RU2794333C1 - Isoindolinone inhibitors of mdm2-p53 interaction with anti-cancer activity - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a compound with formula (I) or its tautomer or pharmaceutically acceptable salt, where R¹ is independently chosen from halogen, nitrile, C_1-4 alkyl, hydroxyC_1-4 alkyl, C_1-4 alkoxy, C_2-4 alkynyl, -O_0.1 -(CR ^x R^y )_v -CO₂ H, -S(O) _d -C_1-6 alkyl and -S(O)_d -heterocyclic group containing 6 ring members containing two heteroatoms, chosen from N and O; R ² is chosen from hydrogen, C_1-4 alkyl, hydroxyC_1-4 alkyl, and -(CR ^x R^y)_u -CO₂ H; s is chosen from 0 and 1; R³ is hydrogen or -(A)_t -(CR ^x R^y)_q -X; t is chosen from 0 and 1; q is chosen from 0, 1 and 2; where when R³ is -(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 equal to 1 and q is not equal to 0; A represents a C_3-6 cycloalkyl group or a heterocyclic group containing 4-5 ring members, wherein said heterocyclic group contains one or two heteroatoms chosen from N and O; X is chosen from hydrogen, halogen, -CN, -OR⁹, -(CH₂ ) _v -CO₂ H, -NHSO₂ R ^x, and -C(=O)NR ^x R ^y ; R⁴ and R⁵ are halogen; R⁶ and R are independently chosen from hydrogen, C_1-6 alkyl, hydroxyC_1-6alkyl, -(CH₂)_j-O-C_1-6 alkyl, -C_1-6 alkyl-NR ^x R^y, - (CR ^x R^y)_p -CONR ^x R^y, a heterocyclic group containing 5 or 6 ring members containing one or two heteroatoms chosen from O and N, -CH₂ -heterocyclic group containing 6 ring members containing two heteroatoms , which are N, and C_3-8 cycloalkyl, where said cycloalkyl or heterocyclic groups may be optionally substituted with one or more R^z groups; R⁹ is chosen from hydrogen and C-_1-6 alkyl; R^x and R^y are independently chosen from hydrogen, halogen, C _1-6 alkyl, and hydroxyC_1-6 alkyl; or groups R^x and R^y together with the nitrogen atom to which they are attached, can combine to form a saturated heterocyclyl group containing 5 ring members; R^z is independently chosen from halogen, C_1-6 alkyl, hydroxy, -(CH₂)_r -CO₂ C_1-6 alkyl, and -(CH₂)_r -CO ₂ H; a, j, d, n, r and p are independently chosen from 0, 1 and 2; m is independently chosen from 1 and 2; u is chosen from 0, 1, 2 and 3; and v is chosen from 0 and 1. The invention also relates to compounds represented by formulas (VIIf), (Iw), and specific compounds represented in the claims. The invention relates to a process for the preparation of compounds with formula (I). The compounds of the invention are intended for use in therapy to inhibit the MDM2-p53 interaction.

EFFECT: derivatives of isoindolin-1-one for use in therapy for inhibition of MDM2-p53 interaction. 45 cl, 1 tbl, 137 ex

Description

FIELD OF TECHNOLOGY

The present invention relates to derivatives of isoindolin-1-one, to pharmaceutical compositions containing these compounds, as well as to the use of these compounds for the treatment of diseases, such as cancer.

RELATED APPLICATIONS

This application relates to UK Patent Application No. 1517217.4, filed September 29, 2015, the contents of which are incorporated herein in their entirety by reference.

BACKGROUND OF THE INVENTION

The gene for transformation-associated protein 53 (TP53) encodes a 53 kDa protein, p53. The tumor suppressor protein p53 responds to cellular stresses such as hypoxia, DNA damage, and oncogenic activation through a series of post-translational modifications, including phosphorylation, acetylation, and methylation, and acts as a signaling node for various signaling pathways to become active. p53 also has additional roles in other physiological processes, including autophagy, cell adhesion, cell metabolism, fertility, and stem cell maturation and development. Phosphorylation of p53 due to activation of kinases including ATM, CHK1 and 2, as well as DNA-PK, leads to the formation of a stabilized and transcriptionally active form of this protein, thus producing a number of gene products. Responses to p53 activation include apoptosis, survival, cell cycle arrest, DNA repair, angiogenesis, invasion, and autoregulation. The specific combination of which, in combination with the genetic background of the cell, leads to the observed cellular effect, i.e. apoptosis, cell cycle arrest or aging. For tumor cells, the apoptosis pathway may be preferable due to the loss of tumor suppressor proteins and associated cell cycle checkpoints associated with oncogenic stress.

It is known that under stress conditions, such as hypoxia or DNA damage, the content of the p53 protein in the cell increases. It is known that p53 initiates the transcription of a number of genes that control the passage of the cell cycle, the start of DNA repair, and programmed cell death. This provides a mechanism for the role of p53 as a tumor suppressor, which is supported by genetic studies.

p53 activity is down-regulated and strongly regulated by a binding interaction with the MDM2 protein, whose transcription itself is directly regulated by p53. p53 is inactivated when its transactivation domain is bound by the MDM2 protein. Upon inactivation, p53 functions are suppressed, and the p53-MDM2 complex becomes a target for ubiquitination.

In normal cells, the balance between active p53 and inactive MDM2-bound p53 is maintained by a self-regulating negative feedback loop. This means that p53 can activate MDM2 expression, which in turn leads to the repression of p53.

Inactivation of p53 due to mutation has been found to be common in about half of sporadic adult cancers. Moreover, in about 10% of tumors, gene amplification and MDM2 overexpression results in the loss of functional p53, allowing malignant transformation and uncontrolled tumor growth.

Inactivation of p53 by a number of mechanisms is a frequent random event in the development and progression of cancer. Such mechanisms include inactivation by mutation, targeting of oncogenic viruses and, in a significant proportion of cases, amplification and/or increased transcription rate of the MDM2 gene resulting in overexpression or increased activation of the MDM2 protein. Amplification of the MDM2 gene leading to overexpression of the MDM2 protein has been observed in tumor samples taken from patients with common sporadically occurring cancers. Overall, approximately 10% of tumors had MDM2 amplification, with the highest percentage found in hepatocellular carcinoma (44%), lung cancer (15%), sarcomas and osteosarcomas (28%), and Hodgkin's 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 leads to an increase in MDM2 protein levels, forming a negative feedback loop. The critical nature of p53 regulation by MDM2 and MDMX has been demonstrated in mouse gene knockout models. MDM2-/- knockout mouse embryos die around the implantation stage. Lethality is eliminated by double knockout of Mdm2 and Trp53. MDM2 inhibits p53 activity directly by binding or overlapping the p53 transactivation domain, as well as by stimulating the proteasome destruction of this complex through the activity of its E3 ubiquitin ligase. In addition, MDM2 is a transcriptional target of p53, and thus, these two proteins are linked by a self-regulating feedback loop, providing a temporary nature of p53 activation.

Induction of the p14ARF protein, a product of the alternate reading frame (ARF) of the p16INK4a locus, is also a mechanism for negative regulation of the p53-MDM2 interaction. p14ARF directly interacts with MDM2 and leads to stimulation of the p53 transcriptional response. Loss of p14ARF as a result of a homozygous mutation in the CDKN2A (INK4A) gene will result in increased levels of MDM2 and hence loss of p53 function and cell cycle control.

Although strong amino acid sequence and structure homology has been shown between MDMX and MDM2, neither of these proteins can serve as a substitute for the other; MDMX-null mice die in utero, while MDM2 knockout is lethal during early embryogenesis, both of which can survive p53 knockout, demonstrating a p53-dependent lethality. MDMX also binds p53 and inhibits p53-dependent transcription, but unlike MDM2, it is not activated by p53 upon transcription and therefore does not form the same self-regulating cycle. In addition, MDMX does not have E3 ubiquitin ligase activity or a nuclear localization signal, although it is thought to play a role in p53 degradation by forming heterodimers with MDM2 and helping to stabilize MDM2.

The therapeutic rationale for MDM2-p53 inhibition is that a potent inhibitor of the protein-protein interaction will release p53 from MDM2 suppressive control and activate p53-mediated cell death in the tumor. In tumors, selectivity has been hypothesized to result from p53 recognition of existing DNA damage or oncogenic activation signals that were previously blocked by the action of MDM2 at normal or overexpressed levels. In normal cells, p53 activation is expected to lead to activation of non-apoptotic pathways and, in general, a protective growth inhibition response. In addition, due to the non-genotoxic mechanism of action of MDM2-p53 inhibitors, they are suitable for the treatment of cancer in particular in pediatric patients.

Approximately 50% of cancer patients contain cells in which TP53, the gene encoding p53, has a mutation that causes the protein to lose its tumor suppressor function and sometimes even give rise to variants of the p53 protein that have new oncogenic functions.

Cancers with high levels of MDM2 amplification include liposarcoma (88%), soft tissue sarcoma (20%), osteosarcoma (16%), esophageal cancer (13%), and certain childhood malignancies, including B-cell malignancies. .

The present invention describes a new range of compounds that selectively inhibit the interaction of MDM2-p53 and have anticancer activity.

