can, for example, be in the form of a unit dosage form, such as in the form of an ampoule, a vial, a suppository, a prefilled syringe, a dragee, a tablet or a capsule.

[1156] One or more pharmaceutically acceptable excipients may be selected according to the desired physical form of the formulation and may, for example, be selected from diluents (e.g. solid diluents, such as fillers or extenders; and liquid diluents, such as solvents and co-solvents), disintegrants, buffers, lubricants, glidants, release controlling agents (e.g. release retarding or delaying polymers or waxes), binders, granulating agents, pigments, plasticizers, antioxidants, preservatives, flavoring agents, taste masking agents, tonicity adjusting agents, and coating agents.

[1157] Those skilled in the art will have the expertise to select the appropriate amount of ingredients for use in the formulation. For example, tablets and capsules typically contain 0%-20% disintegrants, 0%-5% lubricants, 0%-5% glidants, and / or 0%-99% (w / w) fillers / or extenders (depending on the drug dose). They may also contain 0%-10% (w / w) polymer binders, 0%-5% (w / w) antioxidants, 0%-5% (w / w) pigments. Slow-release tablets will additionally contain 0%-99% (w / w) polymers (depending on the dose). The film coating of a tablet or capsule typically contains 0%-10% (w / w) release-controlling (e.g., delayed) polymers, 0%-3% (w / w) pigments, and / or 0%-2% (w / w) plasticizers.

[1158] Parenteral formulations typically contain 0%-20% (w / w) buffer, 0%-50% (w / w) cosolvent, and / or 0%-99% (w / w) water for injection (WFI) (depending on the dose and whether it is lyophilized). Formulations for intramuscular depots may also contain 0%-99% (w / w) oil.

[1159] Pharmaceutical compositions for oral administration can be obtained by combining the active ingredient with a solid carrier, granulating the resulting mixture if desired, and processing the mixture into tablets, dragee cores or capsules after adding suitable excipients if desired or necessary. It is also possible to incorporate them into a polymer or wax matrix that allows the active ingredient to diffuse or release in measured amounts.

[1160] The compounds of the present invention can also be formulated into solid dispersions. Solid dispersions are uniform, extremely fine dispersed phases of two or more solids. Solid solutions (molecular dispersions) are a type of solid dispersions that are well known for use in pharmaceutical technology (see Chiou and Riegelman, J. Pharm. Sci., 60, 1281-1300 (1971)) and can be used to increase the dissolution rate of poorly water-soluble drugs and to increase the bioavailability of the drug.

[1161] The present invention also provides solid dosage forms comprising the solid solutions described herein. Solid dosage forms include tablets, capsules, chewable tablets, and dispersible or effervescent tablets. Known excipients can be blended with the solid solution to provide the desired dosage form. For example, a capsule can contain a solid solution blended with the following: (a) a disintegrant and a lubricant; or (b) a disintegrant, a lubricant, and a surfactant. In addition, a capsule can contain an extender, such as lactose or microcrystalline cellulose. Tablets can contain a solid solution blended with at least one disintegrant, a lubricant, a surfactant, an extender, and a glidant. Chewable tablets can contain a solid solution blended with an extender, a lubricant, and, if necessary, additional sweeteners (such as artificial sweeteners), and suitable flavorings. The solid solution can also be formed by spraying a solution of a drug and a suitable polymer onto an inert carrier, such as a sugar bead ('sugar pill') on the surface. These beads can then be filled into capsules or pressed into tablets.

[1162] The drug formulation may be presented to the patient in a "patient pack" which contains an entire course of treatment in a single package, typically a blister pack. Patient packs have an advantage over traditional prescriptions in which a pharmacist dispenses a patient's supply of medication from a bulk supply because the patient always has access to a package insert contained in the patient pack, which is typically absent from a patient prescription. The inclusion of a package insert has been shown to increase patient compliance with a physician's instructions.

[1163] Compositions for topical use and nasal delivery include ointments, creams, sprays, patches, gels, liquid drops, and inserts (eg, intraocular inserts).Such compositions can be formulated according to known methods.

[1164] Examples of formulations for rectal or intravaginal administration include pessaries and suppositories, which may be formed, for example, from shaped moldable or waxy materials containing the active compound. Solutions of the active compound may also be used for rectal administration.

[1165] Compositions for administration by inhalation may take the form of inhalable powder compositions or liquid or powder sprays and may be administered in standard form using a powder inhaler device or an aerosol dispensing device. Such devices are well known. For administration by inhalation, powder formulations typically comprise the active compound and an inert solid powdered diluent, such as lactose.

[1166] The compound of formula (I) will generally be present in a unit dosage form and thus, will generally contain enough compound to provide the desired level of biological activity. For example, the formulation may contain 1 nanogram to 2 grams of active ingredient, such as 1 nanogram to 2 milligrams of active ingredient. Within these ranges, a specific subrange of the compound is 0.1 milligram to 2 grams of active ingredient (more typically 10 milligrams to 1 gram, such as 50 milligrams to 500 milligrams), or 1 microgram to 20 milligrams (e.g. 1 microgram to 10 milligrams, such as 0.1 milligram to 2 milligrams of active ingredient).

[1167] For oral compositions, unit dosage forms may contain 1 mg to 2 g, more usually 10 mg to 1 g, for example 50 mg to 1 g, for example 100 mg to 1 g, of active compound.

[1168] The active compound will be administered to a patient in need thereof (eg, a human or animal patient) in an amount sufficient to achieve the desired therapeutic effect.

[1169] Treatment

[1170] The compounds of formula (I) and subgroups as defined herein may be useful in the prevention or treatment of a variety of disease states or conditions mediated by MDM2 / p53. Examples of such disease states and conditions are set forth above.

[1171] The compounds are generally administered to a subject in need of such administration, such as a human or animal patient, typically a human.

[1172] The compound will generally be administered in an amount that is therapeutically or prophylactically useful and generally non-toxic. However, in certain circumstances (e.g., in the case of life-threatening diseases), the benefits of administering a compound of formula (I) may outweigh the disadvantages of any toxic effects or side effects, in which case it may be considered desirable to administer the compound in an amount that is relevant to the degree of toxicity.

[1173] The compounds may be administered chronically to maintain a beneficial therapeutic effect or may be administered for only a short period of time. Alternatively, they may be administered continuously or in a manner providing intermittent administration (eg, pulsed).

[1174] A typical daily dose of a compound of formula (I) may be in the range of 100 picograms to 100 milligrams per kilogram of body weight, more typically 5 nanograms to 25 milligrams per kilogram of body weight, and more typically 10 nanograms to 15 milligrams per kilogram of body weight (e.g. 10 nanograms to 10 milligrams, and more typically 1 microgram to 20 milligrams per kilogram of body weight, e.g. 1 microgram to 10 milligrams per kilogram of body weight), although higher or lower doses may be administered where desired. A compound of formula (I) may be administered daily or, for example, repeated administration every 2 days, or 3 days, or 4 days, or 5 days, or 6 days, or 7 days, or 10 days, or 14 days, or 21 days, or 28 days.

[1175] Dosage can also be expressed as the amount of drug administered relative to the patient's body surface area (mg / m 2 A typical daily dose of a compound of formula (I) may be in the range of: 3700 pg / m 2 Up to 3700 mg / m 2 , more usually 185ng / m 2 Up to 925 mg / m 2 , and more typically 370 ng / m 2 Up to 555 mg / m 2 (e.g. 370ng / m 2 Up to 370 mg / m 2 , and more usually 37 mg / m 2 Up to 740 mg / m 2 , for example 37 mg / m 2 Up to 370 mg / m 2 ), although higher or lower doses may be used where necessary. The compound of formula (I) may be administered daily or, for example, repeated every 2 days, or 3 days, or 4 days, or 5 days, or 6 days, or 7 days, or 10 days, or 14 days, or 21 days, or 28 days.

[1176] The compound of the present invention can be orally administered in a certain dosage range, for example, 0.1 mg to 5000 mg, or 1 mg to 1500 mg, 2 mg to 800 mg, or 5 mg to 500 mg, for example, 2 mg to 200 mg or 10 mg to 1000 mg, and the specific examples of dosage include 10 mg, 20 mg, 50 mg and 80 mg. The compound can be administered once a day or more than once. The compound can be administered continuously (i.e., taken every day without interruption during the duration of the treatment regimen). Alternatively, the compound can be administered intermittently (i.e., taken continuously for a given period of time, such as one week, then stopped for a period of time, such as one week, and then taken continuously for a period of time, such as one week, etc.). Examples of treatment regimens involving intermittent administration include regimens in which the following cycles are administered: take one week, rest one week; or take two weeks, rest one week; or take three weeks, rest one week; or take two weeks, rest two weeks; or take four weeks, rest two weeks; or take one week, rest three weeks, for one or more cycles, such as 2, 3, 4, 5, 6, 7, 8, 9 or 10 or more cycles. The discontinuous treatment can also be based on days, rather than full weeks. For example, the treatment can include daily administration for 1 to 6 days, no administration for 1 to 6 days, and repeating the pattern during the treatment regimen. The number of days (or weeks) in which the compound of the present invention is not administered does not necessarily have to be equal to the number of days (or weeks) in which the compound of the present invention is administered.

[1177] In one embodiment, the compounds of the invention may be administered at 3 mg / m per day. 2 Up to 125 mg / m 2 The amount of the drug is administered. Treatment may be by continuous daily dosing, or more usually by multiple cycles of treatment separated by treatment breaks. An example of a single treatment cycle is 5 consecutive daily doses followed by 3 weeks of no treatment.

[1178] A specific dosing regimen is once a day (e.g., oral) for a week (e.g., 5 days of treatment), followed by a 1-week, 2-week, or 3-week treatment break. An alternative dosing regimen is once a week (e.g., oral) for 1, 2, 3, or 4 weeks.

[1179] In a particular dosing regimen, the patient will be given a 1 hour daily infusion of a compound of formula (I) for up to ten days, particularly up to five days a week, with the treatment repeated at desired intervals, such as two to four weeks, particularly every three weeks.

[1180] More specifically, patients may be given an infusion of a compound of formula (I) over a period of 1 hour per day for 5 days with the treatment repeated every three weeks.

[1181] In another specific dosing regimen, patients are given an infusion over 30 minutes to 1 hour, followed by a maintenance infusion of variable duration, such as 1 hour to 5 hours, such as 3 hours.

[1182] The compounds of the present invention can also be administered by push injection or continuous infusion. The compounds of the present invention can be administered once a day to once a week, or once every two weeks, or once every three weeks, or once every four weeks during the treatment cycle. If administered daily during the treatment cycle, the daily administration can be discontinuous in the weeks of the treatment cycle: for example, administration for one week (or several days), no administration for one week (or several days), and the pattern is repeated during the treatment cycle.