BRIEF DESCRIPTION OF THE INVENTION

According to one aspect of the present invention, a compound of formula (I) is provided:

or a tautomer or solvate or pharmaceutically acceptable salt thereof, wherein:

R ¹ is independently selected from hydroxy, halogen, nitro, nitrile, C _1-4 alkyl, haloC _1-4 alkyl, hydroxyC _1-4 alkyl, C _2-6 alkenyl, C _1-4 alkoxy, haloC _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 -heterocyclic group containing 3-6 ring members, and - S(O) _d -N(R ⁸ ) ₂ ;

R ² is selected from hydrogen, C _1-4 alkyl, C _2-6 alkenyl, hydroxyC _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 ;

s is chosen from 0 and 1;

R ³ is hydrogen or -(A) _t -(CR ^x R ^y ) _q -X;

t is selected from 0 and 1;

q is selected from 0, 1 and 2;

where when R ³ is -(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 equal to 1 and q is not equal to 0;

A represents a C _3-6 cycloalkyl group or a heterocyclic group containing 3-6 ring members, where the specified heterocyclic group contains one or more (for example, 1, 2 or 3) heteroatoms selected from N, O, S and their oxidized forms ;

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 ;

R ⁴ and R ⁵ are independently selected from halo, nitrile, C _1-4 alkyl, haloC _1-4 alkyl, C _1-4 alkoxy, and haloC _1-4 alkoxy;

R ⁶ and R ⁷ are independently selected from hydrogen, C _1-6 alkyl, haloC _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, hydroxy, hydroxyC _1-6 alkyl, -COOC _1-6 alkyl, - (CH ₂ ) _j -O-C _1-6 alkyl, -(CH ₂ ) _j -O-(hydroxyC _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 containing 3-7 ring members, -CH ₂ -heterocyclic group containing 3-7 ring members, -CH ₂ -O-heterocyclic group containing 3-7 ring members, -CH ₂ -NH-heterocyclic group containing 3-7 ring members, -CH ₂ - N(C _1-6 alkyl)-heterocyclic group containing 3-7 ring members, -C(=O)NH-heterocyclic group containing 3-7 ring members, C _3-8 cycloalkyl, -CH ₂ -C _{3- 8} cycloalkyl, -CH ₂ -O-C _3-8 cycloalkyl and C _3-8 cycloalkenyl, where said cycloalkyl, cycloalkenyl or heterocyclic groups may be optionally substituted with one or more R ^z groups, and where in each case the heterocyclic group contains one or more than (eg 1, 2 or 3) heteroatoms selected from N, O, S and their oxidized forms;

or groups R ⁶ and R ⁷ together with the carbon atom to which they are attached, can be combined to form a C _3-6 cycloalkyl or heterocyclyl group containing 3-6 ring members, where the specified heterocyclic group contains one or more (for example, 1, 2 or 3) heteroatoms selected from N, O, S and their oxidized forms, and wherein said C _3-6 cycloalkyl and heterocyclyl groups may be optionally substituted with one or more R ^z groups;

R ⁸ and R ⁹ are independently selected from hydrogen, C _1-6 alkyl, haloC _1-6 alkyl, hydroxyC _1-6 alkyl, -(CH ₂ ) _k -O-C _1-6 alkyl, -(CH ₂ ) _k - O-(hydroxyC _1-6 alkyl), hydroxyC _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;

R ^x and R ^y are independently selected from hydrogen, halogen, nitro, nitrile, C _1-6 alkyl, haloC _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, hydroxy, hydroxyC _1-6 alkyl, C _{1 -6} alkoxy, -(CH ₂ ) _k -O-C _1-6 alkyl, hydroxyC _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;

or the R ^x and R ^y groups, together with the carbon or nitrogen atom to which they are attached, may combine to form a C _3-6 cycloalkyl or saturated heterocyclyl group containing 3-6 ring members which may optionally be fused to form an aromatic heterocyclyl group , consisting of 3-5 members of the ring;

or when present on a carbon atom, the R ^x and R ^y groups can combine to form a ═CH ₂ group;

R ^z is independently selected from halo, nitro, nitrile, C _1-6 alkyl, haloC _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, =O, hydroxy, hydroxyC _1-6 alkyl, C _1-6 alkoxy, -(CH ₂ ) _k -O-C _1-6 alkyl, hydroxyC _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 , heterocyclyl group containing 3-6 ring members, heterocyclyl group containing 3-6 ring members substituted with -C(=O)C _1-4 alkyl, heterocyclyl group , containing 3-6 ring members, substituted with -C(=O)OC _1-4 alkyl, heterocyclyl group containing 3-6 ring members, substituted with -C(=O)N(H) _e (C _1-4 alkyl) _2-e , -C(=O)heterocyclyl group containing 3-6 ring members, C _3-8 cycloalkyl and C _3-8 cycloalkenyl, where if R ⁷ is pyridine, then R ^z is not -NH ₂ ;

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

k and m are independently selected from 1 and 2;

u is selected from 0, 1, 2 and 3; And

v and w are independently chosen from 0 and 1;

According to a further aspect of the present invention there is provided a compound of formula (I):

or a tautomer or solvate or pharmaceutically acceptable salt thereof, wherein:

R ¹ is independently selected from hydroxy, halogen, nitro, nitrile, C _1-4 alkyl, haloC _1-4 alkyl, hydroxyC _1-4 alkyl, C _2-6 alkenyl, C _1-4 alkoxy, haloC _1-4 alkoxy, C _2-4 alkynyl, -(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 -heterocyclic group containing 3-6 ring members, and -S(O) _d -N(R ⁸ ) ₂ ;

R ² is selected from hydrogen, C _1-4 alkyl, C _2-6 alkenyl, hydroxyC _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 ;

s is chosen from 0 and 1;

R ³ is hydrogen or -(A) _t- (CR ^x R ^y ) _q -X;

t is selected from 0 and 1;

q is selected from 0, 1 and 2;

where when R ³ is -(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 equal to 1 and q is not equal to 0;

A represents a C _3-6 cycloalkyl group or a heterocyclic group containing 3-6 ring members, where the specified heterocyclic group contains one or more (for example, 1, 2 or 3) heteroatoms selected from N, O, S and their oxidized forms ;

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 ;

R ⁴ and R ⁵ are independently selected from halo, nitrile, C _1-4 alkyl, haloC _1-4 alkyl, C _1-4 alkoxy, and haloC _1-4 alkoxy;

R ⁶ and R ⁷ are independently selected from hydrogen, C _1-6 alkyl, haloC _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, hydroxy, hydroxyC _1-6 alkyl, -COOC _1-6 alkyl, - (CH ₂ ) _j -O-C _1-6 alkyl, -(CH ₂ ) _j -O-(hydroxyC _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 containing 3-7 ring members, -CH ₂ -heterocyclic group containing 3-7 ring members, -CH ₂ -O-heterocyclic group containing 3-7 ring members, -CH ₂ -NH-heterocyclic group containing 3-7 ring members, -CH ₂ - N(C _1-6 alkyl)-heterocyclic group containing 3-7 ring members, -C(=O)NH-heterocyclic group containing 3-7 ring members, C _3-8 cycloalkyl, -CH ₂ -C _{3- 8} cycloalkyl, -CH ₂ -O-C _3-8 cycloalkyl and C _3-8 cycloalkenyl, where said cycloalkyl, cycloalkenyl or heterocyclic groups may be optionally substituted with one or more R ^z groups, and where in each case the heterocyclic group contains one or more than (eg 1, 2 or 3) heteroatoms selected from N, O, S and their oxidized forms;

or groups R ⁶ and R ⁷ together with the carbon atom to which they are attached, can be combined to form a C _3-6 cycloalkyl or heterocyclyl group containing 3-6 ring members, where the specified heterocyclic group contains one or more (for example, 1, 2 or 3) heteroatoms selected from N, O, S and their oxidized forms, and wherein said C _3-6 cycloalkyl and heterocyclyl groups may be optionally substituted with one or more R ^z groups;

R ⁸ and R ⁹ are independently selected from hydrogen, C _1-6 alkyl, haloC _1-6 alkyl, hydroxyC _1-6 alkyl, -(CH ₂ ) _k -O-C _1-6 alkyl, -(CH ₂ ) _k - O-(hydroxyC _1-6 alkyl), hydroxyC _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;

R ^x and R ^y are independently selected from hydrogen, halogen, nitro, nitrile, C _1-6 alkyl, haloC _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, hydroxy, hydroxyC _1-6 alkyl, C _{1 -6} alkoxy, -(CH ₂ ) _k -O-C _1-6 alkyl, hydroxyC _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;

or the R ^x and R ^y groups, together with the carbon or nitrogen atom to which they are attached, may combine to form a C _3-6 cycloalkyl or saturated heterocyclyl group containing 3-6 ring members which may optionally be fused to form an aromatic heterocyclyl group , consisting of 3-5 members of the ring;

or when present on a carbon atom, the R ^x and R ^y groups can combine to form a ═CH ₂ group;

R ^z is independently selected from halo, nitro, nitrile, C _1-6 alkyl, haloC _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, =O, hydroxy, hydroxyC _1-6 alkyl, C _1-6 alkoxy, -(CH ₂ ) _k -O-C _1-6 alkyl, hydroxyC _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 , heterocyclyl group containing 3-6 ring members, heterocyclyl group containing 3-6 ring members substituted with -C(=O)C _1-4 alkyl, heterocyclyl group , containing 3-6 ring members, substituted with -C(=O)OC _1-4 alkyl, heterocyclyl group containing 3-6 ring members, substituted with -C(=O)N(H) _e (C _1-4 alkyl) _2-e , -C(=O)heterocyclyl group containing 3-6 ring members, C _3-8 cycloalkyl and C _3-8 cycloalkenyl, where if R ⁷ is pyridine, then R ^z is not -NH ₂ ;

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

k and m are independently selected from 1 and 2;

u is selected from 0, 1, 2 and 3; And

v and w are independently chosen from 0 and 1;

According to additional aspects of the present invention, there is provided a compound of formula (I) for use in the prevention or treatment of a disease or condition described herein, methods for preventing or treating a disease or condition described herein, comprising administering to a patient a compound of formula (I), pharmaceutical compositions containing a compound of formula (I), and methods for synthesizing a compound of formula (I).

DEFINITIONS

Unless the context indicates otherwise, references to Formula (I) throughout this document (including uses, methods, and other aspects of the present invention) include references to all other subformulas, subgroups, embodiments, and examples defined herein.

"Activity" is a measure of the activity of a drug, expressed as the amount required to produce an effect of a certain strength. A highly active drug elicits a greater response at low concentrations. Activity is proportional to affinity and potency. Affinity is the ability of a drug to bind to a receptor. Efficiency is the relationship between receptor occupancy and the ability to initiate a response at the molecular, cellular, tissue or system level.

The term "antagonist" refers to a type of receptor ligand or drug that blocks or attenuates agonist-mediated biological responses. Antagonists have an affinity for, but no agonistic effect on, cognate receptors, and binding will disrupt the interaction and inhibit the function of any ligand (eg, endogenous ligands or substrates, agonist or inverse agonist) at the receptors. Antagonism can arise directly or indirectly, and can also be mediated by any mechanism and at any physiological level. In this regard, ligand antagonism under different circumstances can manifest itself in functionally different ways. Antagonists mediate their action through binding to the active site or allosteric sites on the receptors, or they may interact at unique binding sites that are not normally involved in the biological regulation of receptor activity. The action of antagonists can be reversible or irreversible, depending on the period of existence of the antagonist-receptor complex, which, in turn, depends on the nature of the relationship between the antagonist and the receptor.

In the context of this document, it is intended that the term "mediated" when used in conjunction with, for example, MDM2/p53 as described herein (and used, for example, in relation to various physiological processes, diseases, conditions, pathological conditions, therapy options, treatments or interventions) is used in a restrictive sense such that the various processes, diseases, conditions, pathological conditions, treatments and interventions for which the term is used are those in which said protein plays a biological role. Where the term is used in relation to a disease, condition or pathological condition, the biological role played by the protein may be direct or indirect and may be necessary and/or sufficient for the symptoms of the disease, condition or pathological condition (or their ethology or progression). Thus, protein function (and in particular aberrant levels of function, e.g., over-expression or under-expression) is not necessarily the direct cause of a disease, condition, or pathological condition: rather, mediated diseases, conditions, or pathological conditions are contemplated to include those having a multifactorial etiology. and combined progression, in which the protein in question is only partially involved. Where the term is used in relation 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 treatment, prevention, or outcome of the intervention. Thus, a disease state or disease state mediated by a protein includes the development of resistance to any particular cancer drug or treatment.

The term "treatment" as used herein in the context of the treatment of a pathological condition, ie. condition, disorder or disease, generally refers to the treatment and therapy of a human or animal (e.g., in veterinary applications) that achieves some desired therapeutic effect, e.g., inhibition of the progression of a pathological condition, and includes reducing the rate of progression, pathological condition, reducing or alleviating at least one symptom associated with or caused by the pathological condition being treated, and curing the pathological condition. For example, the treatment may be the reduction of one or more symptoms of the disease or the complete elimination of the disease.

The term "prophylaxis" (i.e., the use of a compound as a prophylactic measure) as used herein in the context of treating a disease state, i.e. condition, disorder, or disease generally refers to prevention or prevention in a human or animal (eg, in veterinary applications) that achieves some desired prophylactic effect, such as preventing or protecting against disease. Prevention includes the complete blocking of all symptoms of a disorder for an indefinite period of time, only slowing down the onset of one or more symptoms of a disease, or reducing the likelihood of a disease occurring.

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

Combinations according to the present invention can lead to a more effective therapeutic effect in comparison with the therapeutic effect of individual compounds/agents when administered separately.

The term "effective" includes beneficial effects such as additivity, synergy, reduced side effects, reduced toxicity, increased time to disease progression, increased survival time, sensitization or resensitization of one agent to another, or increased clinical response rate. Preferably, the effect may allow the patient to receive lower doses of each or any of the components, which will reduce the toxicity of chemotherapy, while providing and/or maintaining the same therapeutic effect. "Synergistic" effect in the context of this document refers to the therapeutic effect provided by the combination, which is greater than the sum of the therapeutic effects of the agents from the combination when they are used separately. "Additive" effect in the context of this document refers to the therapeutic effect provided by the combination, which is superior to the therapeutic effect of any agent from the combination when used separately. The term "percentage of positive clinical response" in the context of this document refers, in the case of a solid tumor, to the degree of reduction in tumor size at a given time point, for example, 12 weeks. Thus, for example, a 50% positive clinical response means a 50% reduction in tumor size. References herein to "clinical response" refer to positive clinical response rates of 50% or more. "Partial response" is defined herein as the percentage of positive clinical response less than 50%.

As used herein, the term "combination" when applied to two or more compounds and/or agents is intended to define a material in which the two or more agents are associated. The terms "combined" or "combination" in this context should be understood accordingly.

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

• compositions (eg, single dose formulations) containing said two or more compounds/agents in a mixture (eg, in one single dose);

• compositions containing material in which the specified two or more compounds/agents are chemically/physicochemically linked (for example, by cross-linking, molecular agglomeration or binding to a common carrier moiety);

• compositions containing a material in which said two or more compounds/agents are chemically/physicochemically co-packaged (eg located on or within lipid vesicles, particles (eg micro- and nanoparticles) or emulsion droplets);

• pharmaceutical kits, pharmaceutical packs, or patient packs in which the two or more compounds/agents are co-packaged or co-presented (eg, as part of a single dose kit);

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

• material (eg, heterogeneous composition) containing at least one of two or more compounds/agents, together with instructions for extemporaneous association of at least one compound to form a physical bond of two or more compounds/agents;

• material (eg, heterogeneous formulation) containing at least one of two or more compounds/agents, together with instructions for combination therapy with two or more compounds/agents;

• a material containing at least one of two or more compounds/agents, together with instructions for administering a patient population that has been (or is being) administered the other(s) of the two or more compounds/agents;

• a material containing at least one of two or more compounds/agents in an amount or form specifically adapted for use in combination with the other(s) of two or more compounds/agents.

In the context of this document, the term "combination therapy" is intended to define therapies that involve the use of a combination of two or more compounds/agents (defined above). Thus, references to "combination therapy", "combinations" and the use of compounds/agents "in combination" in this application may refer to compounds/agents that are administered as part of one general treatment regimen. As such, the dosage of each of the two or more compounds/agents may be different: they may each be administered at the same time or at different times. Accordingly, it is to be understood that the compounds/agents of the combination may be administered sequentially (eg, before or after) or simultaneously, in the same pharmaceutical formulation (ie, together) or in different pharmaceutical formulations (ie, separately). Simultaneous administration in one formulation means as a single formulation, while simultaneous administration in different pharmaceutical formulations is not a single formulation. The dosages of each of the two or more compounds/agents in combination therapy may also vary depending on the route of administration.

In the context of this document, the term "pharmaceutical kit" defines a set of one or more single doses of a pharmaceutical composition together with means for dispensing (for example, a dispenser) and/or means for delivery (for example, an inhaler or syringe), all of which are optionally in common outer packaging. In pharmaceutical kits containing a combination of two or more compounds/agents, the individual compounds/agents may be single or non-single formulations. The single dose(s) may be enclosed in a blister pack. The pharmaceutical kit may optionally further include instructions for use.

In the context of this document, the term "pharmaceutical package" defines a set of one or more single doses of a pharmaceutical composition, which are not necessarily in a common outer package. In pharmaceutical packages containing a combination of two or more compounds/agents, the individual compounds/agents may be single or non-single formulations. The single dose(s) may be enclosed in a blister pack. The pharmaceutical packaging may optionally further include instructions for use.

The term "optionally substituted" as used herein refers to a group that may be unsubstituted or substituted with a substituent as defined herein.

The prefix "C _x-y " (where x and y are integers) in the context of this document refers to the number of carbon atoms in a particular group. Thus, a C _1-6 alkyl group contains 1 to 6 carbon atoms, a C _3-6 cycloalkyl group contains 3 to 6 carbon atoms, a C _1-4 alkoxy group contains 1 to 4 carbon atoms, and so on.

The term "halo" or "halogen" in the context of this document refers to fluorine, chlorine, bromine or iodine, in particular fluorine or chlorine.

Every single hydrogen atom in a compound (eg, in an alkyl group or when a hydrogen atom is mentioned) includes all hydrogen isotopes, in particular ¹ H and ² H (deuterium).

The term "oxo" in the context of this document refers to the group =O.

The term "C _1-4 alkyl" in the context of this document as a group or part of a group refers to a linear or branched hydrocarbon group containing from 1 to 4 carbon atoms, respectively. Examples of such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, and the like.

The term "C _2-4 alkenyl" or "C _2-6 alkenyl" as used herein, as a group or part of a group, refers to a linear or branched hydrocarbon group containing 2 to 4 or 2 to 6 carbon atoms, respectively, 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. .

The term "C _2-4 alkynyl" or "C _2-6 alkynyl" as used herein, as a group or part of a group, refers to a linear or branched hydrocarbon group containing 2 to 4 or 2 to 6 carbon atoms, respectively, and also 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) groups.

The term "C _1-4 alkoxy" in the context of this document as a group or part of a group refers to -O-C _1-4 alkyl group, where C _1-4 alkyl is as defined herein. Examples of such groups include methoxy, ethoxy, propoxy, butoxy, and the like.

The term "C _3-6 cycloalkyl" as used herein refers to a saturated monocyclic hydrocarbon ring of 3-6 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl and the like.