[1183] In another specific dosing regimen, the patient is given a continuous infusion for a period of 12 hours to 5 days, particularly a 24 hour to 72 hour continuous infusion.

[1184] Ultimately, however, the amount of compound administered and the type of composition used will be commensurate with the nature of the disease or physiological condition being treated and will be at the discretion of the physician.

[1185] It may be beneficial to use the compounds of the invention as single agents or in combination with additional agents that act via different mechanisms to regulate cell growth to treat two of the characteristic features of cancer development. Combination experiments can be performed, for example, as described in Chou TC, Talalay P., "Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors", Adv Enzyme Regulat 1984; 22: 27-55.

[1186] The compounds as defined herein may be administered as the sole therapeutic agent or they may be administered in combination therapy with one or more other compounds (or treatments) to treat a particular disease state, such as a neoplastic disease, such as cancer as defined above. For the treatment of the above conditions, the compounds of the invention may advantageously be used in combination with one or more other agents, more specifically, in combination with other anticancer agents or adjuvants (auxiliary agents in treatment) for use in cancer treatment. Examples of other therapeutic agents or treatments that may be administered (either simultaneously or at different time intervals) with the compounds of formula (I) include, but are not limited to:

[1187] Topoisomerase I inhibitors

[1188] Antimetabolites

[1189] Tubulin targeting agents

[1190] DNA binding agents and topoisomerase II inhibitors

[1191] Alkylating agent

[1192] Monoclonal antibodies

[1193] Antihormonal agents

[1194] Signal transduction inhibitors

[1195] Proteasome inhibitors

[1196] DNA methyltransferase inhibitors

[1197] Cytokines and retinoids

[1198] Chromatin-targeted therapy

[1199] Radiation therapy, and

[1200] Other therapeutic or prophylactic agents.

[1201] Specific examples of the anticancer agent or adjuvant (or its salt) include, but are not limited to, any one of the agents selected from the following groups (i) to (xlviii) and optionally group (xlix):

[1202] (i) platinum compounds, such as cisplatin (optionally in combination with amifostine), carboplatin or oxaliplatin;

[1203] (ii) Taxane compounds, such as paclitaxel, paclitaxel protein-bound particles (Abraxane TM ), docetaxel, cabazitaxel, or larotaxel;

[1204] (iii) topoisomerase I inhibitors, such as camptothecin compounds, for example, camptothecin, irinotecan (CPT11), SN-38, or topotecan;

[1205] (iv) topoisomerase II inhibitors, such as antitumor epipodophyllotoxin or podophyllotoxin derivatives, such as etoposide or teniposide;

[1206] (v) vinca alkaloids, for example vinblastine, vincristine, Onco-TCS, vinorelbine, vindesine, vinflunine or vinvesir;

[1207] (vi) nucleoside derivatives, for example 5-fluorouracil (5-FU, optionally in combination with leucovorin), gemcitabine, capecitabine, tegafur, UFT, S1, cladribine, cytarabine (Ara-C, cytosine arabinoside), fludarabine, clofarabine, or nelarabine;

[1208] (vii) antimetabolites, such as clofarabine, aminopterin, or methotrexate, azacitidine, cytarabine, floxuridine, pentostatin, thioguanine, thiopurine, 6-mercaptopurine, or hydroxyurea;

[1209] (viii) Alkylating agents such as nitrogen mustards or nitrosoureas, for example cyclophosphamide, chlorambucil, carmustine (BCNU), bendamustine, thiotepa, melphalan, treosulfan, lomustine (CCNU), altretamine, busulfan, dacarbazine, azine, estramustine, fotemustine, ifosfamide (optionally in combination with mesna), pipobroman, procarbazine, streptozocin, temozolomide, uracil, mechlorethamine, methylcyclohexylchloroethylnitrosourea, or nimustine (ACNU);

[1210] (ix) anthracyclines, anthracenediones and related drugs, such as daunorubicin, doxorubicin (optionally in combination with dexrazoxane), liposomal formulations of doxorubicin (e.g. Caelyx TM 、Myocet TM , Doxil TM ), idarubicin, mitoxantrone, epirubicin, amsacrine, or valrubicin;

[1211] (x) an epothilone, such as ixabepilone, patupilone, BMS-310705, KOS-862 and ZK-EPO, epothilone A, epothilone B, deoxyepothilone B (also known as epothilone D or KOS-862), azaepothilone B (also known as BMS-247550), aulimalide, isolaulimalide, or luetherobin;

[1212] (xi) DNA methyltransferase inhibitors, for example temozolomide, azacytidine or decitabine;

[1213] (xii) antifolates, such as methotrexate, pemetrexed disodium, or raltitrexed;

[1214] (xiii) cytotoxic antibiotics, for example, antinomycin D, bleomycin, mitomycin C, dactinomycin, carminomycin, daunomycin, levamisole, plicamycin, or mithramycin;

[1215] (xiv) tubulin binding agents, such as combrestatin, colchicine or nocodazole;

[1216] (xv) signal transduction inhibitors, such as kinase inhibitors, for example receptor tyrosine kinase inhibitors (e.g. EGFR (epidermal growth factor receptor) inhibitors, VEGFR (vascular endothelial growth factor receptor) inhibitors, PDGFR (platelet-derived growth factor receptor) inhibitors, Axl inhibitors, MTKI (multi-targeted kinase inhibitors), Raf inhibitors, ROCK inhibitors, mTOR inhibitors, MEK inhibitors or PI3K inhibitors), for example imatinib mesylate, erlotinib, gefitinib, dapoxetine Dasatinib, lapatinib, dovotinib, axitinib, nilotinib, vandetanib, vatalinib, pazopanib, sorafenib, sunitinib, temsirolimus, everolimus (RAD 001), vemurafenib (PLX4032 or RG7204), dabrafenib, encorafenib, selumetinib (AZD6244), trametinib (GSK121120212), dactolisib (BEZ235), buparlisib (BKM-120; NVP-BKM-120), BYL7 19. copanlisib (BAY-80-6946), ZSTK-474, CUDC-907, apitolisib (GDC-0980; RG-7422), pictilisib (pictrelisib, GDC-0941, RG-7321), GDC-0032, GDC-0068, GSK-2636771, idelalisib (formerly known as CAL-101, GS 1101, GS-1101), MLN1117 (INK1117), MLN0128 (INK128), IPI-145 (INK1197), LY-3023414, ipatasertib, afuresertib, MK-2206, MK-8156, LY-3023414, LY294002, SF1126 or PI-103, sonolisib (PX-866), or AT13148;

[1217] (xvi) Aurora kinase inhibitors, such as AT9283, barasertib (AZD1152), TAK-901, MK0457 (VX680), cenisertib (R-763), danusertib (PHA-739358), alisertib (MLN-8237), or MP-470;

[1218] (xvii) CDK inhibitors, such as AT7519, roscovitine, seliciclib, avocidib (flavopiridol), dinaciclib (SCH-727965), 7-hydroxy-staurosporine (UCN-01), JNJ-7706621, BMS-387032 (also known as SNS-032), PHA533533, ZK-304709, or AZD-5438 and including CDK4 inhibitors, such as palbociclib (PD332991) and ribociclib (LEE-011);

[1219] (xviii) PKA / B inhibitors and PKB (akt) pathway inhibitors, such as AT13148, AZ-5363, Semaphore, SF1126, and MTOR inhibitors, such as rapamycin analogs, AP23841 and AP23573, calmodulin inhibitors (forkhead translocation inhibitors), API-2 / TCN (triciribine), RX-0201, enzastaurin HCl (LY317615), NL-71-101, SR-13668, PX-316, or KRX-0401 (perifosine / NSC 639966);

[1220] (xix) Hsp90 inhibitors, such as onalespib (AT13387), herbimycin, geldanamycin (GA), 17-allylamino-17-demethoxygeldanamycin (17-AAG), such as NSC-330507, Kos-953, and CNF-1010, 17-dimethylaminoethylamino-17-demethoxygeldanamycin hydrochloride (17-DMAG), such as NSC-707545 and Kos-1022, NVP-AUY922 (VER-52296), NVP-BEP800, CNF-2024 (BIIB-021, an oral purine), ganetespib (STA-9090), SNX-5422 (SC-102112), or IPI-504;

[1221] (xx) monoclonal antibodies (unconjugated or conjugated with radioisotopes, toxins or other agents), antibody derivatives and related agents, such as anti-CD antibodies, anti-VEGFR antibodies, anti-HER2 antibodies or anti-EGFR antibodies, for example, rituximab (CD20), ofatumumab (CD20), ibritumomabtiuxetan (CD20), GA101 (CD20), tositumomab (CD20), epratuzumab (CD22), lintuzumab (CD33), gemtuzumab ozogamicin (CD34), and rituximab (CD20). ozogamicin (CD33), alemtuzumab (CD52), galiximab (CD80), trastuzumab (HER2 antibody), pertuzumab (HER2), trastuzumab-DM1 (HER2), ertumaxomab (HER2 and CD3), cetuximab (EGFR), panitumumab (EGFR), necitumumab (EGFR), umab)(EGFR), nimotuzumab(EGFR), bevacizumab(VEGF), catumaxumab(EpCAM and CD3), abagovomab(CA125), farletuzumab(folate receptor), elotuzumab(CS1), denosumab(RANK ligand), figitumumab(IGF1R), CP751,871 (IGF1R), mapatumumab (TRAIL receptor), metMAB (met), mitumomab (GD3 ganglioside), naptumomab ( estafenatox (5T4), or siltuximab (IL6), or immunomodulators, such as CTLA-4 blocking antibodies and / or antibodies against PD-1 and PD-L1 and / or PD-L2, for example, ipilimumab (CTLA4), MK-3475 (pembrolizumab, formerly lambrolizumab, anti-PD-1), nivolumab (anti-PD-1), BMS-936559 (anti-PD-L1), MPDL320A, AMP-514 or MEDI4736 (anti-PD-L1), or tremelimumab (formerly ticilimumab, CP-675,206, anti-CTLA-4);

[1222] (xxi) estrogen receptor antagonists or selective estrogen receptor modulators (SERMs) or estrogen synthesis inhibitors, such as tamoxifen, fulvestrant, toremifene, droloxifene, faslodex, or raloxifene;

[1223] (xxii) aromatase inhibitors and related drugs, such as exemestane, anastrozole, letrazole, testolactone, aminoglutethimide, mitotane or vorozole;

[1224] (xxiii) anti-androgens (i.e., androgen receptor antagonists) and related agents, such as bicalutamide, nilutamide, flutamide, cyproterone, or ketoconazole;