The term "C _3-6 cycloalkenyl" as used herein refers to a partially saturated monocyclic hydrocarbon ring of 3-6 carbon atoms and containing one or more (usually one) carbon-carbon double bond(s). Examples of such groups include cyclopentenyl, cyclohexenyl and cyclohexadienyl.

The term "hydroxyC _1-4 alkyl" as used herein, as a group or part of a group, refers to a C _1-4 alkyl group as defined herein, wherein one or more (e.g., 1, 2, or 3) than one carbon atom is substituted with a hydroxyl group. Therefore, the term "hydroxyC _1-4 alkyl" includes monohydroxyC _1-4 alkyl as well as polyhydroxyC _1-4 alkyl. The hydroxyl group may be substituted with one, two, three or more hydrogen atoms, so hydroxyC _1-4 alkyl may contain one, two, three or more hydroxyl groups. Examples of such groups include hydroxymethyl, hydroxyethyl, hydroxypropyl, and the like.

The term "haloC _1-4 alkyl" as used herein, as a group or part of a group, refers to a C _1-4 alkyl group as defined herein, wherein one or more (eg, 1, 2, or 3) than one carbon atom is substituted by halogen . Therefore, the term "haloC _1-4 alkyl" includes monohaloC _1-4 alkyl and also polyhaloC _1-4 alkyl. Halogen may be substituted with one, two, three or more hydrogen atoms, so haloC _1-4 alkyl may contain one, two, three or more halogen atoms. Examples of such groups include fluoroethyl, fluoromethyl, difluoromethyl, trifluoromethyl or trifluoroethyl and the like.

The term "haloC _1-4 alkoxy" in the context of this document as a group or part of a group refers to -O-C _1-4 alkyl group as defined herein, where one or more (for example, 1, 2 or 3) than one atom carbon is replaced by halogen. Therefore, the term "haloC _1-4 alkoxy" includes monohalo C _1-4 alkoxy and also polyhalo C _1-4 alkoxy. Halogen may be substituted with one, two, three or more hydrogen atoms, so haloC _1-4 alkoxy may contain one, two, three or more halogen atoms. Examples of such groups include fluoroethyloxy, difluoromethoxy or trifluoromethoxy and the like.

The term "heterocyclyl group" in the context of this document will, unless the context indicates otherwise, include aromatic and non-aromatic ring systems. Thus, for example, the term "heterocyclyl group" includes aromatic, non-aromatic, unsaturated, partially saturated and saturated heterocyclyl ring systems. In general, unless the context otherwise indicates, such groups may be monocyclic or bicyclic (including fused, spiro and bridged bicyclic groups) and may contain, for example, 3-12 ring members, more typically 5-10 ring members. Mention of 4-7 ring members includes 4, 5, 6, or 7 ring atoms, and mention of 4-6 ring members includes 4, 5, or 6 ring atoms. Examples of monocyclic groups are groups containing 3, 4, 5, 6, 7 and 8 ring members, more commonly 3-7 or 4-7 and preferably 5, 6 or 7 ring members, more preferably 5 or 6 ring members. Examples of bicyclic groups are groups containing 8, 9, 10, 11 and 12 ring members, more often 9 or 10 ring members. The heterocyclyl groups may be heteroaryl groups containing 5-12 ring members, more typically 5-10 ring members. When a heterocyclyl group is referred to herein, the heterocyclyl ring may, unless the context indicates otherwise, be optionally substituted, i.e. unsubstituted or substituted with one or more (eg 1, 2, 3 or 4, in particular one or two) substituents as defined herein.

The heterocyclyl group may be, for example, a five-membered or six-membered monocyclic ring or a bicyclic structure formed from fused five- and six-membered rings, or two fused six-membered rings, or two fused five-membered rings. Each ring may contain up to five heteroatoms, specifically selected from nitrogen, sulfur and oxygen and oxides of nitrogen or sulfur. In particular, the heterocyclyl ring will contain up to 4 heteroatoms, more specifically up to 3 heteroatoms, more often up to 2, for example one heteroatom. In one embodiment, the heterocyclyl ring will contain one or two heteroatoms selected from N, O, S, and N or S oxides. In one embodiment, the heterocyclyl ring contains at least one nitrogen atom in the ring. The nitrogen atoms in the heterocyclyl rings may be basic, as in the case of imidazole or pyridine, or substantially non-basic, as in the case of the indole or pyrrole nitrogen. In general, the number of basic nitrogen atoms present in the heterocyclyl group, including any amino ring substituents, will be less than five.

Heterocyclyl groups may be attached via a carbon atom or a heteroatom (eg nitrogen). Likewise, heterocyclyl groups may be substituted on a carbon atom or a heteroatom (eg nitrogen).

Examples of five-membered aromatic heterocyclyl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl.

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

The term "heteroaryl" is used herein to refer to an aromatic heterocyclyl group. The term "heteroaryl" embraces polycyclic (eg, 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 group may be attached through an aromatic ring or through a non-aromatic ring.

Examples of heteroaryl groups are monocyclic and bicyclic groups containing five to twelve ring members, and more typically five to ten ring members.

Examples of five-membered heteroaryl groups include, but are not limited to, pyrrole, furan, thiophene, imidazole, furazan, oxazole, oxadiazole, oxatriazole, isoxazole, thiazole, thiadiazole, isothiazole, pyrazole, triazole, and tetrazol.

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

The bicyclic heteroaryl group may be, for example, a group selected from:

a) a benzene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 heteroatoms in the ring;

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

c) a pyrimidine ring fused to a 5- or 6-membered ring containing 0, 1 or 2 heteroatoms in the ring;

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

e) a pyrazole ring fused to a 5- or 6-membered ring containing 0, 1 or 2 heteroatoms in the ring;

e) an imidazole ring fused to a 5- or 6-membered ring containing 0, 1 or 2 heteroatoms in the ring;

g) an oxazole ring fused to a 5- or 6-membered ring containing 0, 1 or 2 heteroatoms in the ring;

h) an isoxazole ring fused to a 5- or 6-membered ring containing 0, 1 or 2 heteroatoms in the ring;

i) a thiazole ring fused to a 5- or 6-membered ring containing 0, 1 or 2 heteroatoms in the ring;

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

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

l) a furan ring fused to a 5- or 6-membered ring containing 0, 1, 2 or 3 heteroatoms in the ring;

m) a cyclohexyl ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; And

o) a cyclopentyl ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms.

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

Specific examples of bicyclic heteroaryl groups containing a six-membered ring fused to a five-membered ring include, but are not limited to, benzofuran, benzothiophene, benzimidazole, benzoxazole, isobenzoxazole, benzisoxazole, benzothiazol, benzisothiazole, isobenzofuran, indole, isoindole, indolizine, indoline, isoindoline, purine (eg adenine, guanine), indazole, pyrazolopyrimidine (eg pyrazolo[1,5-a]pyrimidine), triazolopyrimidine (eg [1,2,4]triazolo[1,5-a]pyrimidine), benzodioxole, imidazopyridine and pyrazolopyridine (eg pyrazolo[1,5-a]pyridine).

Specific examples of bicyclic heteroaryl groups containing two fused six-membered rings include, but are not limited to, quinoline, isoquinoline, chroman, thiochroman, isochroman, chromene, isochromene, benzodioxane, quinolysine, benzoxazine, pyridopyridine, quinoxaline, quinazoline, cinnoline, phthalazine, naphthyridine and pteridine.

Examples of polycyclic heteroaryl groups containing an aromatic ring and a non-aromatic ring include tetrahydroisoquinoline, tetrahydroquinoline, dihydrobenzothiophene, dihydrobenzofuran, 2,3-dihydrobenzo[1,4]dioxine, benzo[1,3]dioxol, 4,5,6,7-tetrahydrobenzofuran , tetrahydrotriazolopyrazine (e.g. 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine), chroman, thiochroman, isochroman, chromene, isochromene, benzodioxane, benzoxazine, benzodiazepine, and indoline .

The nitrogen-containing heteroaryl ring must contain at least one nitrogen atom in the ring. Said nitrogen-containing heteroaryl ring may be N-linked or C-linked. Each ring may additionally contain up to four other heteroatoms specifically selected from nitrogen, sulfur and oxygen. In particular, the heteroaryl ring will contain up to 3 heteroatoms, eg 1, 2 or 3, more often up to 2 nitrogen atoms, eg one nitrogen atom. The nitrogen atoms in the heteroaryl rings may be basic, as in the case of imidazole or pyridine, or substantially nonbasic, as in the case of the indole or pyrrole nitrogen. In general, the number of basic nitrogen atoms present in the heteroaryl group, including any amino ring substituents, will be less than five.

Examples of nitrogen-containing heteroaryl groups include, but are not limited to, monocyclic groups such as pyridyl, pyrrolyl, imidazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl ( for example 1,2,3-triazolyl, 1,2,4-triazolyl), tetrazolyl, as well as bicyclic groups such as quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzisoxazole, benzothiazolyl and benzisothiazole, indolyl, 3H-indolyl, isindolyl, indolizinyl, isoindolinyl, purinyl (eg, adenine [6-aminopurine], guanine [2-amino-6-hydroxypurine]), indazolyl, quinolizinyl, benzoxazinyl, benzodiazepinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl.

Examples of nitrogen-containing polycyclic heteroaryl groups containing an aromatic ring and a non-aromatic ring include tetrahydroisoquinolinyl, tetrahydroquinolinyl and indolinyl.