[1225] (xxiv) hormones and their analogues, such as medroxyprogesterone, diethylstilbestrol (also known as diethylstilbestrol), or octreotide;

[1226] (xxv) steroids, for example dromostanolone propionate, megestrol acetate, nandrolone (decanoate, phenylpropionate), fluoxymestrone or gossypol;

[1227] (xxvi) steroidal cytochrome P450 17α-hydroxylase-17,20-lyase inhibitors (CYP17), such as abiraterone;

[1228] (xxvii) gonadotropin-releasing hormone agonists or antagonists (GnRA), such as abarelix, goserelin acetate, histrelin acetate, leuprolide acetate, triptorelin, buserelin, or deslorelin;

[1229] (xxviii) glucocorticoids, such as prednisone, prednisolone, dexamethasone;

[1230] (xxix) Differentiating agents such as retinoids, retinoids, vitamin D or retinoic acid and retinoic acid metabolism blockers (RAMBAs), for example, accutane, alitretinoin, bexarotene, or tretinoin;

[1231] (xxx) Farnesyl transferase inhibitors, such as tipifarnib;

[1232] (xxxi) Chromatin-targeted therapies, such as histone deacetylase (HDAC) inhibitors, for example sodium butyrate, suberoylanilide hydroxamic acid (SAHA), depsipeptide (FR 901228), dacinostat (NVP-LAQ824), R306465 / JNJ-16241199, JNJ-26481585, trichostatin A, vorinostat, chlamydocin, A-173, JNJ-MGCD-0103, PXD-101, or apicidin;

[1233] (xxxii) drugs targeting the ubiquitin-proteasome pathway, including proteasome inhibitors such as bortezomib, carfilzomib, CEP-18770, MLN-9708, or ONX-0912; NEDD8 inhibitors; HDM2 antagonists and deubiquitinating enzymes (DUBs);

[1234] (xxxiii) photodynamic drugs, such as porfimer sodium or temoporfin;

[1235] (xxxiv) Anticancer agents derived from marine organisms, such as trabectidin;

[1236] (xxxv) radiolabelled drugs for use in radioimmunotherapy, for example with isotopes emitting beta particles (e.g. iodine-131, yttrium-90) or alpha particles (e.g. bismuth-213 or actinium-225), for example ibritumomab or iodotositumomab or alpha radium-223;

[1237] (xxxvi) telomerase inhibitors, for example telomestatin;

[1238] (xxxvii) Matrix metalloproteinase inhibitors, for example batimastat, marimastat, prinostat or metastat;

[1239] (xxxviii) recombinant interferons (such as interferon-γ and interferon α) and interleukins (such as interleukin 2), such as aldesleukin, denileukin diftitox, interferon α2a, interferon α2b, or pegylated interferon α2b;

[1240] (xxxix) Selective immune response modifiers, such as thalidomide or lenalidomide;

[1241] (xl) Therapeutic vaccines, such as sipuleucel-T (Provenge) or OncoVex;

[1242] (xli) Cytokine activators, including Picibanil, Romurtide, Sizofiran, Virulizin, or Thymosin;

[1243] (xlii) arsenic trioxide;

[1244] (xliii) G protein-coupled receptor (GPCR) inhibitors, such as atrasentan;

[1245] (xliv) enzymes, such as L-asparaginase, pegaspargase, rasburicase, or pegademase;

[1246] (xlv) DNA repair inhibitors, such as PARP inhibitors, for example olaparib, velaparib, iniparib, INO-1001, AG-014699, or ONO-2231;

[1247] (xlvi) death receptor (e.g., TNF-related apoptosis-inducing ligand (TRAIL) receptor) agonists, such as mapatumumab (formerly known as HGS-ETR1), conatumumab (formerly known as AMG 655), PRO95780, lexatumumab, dulanermin, CS-1008, apomab, or recombinant TRAIL ligands, such as recombinant human TRAIL / Apo2 ligand;

[1248] (xlvii) Immunotherapy, such as immune checkpoint inhibitors; cancer vaccines and CAR-T cell therapy;

[1249] (xlviii) modulators of cell death (apoptosis), including Bcl-2 (B-cell lymphoma 2) antagonists, such as venetoclax (ABT-199 or GDC-0199), ABT-737, ABT-263, TW-37, sabutoclax, obatoclax, and MIM1 and IAP antagonists, including LCL-161 (Novartis), Debio-1143 (Debiopharma / Ascenta), AZD5582, Birinapant / TL-32711 (TetraLogic), CUDC-427 / GDC-0917 / RG-7459 (Genentech), JP1201 (Joyant), T-3256336 (Takeda), GDC-0152 (Genentech), or HGS-1029 / AEG-40826 (HGS / Aegera);

[1250] (xlix) Prophylactic (adjuvant) agents; i.e., agents that reduce or alleviate some of the side effects associated with chemotherapeutic agents, e.g.

[1251] - Antiemetics;

[1252] - Agents that prevent chemotherapy-related neutropenia or shorten the duration of chemotherapy-related neutropenia and prevent complications caused by decreased levels of platelets, red blood cells or white blood cells, such as interleukin-11 (e.g., oprelvekin), erythropoietin (EPO) and its analogs (e.g., darbepoetin alfa), colony stimulating factor analogs, such as granulocyte macrophage colony stimulating factor (GM-CSF) (e.g., sargramostim), and granulocyte colony stimulating factor (G-CSF) and its analogs (e.g., filgrastim, pegfilgrastim);

[1253] - agents that inhibit bone resorption, such as denosumab or bisphosphonates, for example zoledronate, zoledronic acid, pamidronate and ibandronate;

[1254] -Agents that suppress inflammation, such as dexamethasone, prednisone, and prednisolone;

[1255] - Agents used to reduce blood levels of growth hormone and IGF-I (and other hormones) in patients with acromegaly or other rare hormone-producing tumors, such as synthetic forms of the hormone somatostatin, for example octreotide acetate;

[1256] -Antidotes for drugs that lower folate levels, such as leucovorin or folinic acid;

[1257] - Medications for pain, for example, opiates such as morphine, diamorphine and fentanyl;

[1258] - nonsteroidal anti-inflammatory drugs (NSAIDs), such as COX-2 inhibitors, for example celecoxib, etoricoxib and lumiracoxib;

[1259] -Agents used for mucositis, such as palifermin;

[1260] -Agents used to treat side effects including anorexia, cachexia, edema, or thromboembolic events, such as megestrol acetate.

[1261] Each of the compounds present in the combination of the present invention can be given according to a dosage regimen that varies independently and via different routes. Thus, the posology of each of the two or more medicaments may be different: each can be administered simultaneously or at different times. Those skilled in the art will know the dosage regimen and the combined therapy to be used via his or her common sense. For example, the compound of the present invention can be used in combination with one or more other medicaments, and the one or more other medicaments are administered according to their existing combination regimens. Examples of standard combination regimens are provided below.

[1262] The taxane compound is advantageously administered at a dose of 50 mg to 400 mg per square meter of body surface area (mg / m 2 ) dose, for example, 75 mg / m per course of treatment 2 Up to 250 mg / m 2 , especially for paclitaxel, at about 175 mg / m per course of treatment 2 Up to 250 mg / m 2 Doses of docetaxel are about 75 mg / m per course of treatment. 2 Up to 150 mg / m 2 dosage.

[1263] Camptothecin compounds are advantageously administered at a dosage of 0.1 mg to 400 mg per square meter of body surface area per treatment course.2 ) is administered at a dose of, for example, 1 mg / m per course of treatment 2 Up to 300 mg / m 2 , especially for irinotecan, at about 100 mg / m per course of treatment 2 Up to 350 mg / m 2 For topotecan, approximately 1 mg / m 2 Up to 2 mg / m 2 dosage.

[1264] The antitumor podophyllotoxin derivative is advantageously administered at a dose of 30 mg to 300 mg per square meter of body surface area (mg / m 2 ) dose, for example, 50 mg / m per course of treatment 2 Up to 250 mg / m 2 , especially for etoposide, at about 35 mg / m per course of treatment 2 Up to 100 mg / m 2 The dose of teniposide is about 50 mg / m per course of treatment. 2 Up to 250 mg / m 2 dosage.

[1265] The antitumor vinca alkaloids are advantageously administered at a dose of 2 mg to 30 mg per square meter of body surface area (mg / m 2 ) dose, especially for vinblastine, about 3 mg / m per course of treatment 2 Up to 12 mg / m 2 The dose of vincristine is about 1 mg / m per course of treatment. 2 Up to 2 mg / m 2 The dose of vinorelbine is about 10 mg / m per course of treatment. 2 Up to 30 mg / m 2 dosage.

[1266] The antitumor nucleoside derivative is advantageously administered at a dosage of 200 mg to 2500 mg per square meter of body surface area (mg / m 2 ) dose, for example, 700 mg / m per course of treatment 2 Up to 1500 mg / m 2 , especially for 5-FU, 200 mg / m per course of treatment 2 Up to 500 mg / m 2 For gemcitabine, the dose is about 800 mg / m 2 Up to 1200 mg / m 2 For capecitabine, approximately 1000 mg / m 2 Up to 2500 mg / m 2dosage.

[1267] Alkylating agents such as nitrogen mustard or nitrosourea are advantageously administered at a dose of 100 to 500 mg per square meter of body surface area (mg / m 2 ) is administered at a dose of, for example, 120 mg / m per course of treatment 2 Up to 200 mg / m 2 , especially for cyclophosphamide, about 100 mg / m per course of treatment 2 Up to 500 mg / m 2 The dosage is about 0.1 mg / kg to 0.2 mg / kg per course of treatment for chlorambucil and about 150 mg / m per course of treatment for carmustine. 2 Up to 200 mg / m 2 For lomustine, approximately 100 mg / m 2 Up to 150 mg / m 2 dosage.

[1268] The antitumor anthracycline derivative is advantageously administered at a dose of 10 mg to 75 mg per square meter of body surface area (mg / m 2 ) dose, for example, 15 mg / m per course of treatment 2 Up to 60 mg / m 2 , especially for doxorubicin, at about 40 mg / m per course of treatment 2 Up to 75 mg / m 2 For daunorubicin, the dosage is about 25 mg / m per course of treatment. 2 Up to 45 mg / m 2 The dose of idarubicin is about 10 mg / m per course of treatment. 2 Up to 15 mg / m 2 dosage.

[1269] Antiestrogens are advantageously administered at a dosage of about 1 mg to 100 mg per day, depending on the specific medicament and the condition being treated. Tamoxifen is advantageously administered orally twice a day at a dosage of 5 mg to 50 mg (typically 10 mg to 20 mg), and sustained treatment is sufficient time to achieve and maintain therapeutic effects. Toremifene is advantageously administered orally once a day at a dosage of about 60 mg, and sustained treatment is sufficient time to achieve and maintain therapeutic effects. Anastrozole is advantageously administered orally once a day at a dosage of about 1 mg. Droloxifene is advantageously administered orally once a day at a dosage of about 20 mg-100 mg. Raloxifene is advantageously administered orally once a day at a dosage of about 60 mg. Exemestane is advantageously administered orally once a day at a dosage of about 25 mg.