The term "non-aromatic" embraces, unless the context otherwise indicates, unsaturated ring systems of a non-aromatic nature, partially saturated and saturated heterocyclyl ring systems. The terms "unsaturated" and "partially saturated" refer to rings in which the ring structure(s) contain atoms that share more than one valence bond, i. the ring contains at least one multiple bond, for example a C=C, C≡C or N=C bond. The term "saturated" refers to rings in which there are no multiple bonds between the atoms of the rings. Saturated heterocyclyl groups include piperidinyl, morpholinyl and thiomorpholinyl. Partially saturated heterocyclyl groups include pyrazolinyl, such as pyrazolin-2-yl and pyrazolin-3-yl.

Examples of non-aromatic heterocyclyl groups are groups containing 3-12 ring members, more typically 5-10 ring members. Such groups may be monocyclic or bicyclic, for example having 3-7 ring members, in particular 4-6 ring members. Such groups in particular contain from 1 to 5 or from 1 to 4 heteroatomic ring members (more often 1, 2 or 3 heteroatomic ring members), usually selected from nitrogen, oxygen and sulfur and their oxides. Heterocyclyl groups may contain, for example, cyclic ether moieties (e.g., as in tetrahydrofuran and dioxane), cyclic thioether moieties (e.g., as in pyrrolidine), cyclic amine moieties (e.g., as in pyrrolidone), cyclic thioamides, cyclic thioethers , cyclic ureas (eg, as in imidazolidin-2-one), cyclic ester moieties (eg, as in butyrolactone), cyclic sulfones (eg, as in sulfolane and sulfolene), cyclic sulfoxides, cyclic sulfonamides, and combinations thereof (eg, thiomorpholine ).

Specific examples include morpholinyl, piperidinyl (e.g. piperidin-1-yl, piperidin-2-yl, piperidin-3-yl and piperidin-4-yl), piperodinonyl, pyrrolidinyl (e.g. pyrrolidin-1-yl, pyrrolidin-2- yl and pyrrolidin-3-yl), pyrrolidonyl, azetidinyl, pyranyl (2H-pyran or 4H-pyran), dihydrothienyl, dihydropyranyl, dihydrofuranyl, dihydrothiazolyl, tetrahydrofuranyl, tetrahydrothienyl, dioxanyl, oxanyl (also known as tetrahydropyranyl) (e.g. oxan- 4-yl), imidazolinyl, imidazolidinonyl, oxazolinyl, thiazolinyl, pyrazolin-2-yl, pyrazolidinyl, piperazinonyl, piperazinyl, and N-alkyl piperazines such as N-methylpiperazinyl. In general, exemplary non-aromatic heterocyclyl groups include saturated groups such as piperidinyl, pyrrolidinyl, azetidinyl, morpholinyl, piperazinyl, and N-alkyl piperazines such as N-methylpiperazinyl.

The terms "oxan" and "oxanil" in the context of this document refer to the group:

which may also be referred to as "tetrahydropyran" or "tetrahydropyranyl".

The nitrogen-containing non-aromatic heterocyclyl ring must contain at least one nitrogen atom in the ring. Said nitrogen-containing heterocyclyl ring may be N-linked or C-linked. Heterocyclic groups may contain, for example, cyclic amine moieties (such as pyrrolidinyl), cyclic amides (such as pyrrolidinonyl, piperidinonyl or caprolactamyl), cyclic sulfonamides (such as isothiazolidinyl 1,1-dioxide, [1,2]thiazinanyl 1,1 -dioxide or [1,2]thiazepanyl 1,1-dioxide) and combinations thereof.

Specific examples of nitrogen-containing non-aromatic heterocyclyl 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), pyrrolidonyl, dihydrothiazolyl, imidazolinil, imidazolidinonyl, oxazolinyl, thiazolinyl, 6H-1,2,5-thiadiazinyl, pyrazolin-2-yl, pyrazolin-3-yl, pyrazolidinyl , piperazinyl, and N-alkyl piperazines such as N-methylpiperazinyl.

The heterocyclyl groups may be polycyclic fused ring systems or bridged ring systems such as the oxa and aza analogues of bicycloalkanes, tricycloalkanes (eg adamantane and oxaadamantane). For an explanation of the difference between fused and bridged ring systems, see Advanced Organic Chemistry by Jerry March, 4th edition, Wiley Interscience, pages 131-133, 1992.

Where the definition of a cyclic group or ring states that said cyclic group contains a specific number of heteroatomic ring members, such as in the phrase "5-6 membered ring containing 0, 1, or 2 nitrogen ring members", that statement is to be understood. as meaning that, with the exception of the specified number of heteroatomic ring members, the remaining ring members are carbon atoms.

The compound of formula (I) may contain saturated cyclic groups, which may be attached to the remainder of the molecule through one or more bonds. In cases where the cyclic group is attached to the rest of the molecule through two or more chains, these bonds (or two such bonds) can be established with the same atom (usually a carbon atom) of the ring or with different atoms of the ring. In cases where bonds are established to the same ring atom, this results in the formation of a cyclic group in which one atom (usually a quaternary carbon) is bonded to two groups. In other words, when the compound of formula (I) contains a cyclic group, this group may either be linked to the remainder of the molecule via a bond, or the cyclic group and the remainder of the molecule may share a common atom, such as in a spiro compound.

Each heterocyclyl group may be unsubstituted or substituted with one or more (eg 1, 2 or 3) substituent groups. For example, heterocyclyl or carbocyclyl groups may be unsubstituted or substituted with 1, 2, 3, or 4 substituents, and specifically, it is unsubstituted or contains 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 atom (when the substituents are the same, the so-called geminal or "heme"-disubstitution takes place).

The combination of substituents is only allowed if such combination results in the formation of a stable or chemically feasible compound (ie one that is substantially unchanged when stored at 40° C. or less for at least a week).

The various functional groups and substituents constituting the compounds of the present invention are specifically selected so that the molecular weight of the compound of the present invention does not exceed 1000. More commonly, the molecular weight of the compound will be less than 750, such as 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 OF THE INVENTION

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

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

The compounds of formula (I) contain a chiral center indicated below by "*":

The compounds of formula (I) contain a stereocenter at the designated position (referred to here as (3)) and are chiral non-racemic. The compounds of formula (I) have stereochemistry indicated by dashed and solid wedge bonds, and the indicated stereoisomer predominates.

Typically at least 55% (eg at least 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%) of the compound of formula (I) is present in the form of the shown stereoisomer. In one general embodiment, 97% (eg, 99%) or more (eg, substantially all) of the total compound of formula (I) may be present as a single stereoisomer.

The compounds may also contain one or more additional chiral centers (eg, in the CR ⁶ R ⁷ OH group and/or in the R ³ group and/or in the -CHR ² group).

Typically, the enantiomeric purity of a compound of formula (I) is at least 10% (eg, at least 20%, 40%, 60%, 80%, 85%, 90%, or 95%). In one general embodiment, the enantiomeric purity of the compound of formula (I) is at least 97% (eg, 99%) or more.

For the purposes of this section, the isoindoline-1-one ring is numbered as shown:

The compounds are named according to the protocols used by software packages for naming chemical compounds.

R ¹ and n

R ¹ is a substituent(s) on the phenyl group linked to -CHR ² -.

n is 0, 1, 2, or 3. In other words, the phenyl group associated with the -CHR ² - group may have 0, 1, 2, or 3 R ¹ substituents.

In one implementation, n is 1, 2, or 3. In one implementation, n is 1 or 2. In one implementation, n is 1.

When n is 2 or 3 (i.e., the phenyl group associated with the -CHR ² - group is substituted with more than one R ¹ ), the R ¹ substituents may be the same or different (i.e., independently selected from the definitions of R ¹ ) .

R ¹ may be attached at the ortho (or o-), meta (or m-), or para (or p-) position of the phenyl group, the position being relative to the point of attachment of the phenyl group to the -CHR ² - group.

R ¹ is independently selected from hydroxy, halogen, nitro, nitrile, C _1-4 alkyl, haloC _1-4 alkyl, hydroxyC _1-4 alkyl, C _2-6 alkenyl, C _1-4 alkoxy, haloC _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 -heterocyclic group containing 3-6 ring members, and -S( O) _d -N(R ⁸ ) ₂ .

R ¹ is independently selected from hydroxy, halogen, nitro, nitrile, C _1-4 alkyl, haloC _1-4 alkyl, hydroxyC _1-4 alkyl, C _2-6 alkenyl, C _1-4 alkoxy, haloC _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 -heterocyclic group containing 3-6 ring members, and -S(O) _d - N(R ⁸ ) ₂ .

R ¹ is independently selected from hydroxy, halogen, nitro, nitrile, C _1-4 alkyl, haloC _1-4 alkyl, hydroxyC _1-4 alkyl, C _2-6 alkenyl, C _1-4 alkoxy, haloC _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 -heterocyclic group containing 3-6 ring members, and -S(O) _d -N(R ⁸ ) ₂ .

In one embodiment, R ¹ is independently selected from halogen, hydroxy, nitrile, C _1-4 alkyl, C _2-4 alkynyl, or C _1-4 alkoxy, for example, R ¹ is independently selected from chlorine, hydroxy, nitrile, methyl, or methoxy.

In one embodiment, R ¹ is independently selected from halo (eg chlorine), C _1-4 alkyl (eg methyl), C _1-4 alkoxy (eg methoxy), -O _0.1 -(CR ^x R ^y ) _v -CO ₂ H (for example, -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 (eg SO ₂ CH ₃ ).

In one embodiment, R ¹ is O ₀ , ₁ -(CR ^x R ^y ) _v -CO ₂ H, in particular -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.

In one embodiment, R ¹ is chlorine or nitrile, in particular chlorine.

In one embodiment, R ¹ is nitro (eg p-NO ₂ ).