[1270] The antibody is advantageously administered at a dose of about 1 mg to 5 mg per square meter of body surface area (mg / m2 ) or as known in the art (if different). Trastuzumab is advantageously administered at a dose of 1 mg to 5 mg per square meter of body surface area (mg / m 2 ), especially 2 mg / m 2 Up to 4 mg / m 2 dosage administration.

[1271] In the case where the compound of formula (I) is used together with one, two, three, four or more other therapeutic agents (usually one or two, more generally one) in a combined therapy, the compound can be used simultaneously or sequentially. In the latter case, the two or more compounds will be used within a period of time and in a certain amount and manner, and the time and amount and manner are sufficient to ensure that a favorable effect or synergistic effect is achieved. When used sequentially, they can be used at closely spaced time intervals (for example, within the time of 5 minutes-10 minutes) or with longer time intervals (for example, separated by 1 hour, 2 hours, 3 hours, 4 hours or longer time or even separated by longer time when necessary), and the precise dosage regimen is commensurate with the characteristics of one or more therapeutic agents. These dosages can be used for example once, twice or more times per course of treatment, and this can be repeated once for example every 7 days, 14 days, 21 days or 28 days.

[1272] It should be understood that the typical method and order of administration of each component of the combination and the corresponding dosage and regimen will depend on the specific other agents and compounds of the invention being administered, their routes of administration, the specific tumor being treated, and the specific host being treated. The optimal method and order of administration and dosage and regimen can be easily determined by those skilled in the art using conventional methods and in light of the information described herein.

[1273] The weight ratio of the compound according to the present invention and one or more other anticancer agents when given as a combination can be determined by those skilled in the art. The ratio and exact dosage and frequency of application depend on the specific compound according to the present invention and one or more other anticancer agents used, the specific condition treated, the severity of the condition treated, the age, body weight, sex, diet, application time and general physical condition of the specific patient, the mode of application and other drugs that the individual may be taking, as known to those skilled in the art. In addition, it is obvious that the effective daily amount can be reduced or increased, depending on the reaction of the subject treated and / or depending on the evaluation of the physician who prescribes the compound of the present invention. The specific weight ratio of the compound of formula (I) of the present invention and other anticancer agents can be in the range of 1 / 10 to 10 / 1, more particularly 1 / 5 to 5 / 1, and even more particularly 1 / 3 to 3 / 1.

[1274] The compounds of the present invention may also be administered in combination with non-chemotherapeutic treatments, such as radiotherapy, photodynamic therapy, gene therapy; surgery and controlled diet. Radiotherapy may be used to achieve radical, palliative, adjuvant, neoadjuvant or preventive purposes.

[1275] The compounds of the present invention also have therapeutic applications for sensitizing tumor cells to radiotherapy and chemotherapy. Therefore, the compounds of the present invention can be used as "radiosensitizers" and / or "chemosensitizers" or can be given in combination with other "radiosensitizers" and / or "chemosensitizers". In one embodiment, the compounds of the present invention are used as chemosensitizers.

[1276] The term "radiosensitizer" is defined as a molecule that is administered to a patient in a therapeutically effective amount to increase the sensitivity of cells to ionizing radiation and / or to facilitate the treatment of a disease that is treatable with ionizing radiation.

[1277] The term "chemosensitizer" is defined as a molecule that is administered to a patient in a therapeutically effective amount to increase the sensitivity of cells to chemotherapy and / or to promote the treatment of a disease that is treatable with a chemotherapeutic agent.

[1278] Many cancer treatment regimens currently use radiosensitizers in conjunction with X-ray irradiation. Examples of X-ray activated radiosensitizers include, but are not limited to, the following: metronidazole, misonidazole, demethyl misonidazole, pimonidazole, etanidazole, nimorazole, mitomycin C, RSU 1069, SR 4233, EO9, RB 6145, nicotinamide, 5-bromodeoxyuridine (BUdR), 5-iododeoxyuridine (IUdR), bromodeoxycytidine, fluorodeoxyuridine (FudR), hydroxyurea, cisplatin, and therapeutically effective analogs and derivatives thereof.

[1279] Photodynamic therapy (PDT) of cancer uses visible light as a radioactive agent for sensitizing agents. Examples of photodynamic radiosensitizers include, but are not limited to, the following: hematoporphyrin derivatives, photoporphyrins, benzoporphyrin derivatives, tin protoporphyrins, pheophorbide-a, bacteriochlorophyll-a, naphthalocyanines, phthalocyanines, zinc phthalocyanines, and therapeutically effective analogs and derivatives thereof.

[1280] The radiosensitizers may be administered in combination with a therapeutically effective amount of one or more other compounds, including but not limited to: compounds that promote the incorporation of the radiosensitizer into target cells; compounds that control the flux of therapeutic agents, nutrients, and / or oxygen to target cells; chemotherapeutic agents that act on tumors with or without additional radiation; or other therapeutically effective compounds used to treat cancer or other diseases.