In one embodiment, R ¹ is nitro in the ortho or meta position.

In one embodiment, R ¹ is independently selected from hydroxy, halo, nitrile, C _1-4 alkyl, haloC _1-4 alkyl, hydroxyC _1-4 alkyl, C _2-6 alkenyl, C _1-4 alkoxy, haloC _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 -heterocyclic group containing 3-6 ring members, and -S(O) _d - N(R ⁸ ) ₂ .

In another embodiment, n is 1 and R ¹ is chlorine or nitrile.

In another embodiment, n is 1 and R ¹ is chlorine.

In another embodiment, n is 1 and R ¹ is a nitrile.

In one embodiment, one of the R ¹ groups or the R ¹ group (where n=1) is in the para position (ie, para relative to the phenyl ring attachment point). In one embodiment, n is 1 and R ¹ is p-chloro or p-nitrile.

In one embodiment, n is 1 and R ¹ is halogen (eg, Cl or F), nitrile, C _1-4 alkoxy (eg, -OCH ₃ ) or C _1-4 alkyl (eg, -CH ₃ ).

In one embodiment, R ¹ is -S(O) _d -C _1-6 alkyl or -S(O) _d -heterocyclic group containing 3-6 ring members and -S(O) _d -N(R ⁸ ) ₂ . In one embodiment, R ¹ is -SC _1-6 alkyl, -S(O)-C _1-6 alkyl, -S(O) ₂ -C _1-6 alkyl, -S(O) _d -heterocyclic group, containing 3-6 ring members, or -S(O) _d -N(C _1-6 alkyl) ₂ .

In another embodiment, R ¹ is -S-CH ₃ , -S(O)-CH ₃ , -S(O) ₂ -CH ₃ , or -S(O) ₂ -morpholinyl. In another embodiment, one or more R ¹ is -SO ₂ CH ₃ or -SO ₂ -heterocyclic group containing 6 ring members, for example, -SO ₂ -(morpholinyl), in particular -SO ₂ -(1-morpholinyl) .

In one embodiment, R ¹ is o-(-S(O) _d -C _1-4 alkyl) or o-(-S(O) _d -heterocyclic group containing 3-6 ring members). In one embodiment, R ¹ is o-S-C _1-4 alkyl, o-(-S(O) _d -C _1-4 alkyl), or o-(-S(O) _d -heterocyclic group containing 3 -6 ring members,). In one embodiment, R ¹ is o-(-S(O) ₂ -CH ₃ )

In one embodiment, R ¹ is -(CH ₂ ) _u -CO ₂ H. In one embodiment, R ¹ is -CO ₂ H. In one embodiment, R ¹ is -(CH ₂ ) _u -CO ₂ H in meta or para position. In one embodiment, R ¹ is -(CH ₂ ) _u -CO ₂ H in the ortho position.

In one embodiment, R ¹ is independently selected from hydroxy, halo, nitrile, C _1-4 alkyl, haloC _1-4 alkyl, hydroxyC _1-4 alkyl, C _2-6 alkenyl, C _1-4 alkoxy, haloC _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 -heterocyclic group containing 3-6 ring members, and -S(O) _d -N(R ⁸ ) ₂ .

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 -heterocyclic group containing 3-6 ring members, and (ii) halogen (eg Cl or F), nitrile or alkyl, in particular chlorine, nitrile or methyl.

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

In one embodiment, n is 2 and R ¹ is (i) -SO ₂ CH ₃ and (ii) chlorine, nitrile, or methyl.

In one embodiment, n is 2 and R ¹ is (i) -CO ₂ H and (ii) chlorine.

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

In one embodiment, when n is 2, the phenyl group linked to -CHR ² - is substituted with (i) hydroxyl and (ii) halogen (eg, Cl or F) or nitrile, eg chlorine, or nitrile.

In one embodiment, the phenyl group linked to -CHR ² - and R ¹ forms a group:

where, in particular, R ¹ represents halogen (eg, chlorine), nitrile or C _1-4 alkyl (eg, -CH ₃ ), and R ^x represents C _1-4 alkyl (eg, -CH ₃ ).

In one embodiment, the phenyl group linked to -CHR ² - and R ¹ forms a group:

where, in particular, R ¹ represents C _1-4 alkyl (eg, -CH ₃ ) and R ^x represents C _1-4 alkyl (eg, -CH ₃ ).

In one embodiment, when n is 2, the phenyl group is substituted with (i) o-OH or o-CH ₂ OH and (ii) halogen (eg Cl or F), nitrile or C _1-4 alkyl, in particular chlorine, or nitrile. In one embodiment, when n is 2, the phenyl group is substituted with (i) hydroxy and (ii) halogen (eg Cl or F) or nitrile, eg chlorine or nitrile. In one embodiment, when n is 2, the phenyl group is substituted with (i) o-hydroxy and (ii) p-Cl or p-CN (eg p-Cl).

In one embodiment, n is 2 and R ¹ is fluoro (eg, at the ortho and para positions of the phenyl group).

In one embodiment, R ¹ is halogen (eg, Cl or F), C _1-4 alkynyl (eg, -C≡CH), nitrile, -(CH ₂ ) _v COOH (eg, -COOH), or SO ₂ C _1-4 alkyl (eg SO ₂ CH ₃ ) and n is 1 or 2.

In one embodiment, R ¹ is halogen (eg, Cl), C _1-4 alkynyl (eg, -C≡CH), nitrile, hydroxyC _1-4 alkyl (eg, CH ₂ OH), -(CH ₂ ) _v COOH (eg -COOH), -S(O) _d -C _1-4 alkyl (eg SCH ₃ , SOCH ₃ or SO ₂ CH ₃ ), -SO ₂ -(1-morpholinyl) or -P(=O )(R ^x ) ₂ , (for example, -P(=O)(CH ₃ ) ₂ ).

In one embodiment, n is 1 and R ¹ is Cl (eg, p-Cl), CN (eg, p-CN), or C _2-4 alkynyl (eg, p-C ₁ alkynyl), or n is 2 , and (i) R ¹ is p-Cl, o-CH ₂ OH; (ii) p-CN, o-CH ₂ OH; or (iii) p-Cl, o-COOH, (iv) p-Cl, o-SCH ₃ , (v) p-Cl, oS(O)CH ₃ , (vi) p-Cl, o-SO ₂ CH ₃ , (vii) p-Cl, o-SO ₂ -(1-morpholinyl), or (viii) p-Cl, o-P(O)(CH ₃ ) ₂ .

In one embodiment, n is 1 and R ¹ is Cl (eg, p-Cl), CN (eg, p-CN), or C _2-4 alkynyl (eg, p-C ₁ alkynyl).

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

In one embodiment, n is 1 and R ¹ is -Cl, -CN, or -OMe (eg, 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).

In one embodiment, n is 2. When n is 2, typically the phenyl group is substituted at the o and p positions. In particular, n is 2 and R ¹ is substituted with p-chloro and o-(-S(O) _d -C _1-4 alkyl) or o-(-S(O) _d -heterocyclic group containing 3-6 ring members ,).

In one embodiment, n is 2 and R ¹ is o-CO ₂ H and p-chlorine.

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

In one embodiment, n is 2 and R ¹ is o-CH ₂ OH and p-chloro.

In one embodiment, n is 2 and R ¹ is o-CH ₂ OH and p-nitrile.

In one embodiment, n is 2 and R ¹ is o-OH and p-chloro.

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

In one embodiment, n is 2 and R ¹ is o-SO ₂ CH ₃ and p-chloro.

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

In one embodiment, R ¹ is -O _0.1 (CR ^x R ^y ) _v COOH (eg, -COOH, -CH ₂ COOH, -OCH ₂ COOH, or -C(CH ₃ ) ₂ COOH.

In one embodiment, n is 2 and R ¹ is p-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).

In one embodiment, R ¹ is halogen (eg, Cl), hydroxyalkyl (eg, -CH ₂ OH), C _1-4 alkynyl (eg, -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.

In one embodiment, R ¹ is halogen (eg, Cl), hydroxyalkyl (eg, -CH ₂ OH), C _1-4 alkynyl (eg, -C≡CH), nitrile, -(CH ₂ ) _v COOH (eg , -COOH) or -SO ₂ C _1-4 alkyl (eg -SO ₂ CH ₃ ) and n is 1 or 2.

In one embodiment, R ¹ is independently selected from hydroxy, halo, nitrile, C _1-4 alkyl, haloC _1-4 alkyl, hydroxyC _1-4 alkyl, C _2-6 alkenyl, C _1-4 alkoxy, haloC _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 (for example, -(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 -heterocyclic group containing 3-6 ring members, and -S(O) _d -N(R ⁸ ) ₂ .

In one embodiment, when n is 2 and one R ¹ is -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 -heterocyclic group containing 3-6 ring members), and one R ¹ is halogen (for example, Cl or F), nitrile or C _1-4 alkyl, in in particular chlorine, nitrile or methyl.

In one embodiment, when n is 2 and one R ¹ is o-(-S(O) _d -C _1-4 alkyl) or o-(-S(O) _d -heterocyclic group containing 3-6 ring members), and one R ¹ is halogen (eg Cl or F), nitrile or C _1-4 alkyl, in particular chlorine, nitrile or methyl.

In one embodiment, when n is 2 and one R ¹ is -O _0.1 -(CR ^x R ^y ) _v -CO ₂ C _1-4 alkyl and one R ¹ is halogen (e.g., Cl or F), nitrile or C _1-4 alkyl, in particular chlorine, nitrile or methyl, such as chlorine.

R ²

R ² is selected from hydrogen, C _1-4 alkyl, C _2-6 alkenyl, hydroxyC _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 .