[1281] Chemosensitizers can be administered in combination with therapeutically effective amounts of one or more other compounds, including but not limited to: compounds that promote the incorporation of chemosensitizers into target cells; compounds that control the flow of therapeutic agents, nutrients, and / or oxygen to target cells; chemotherapeutic agents that act on tumors; or other therapeutically effective compounds for the treatment of cancer or other diseases. Calcium antagonists, such as verapamil, have been found to be useful in combination with anti-neoplastic agents for establishing chemosensitivity in tumor cells that are resistant to received chemotherapeutic agents and for enhancing the efficacy of these compounds in drug-sensitive malignancies.

[1282] For use in combination therapy with additional chemotherapeutic agents, the compound of formula (I) and one, two, three, four or more other therapeutic agents can, for example, be formulated together into a dosage form containing two, three, four or more therapeutic agents, i.e., a single pharmaceutical composition containing all components. In an alternative, the individual therapeutic agents can be formulated separately and presented together in the form of a kit, optionally together with their instructions for use.

[1283] In one embodiment, the pharmaceutical composition comprises a compound of Formula I and a pharmaceutically acceptable carrier and optionally one or more therapeutic agents.

[1284] In another embodiment, the invention relates to the use of a combination according to the invention for the manufacture of a pharmaceutical composition for inhibiting the growth of tumor cells.

[1285] In another embodiment, the invention relates to a product containing a compound of formula I and one or more anticancer agents as a combined preparation for simultaneous, separate or sequential use in the treatment of a patient suffering from cancer.

[1286] Example

[1287] The present invention will now be described by reference to the specific embodiments described in the following examples, but the present invention is not limited thereto. Compounds are named using an automatic naming software package such as AutoNom (MDL) or ChemAxon Structure toName or as named by a chemical supplier. In the examples, the following abbreviations are used:

[1288]

[1289]

[1290]

[1291] Column chromatography

[1292] Purification using column chromatography can be achieved, for example, using the Biotage automated rapid purification system, wherein UV monitoring is performed at 298 nm and collection is performed at 254 nm. In most cases, Biotage automated chromatography pre-filled silica cartridges are used. In specified cases, purification of some compounds is performed using a Biotage C18 reversed phase silica column, the post having octadecyl (end-capped) functionalized silica, or using a Biotage KP-NH cartridge to separate highly polar compounds, the cartridge using primary amine bonded silica.

[1293] If necessary, semi-preparative HPLC can be performed, for example using one of the following machines: (i) Varian Prostar modular HPLC system with a binary pumping system, UV detector and fraction collector and controlled by Varian Star software. (ii) Agilent 1200 HPLC system with a binary pump, autosampler, fraction collector and diode array detector and controlled by Agilent ChemStation software.

[1294] Analytical LC-MS System Description

[1295] In the following examples, many of the compounds prepared were characterized by mass spectrometry using the system and appropriate operating conditions described below. Where atoms with different isotopes are present and a single mass is quoted, the mass quoted for the compound is the monoisotopic mass (i.e. 35 Cl; 79 Br etc.). Several systems can be used, as described below, and these can be equipped with very similar operating conditions and can be set to run under very similar operating conditions. Possible operating conditions are also described below.

[1296] Agilent 1200SL-6140 LC-MS System - RAPID:

[1297] HPLC system: Agilent 1200 Series SL

[1298] Mass spectrometer detector: Agilent 6140 single quadrupole

[1299] Second detector: Agilent 1200MWD SL

[1300] Agilent MS operating conditions:

[1301] Capillary voltage: 3000V at ES positive ions (2700V at ES negative ions)

[1302] Fragmentor / Gain: 190 at ES positive (160 at ES negative)

[1303] Gain: 1

[1304] Drying gas flow rate: 12.0 L / min

[1305] Gas temperature: 345℃

[1306] Atomizer pressure: 60psig

[1307] Scanning range: 125amu-800amu

[1308] Ionization mode: electrospray positive-negative switching

[1309] Shimadzu Nexera LC-MS System

[1310] HPLC system: Shimadzu SIL-30AC autosampler / 2×Shimadzu LC-30AD pumps

[1311] Mass spectrometer detector: Shimadzu LCMS-2020 single quadrupole MS

[1312] Second detector: Shimadzu SPD-M20A diode array detector

[1313] Shimadzu MS operating conditions:

[1314] Qarray DC voltage: 20V at ES positive ions (-20V at ES negative ions)

[1315] Drying gas flow rate: 20.0 L / min

[1316] DL temperature: 300℃

[1317] Heating block temperature: 350°C

[1318] Atomizing gas flow rate: 1.5 L / min

[1319] Scanning range: 100amu-750amu

[1320] Ionization mode: electrospray positive-negative switching

[1321] Mass-Directed Purification LC-MS System

[1322] Preparative LC-MS is a standard and effective method for purifying small organic molecules, such as compounds described herein. The methods for liquid chromatography (LC) and mass spectrometry (MS) can be modified to provide better separation of crude material and improved detection of samples by MS. Optimization of preparative gradient LC methods will involve changing the column, volatile eluents and modifiers, and gradients. Methods for optimizing preparative LC-MS methods and then using them to purify compounds are well known in the art. Such methods are described in Rosentreter U, Huber U.; Optimal fraction collecting in preparative LC / MS; J Comb Chem.; 2004; 6(2), 159-64; and Leister W, Strauss K, Wisnoski D, Zhao Z, Lindsley C., Develop...

Claims

1. Use of a compound selected from the following formula It is used to prepare the following compounds

Images