In one implementation, and is selected from 0, 1, or 2. In one implementation, and is selected from 0 or 1.

In one embodiment, R ² is selected from hydrogen, C _1-4 alkyl, C _2-6 alkenyl, hydroxyC _1-4 alkyl, and -(CR ^x R ^y ) _u -CO ₂ H. In one embodiment, R ² is selected from hydrogen , C _1-4 alkyl, hydroxyC _1-4 alkyl, and -(CR ^x R ^y ) _u -CO ₂ H. In one embodiment, R ² is selected from hydrogen, C _1-4 alkyl, C _2-6 alkenyl, and hydroxyC _{1 -4} alkyl. In another embodiment, R ² is selected from hydrogen and -(CH ₂ ) _u -CO ₂ H (eg, -CH ₂ -CO ₂ H).

In one embodiment, R ² is hydrogen, C _1-4 alkyl (eg, -CH ₃ ), hydroxyC _1-4 alkyl (eg, CH ₂ OH), or -(CH ₂ ) _u COOH (eg, -COOH, - CH ₂ COOH, -CH ₂ CH ₂ -CO ₂ H, -(CH(CH ₃ ))-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).

In one embodiment, R ² is selected from hydrogen, C _1-4 alkyl, C _2-6 alkenyl, and hydroxyC _1-4 alkyl.

In one embodiment, R ² is hydrogen, C _1-4 alkyl (eg, -CH ₃ ), hydroxyC _1-4 alkyl (eg, CH ₂ OH), or -(CH ₂ ) _u COOH (eg, -CH ₂ COOH ). In one embodiment, R ² is selected from hydrogen, -CH ₃ , -CH ₂ OH, and -CH ₂ CO ₂ H.

In one embodiment, R ² is selected from hydrogen, -CH ₃ , -CH ₂ OH, -CH=CH ₂ and -CH(OH)CH ₂ OH.

In one embodiment, R ² is selected from hydrogen, -CH ₃ , -CH ₂ OH, and -CH ₂ CO ₂ H.

In one embodiment, R ² is hydrogen or C _1-4 alkyl (eg, -CH ₃ or -CH ₂ CH ₃ ).

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

In one embodiment, R ² is 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).

) или -(С(СН₃)₂-CO₂H).In one embodiment, R ² is -(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).

In one embodiment, R ² is hydrogen, C _1-4 alkyl (eg, -CH ₃ ) or -(CH ₂ ) _u COOH (eg, -CH ₂ COOH, -CH ₂ CH ₂ -CO ₂ H or -( CH(CH ₃ ))-CO ₂ H).

In one embodiment, R ² is hydrogen, C _1-4 alkyl (eg, -CH ₃ ) or -(CH ₂ ) _u COOH (eg, -CH ₂ COOH).

In one embodiment, R ² is -(CR ^x R ^y ) _u -CO ₂ H (eg, -CH ₂ -CO ₂ H).

,

или -(С(СН₃)₂-CO₂H.In another embodiment, R ² is selected from -(CH(CH ₃ ))-CO ₂ H and -(C(CH ₃ ) ₂ -CO ₂ H) (for example,

,

or -(C(CH ₃ ) ₂ -CO ₂ H.

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 pharmaceutically acceptable salt thereof:

When R ² is not hydrogen, the compound of formula (I) may exist in the form of at least two diastereisomers:

For the avoidance of doubt, general formula (I) and all sub-formulas encompass individual diastereoisomers and mixtures of diastereoisomers that are linked as epimers in the -CHR ² - group. In one embodiment, the compound of formula I is a diastereoisomer 1A or a tautomer or solvate or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of formula I is a 1B diastereoisomer or a tautomer or solvate or a pharmaceutically acceptable salt thereof.

In one embodiment, the compound is the diastereoisomer 1A and R ² is selected from:

i. C _1-4 alkyl, C _2-6 alkenyl, hydroxy C _1-4 alkyl, -(R ^x R ^y ) _u -CO ₂ H (for example, -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

ii. C _1-4 alkyl, C _2-6 alkenyl and hydroxyC _1-4 alkyl.

In one embodiment, the compound is the diastereoisomer 1A and R ² is selected from:

i. C _1-4 alkyl, C _2-6 alkenyl, hydroxyC _1-4 alkyl, -(CH ₂ ) _u -CO ₂ H, -(CH ₂ ) _u -CO ₂ C _1-4 alkyl and -(CH ₂ ) _u ^{-CONRxRy ;} or

ii. C _1-4 alkyl, C _2-6 alkenyl and hydroxyC _1-4 alkyl.

In another embodiment, R ² is 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),

In another embodiment, R ² is selected from hydrogen and -(CH ₂ ) _u -CO ₂ H (eg, -CH ₂ -CO ₂ H).

In one embodiment, the compound is the diastereoisomer 1A and R ² is selected from:

i. -CH ₃ , -CH ₂ OH, -CH=CH ₂ and -CH(OH)CH ₂ OH; or

ii. C _1-4 alkyl (eg -CH ₃ or -CH ₂ CH ₃ ); or

iii. -CH ₃ and -CH ₂ CH ₃ .

In one embodiment, the compound is the diastereoisomer 1B and R ² is selected from:

i. C _1-4 alkyl, C _2-6 alkenyl, hydroxyC _1-4 alkyl, -(R ^x R ^y ) _u -CO ₂ H (for example, -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

ii. C _1-4 alkyl, C _2-6 alkenyl and hydroxyC _1-4 alkyl.

In one embodiment, the compound is the diastereoisomer 1B and R ² is selected from:

i. C _1-4 alkyl, C _2-6 alkenyl, hydroxyC _1-4 alkyl, -(CH ₂ ) _u -CO ₂ H, -(CH ₂ ) _u -CO ₂ C _1-4 alkyl and -(CH ₂ ) _u ^{-CONRxRy ;} or

ii. C _1-4 alkyl, C _2-6 alkenyl and hydroxyC _1-4 alkyl.

In another embodiment, R ² is selected from hydrogen and -(CH ₂ ) _u -CO ₂ H (eg, -CH ₂ -CO ₂ H).

In one embodiment, the compound is the diastereoisomer 1B and R ² is selected from:

i. -CH ₃ , -CH ₂ OH, -CH=CH ₂ and -CH(OH)CH ₂ OH; or

ii. C _1-4 alkyl (eg -CH ₃ or -CH ₂ CH ₃ ); or

iii. -CH ₃ and -CH ₂ CH ₃ .

In another embodiment, R ² is 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),

In one embodiment, R ² is selected from C _1-4 alkyl, hydroxyC _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 (particularly -CH ₂ -CO ₂ H) and the compound is the diastereoisomer 1A.

In one embodiment, R ² is selected from C _1-4 alkyl, hydroxyC _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 (in particular -CH ₂ -CO ₂ H) and the compound is the diastereoisomer 1B.

In one embodiment, R ² is hydroxyC _1-4 alkyl (eg, —CH ₂ OH) and the compound is the 1A diastereoisomer.

In one embodiment, R ² is -(CH ₂ ) _u -CO ₂ H (eg, -CH ₂ -CO ₂ H) and the compound is the 1A diastereoisomer.

In one embodiment, R ² and the hydrogen atom on the carbon atom to which it is attached are ² H (ie, deuterium).

R ³ and s

R ³ is hydrogen or -(A) _t -(CR ^x R ^y ) _q -X;

s is chosen from 0 and 1;

t is selected from 0 and 1;

q is selected from 0, 1 and 2;

where when R ³ is -(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 equal to 1 and q is not equal to 0;

A represents a C _3-6 cycloalkyl group or a heterocyclic group containing 3-6 ring members, where the specified heterocyclic group contains one or more (for example, 1, 2 or 3) heteroatoms selected from N, O, S and their oxidized forms ;

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 ;

R ⁹ is independently selected from hydrogen, C _1-6 alkyl, haloC _1-6 alkyl, hydroxyC _1-6 alkyl, -(CH ₂ ) _k -O-C _1-6 alkyl, -(CH ₂ ) _k -O-( hydroxyC _1-6 alkyl), hydroxyC _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;

R ^x and R ^y are independently selected from hydrogen, halogen, nitro, nitrile, C _1-6 alkyl, haloC _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, hydroxy, hydroxyC _1-6 alkyl, C _{1 -6} alkoxy, -(CH ₂ ) _k -O-C _1-6 alkyl, hydroxyC _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;

or the R ^x and R ^y groups, together with the carbon or nitrogen atom to which they are attached, may combine to form a C _3-6 cycloalkyl or saturated heterocyclyl group containing 3-6 ring members which may optionally be fused to form an aromatic heterocyclyl group , consisting of 3-5 members of the ring, or can be combined to form a group =CH;

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

k is selected from 1 and 2; And

v is independently chosen from 0 and 1.

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

In one embodiment, R ³ is hydrogen or -(A) _t- (CR ^x R ^y ) _q -X;

s is chosen from 0 and 1;

t is selected from 0 and 1;

q is selected from 0, 1 and 2;

where when R ³ is -(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 equal to 1 and q is not equal to 0;

A represents a C _3-6 cycloalkyl group or a heterocyclic group containing 3-6 ring members, where the specified heterocyclic group contains one or more (for example, 1, 2 or 3) heteroatoms selected from N, O, S and their oxidized forms ;

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 ;

R ⁹ is independently selected from hydrogen and -C _1-6 alkyl;

R ^x and R ^y are independently selected from hydrogen and -C _1-6 alkyl;

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

v is independently chosen from 0 and 1.

In one embodiment, R ³ is hydrogen or -(A) _t -(CR ^x R ^y ) _q -X;

s is chosen from 0 and 1;

t is selected from 0 and 1;

q is selected from 0, 1 and 2;

where when R ³ is -(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 equal to 1 and q is not equal to 0;

A represents a C _3-6 cycloalkyl group or a heterocyclic group containing 3-6 ring members, where the specified heterocyclic group contains one or more (for example, 1, 2 or 3) heteroatoms selected from N, O, S and their oxidized forms ;

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 ;

R ⁹ is independently selected from hydrogen and -C _1-6 alkyl;

R ^x and R ^y are independently selected from hydrogen and -C _1-6 alkyl;

v is independently chosen from 0 and 1.

In one embodiment, R ³ is hydrogen or -(A) _t -(CR ^x R ^y ) _q -X;

s is chosen from 0 and 1;

t is selected from 0 and 1;

q is selected from 0, 1 and 2;

where when R ³ is -(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 equal to 1 and q is not equal to 0;

A represents a C _3-6 cycloalkyl group or a heterocyclic group containing 3-6 ring members, where the specified heterocyclic group contains one or more (for example, 1, 2 or 3) heteroatoms selected from N, O, S and their oxidized forms ;

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

R ⁹ is independently selected from hydrogen and -C _1-6 alkyl;

R ^x and R ^y are independently selected from hydrogen and -C _1-6 alkyl;

v is independently chosen from 0 and 1.

In one embodiment, R ³ is hydrogen or -(A) _t -(CR ^x R ^y ) _q -X;

s is chosen from 0 and 1;

t is selected from 0 and 1;

q is selected from 0, 1 and 2;

where when R ³ is -(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 equal to 1 and q is not equal to 0;

A represents a C _3-6 cycloalkyl group or a heterocyclic group containing 3-6 ring members, where the specified heterocyclic group contains one or more (for example, 1, 2 or 3) heteroatoms selected from N, O, S and their oxidized forms ;

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

R ⁹ is independently selected from hydrogen and -C _1-6 alkyl;

R ^x and R ^y are independently selected from hydrogen and -C _1-6 alkyl;

v is independently chosen from 0 and 1.

In one embodiment, R ³ is hydrogen and s is 1, i. fragment -(CH ₂ ) _s R ³ is -CH ₃ .

In one embodiment, R ³ is hydrogen and s is 0, i. fragment -(CH ₂ ) _s R ³ is -H.

In one embodiment, t is 1 and A is a C _3-6 cycloalkyl group or a heterocyclic group containing 3-6 ring members, wherein said heterocyclic group contains one or more (e.g., 1 or 2) heteroatoms selected from N, O , S and their oxidized forms.

In one embodiment, t is 1 and A is a C _3-6 cycloalkyl group. In one embodiment, A is a C _3-5 cycloalkyl group. For example, A is selected from a cyclopropyl group, a cyclobutyl group, and a cyclopentyl group. In one embodiment, A is a cyclopropyl group. In one embodiment, A is a cyclobutyl group.

In particular, t is 1 and A is cyclopropyl.

In one embodiment, t is 1 and A is a heterocyclic group containing 3-6 ring members, wherein said heterocyclic group contains one or more (e.g., 1, 2, or 3) heteroatoms selected from N, O, S, and their oxidized forms.

In one embodiment, t is 1 and A is a heterocyclic group containing 3-5 ring members, wherein said heterocyclic group contains one or more (e.g., 1, 2, or 3) heteroatoms selected from N, O, S, and their oxidized forms.

In one embodiment, t is 1 and A is an unsaturated heterocyclic group containing 3-5 ring members, wherein said heterocyclic group contains one or more (e.g., 1, 2, or 3) heteroatoms selected from N, O, S, and their oxidized forms, in particular, O.

In one embodiment, t is 1 and A is a saturated heterocyclic group containing 3-5 ring members, wherein said heterocyclic group contains one or more (e.g., 1, 2, or 3) heteroatoms selected from N, O, S, and their oxidized forms, in particular, O.

In one embodiment, t is 1 and A is a heterocyclic group selected from morpholinyl, piperidinyl (e.g., piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, and piperidin-4-yl), piperidinonyl, pyrrolidinyl (e.g., pyrrolidin-1-yl, pyrrolidin-2-yl, and pyrrolidin-3-yl), pyrrolidonyl, azetidinyl, oxetanyl, pyranyl (2H-pyran or 4H-pyran), dihydrothienyl, dihydropyranyl, dihydrofuranyl, dihydrothiazolyl, tetrahydrofuranyl ( e.g. tetrahydrofuran-3-yl), tetrahydrothienyl, dioxanyl, oxanyl (e.g. oxan-4-yl), imidazolinyl, imidazolidinonyl, oxazolinyl, thiazolinyl, pyrazolin-2-yl, pyrazolidinyl, piperazinonyl, piperazinyl and N-alkyl piperazines such as N-methylpiperazinyl.

In one embodiment, t is 1 and A is a heterocyclic group selected from morpholinyl, piperidinyl (e.g., piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, and piperidin-4-yl), piperidinonyl, pyrrolidinyl (e.g. pyrrolidin-1-yl, pyrrolidin-2-yl and pyrrolidin-3-yl), pyrrolidonyl, azetidinyl, oxetanyl, pyranyl (2H-pyran or 4H-pyran), dihydropyranyl, dihydrofuranyl, dihydrothiazolyl, tetrahydrofuranyl (e.g. tetrahydrofuran -3-yl), dioxanyl, oxanyl (eg oxan-4-yl), imidazolinyl, imidazolidinonyl, oxazolinyl, pyrazolin-2-yl, pyrazolidinyl, piperazinonyl, piperazinyl, and N-alkyl piperazines such as N-methylpiperazinyl.

In particular, t is 1 and A is a heterocyclic group which is oxetanyl (eg oxetan-3-yl).

In particular, t is 1 and A is a heterocyclic group which is tetrahydrofuranyl (eg tetrahydrofuran-3-yl).

In one embodiment, X is hydrogen, s is 0, and R ³ is a heterocyclic group containing 3-6 ring members, wherein said heterocyclic group contains one or more (e.g., 1, 2, or 3) heteroatoms selected from N , O, S and their oxidized forms. In particular, R ³ is tetrahydrofuranyl (eg tetrahydrofuran-3-yl).

In one embodiment, s is 0 and t is 1, and A is attached directly to the oxygen atom associated with isoindolinone. In one embodiment, s is 1 and the cycloalkyl group is attached via a methylene group (ie -CH ₂ -) to the oxygen atom associated with isoindolinone.

In one embodiment, A is tetrahydrofuranyl and X is hydrogen.

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

In one implementation, q is 0. In one implementation, q is 1. In one implementation, q is 2.

In one embodiment, A is oxetanyl and X is fluoro.

When q is not 0, R ^x and R ^y are selected from hydrogen, halogen (eg fluorine), hydroxy, and methyl, eg hydrogen, and methyl, eg hydrogen.

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 of R ^x and R ^y are hydrogen, i.e. the three R ^x and R ^y are hydrogen.

In one embodiment, -(CR ^x R ^y ) _q - is selected from -CH ₂ and -CH ₂ CH ₂ .

In one embodiment, R ^x and R ^y together form a saturated heterocyclic group containing 3-6 ring members.

In one embodiment, t is 0 and -(CR ^x R ^y ) _q - is -CH ₂ -. In one embodiment, t is 0, s is 0, -(CR ^x R ^y ) _q - is -CH ₂ - and X is hydroxy.

In one embodiment, X is selected from hydrogen, halogen, -CN, -OH, -O-C _1-4 alkyl, -O-hydroxyC _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 .

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 R ^y (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 ).

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 .

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 .

In one embodiment, X is selected from -OH and -C(=O)NH ₂ , i.e. -HE.

In one embodiment, X is -C(=O)NR ^x R ^y (eg, -C(=O)NH ₂ or -C(=O)NH(CH ₃ ).

In one embodiment, R ^x and R ^y are selected from hydrogen, halogen (eg, fluorine), hydroxy, and methyl. In one embodiment, R ^x and R ^y are hydrogen and methyl. In one embodiment, R ^x and R ^y together form a saturated heterocyclic group containing 3-6 ring members.

In another embodiment, A is a C _3-6 cycloalkyl group (i.e., 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 pharmaceutically acceptable salt thereof:

In another embodiment, A is a C _3-6 cycloalkyl group (i.e., 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 its tautomer or solvate or pharmaceutically acceptable salt:

In another embodiment, A is a C _3-6 cycloalkyl group (i.e., 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:

In another embodiment, the compound of formula (I) is a compound of formula (Ig') and g is 2.

In another embodiment, A is a C _3-6 cycloalkyl group (i.e., g is 1, 2, or 3) and t is 1 and s is 1, and said cycloalkyl group is geminally disubstituted (i.e., the group -(CR ^x R ^y ) _q -X and -CH ₂ -O-isoindolinone group 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 thereof, or pharmaceutically acceptable salt:

In one embodiment, A is a cyclopropyl group (i.e., g is 1), t is 1, and s is 1. Therefore, a cycloalkyl group is a cyclopropyl group and a compound of formula (I) is a compound of formula (Ii) or its tautomer or solvate or pharmaceutically acceptable salt:

In one embodiment, A is a C _3-6 cycloalkyl group (i.e., 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 formula (Ij) or a tautomer or solvate or pharmaceutically acceptable salt thereof:

In one embodiment, A is a C _3-6 cycloalkyl group (i.e., g is 1, 2, or 3), t is 1, s is 1, and X is -C(=O)NH ₂ , and the compound formula (I) is a compound of formula (Ik) or a tautomer or solvate or pharmaceutically acceptable salt thereof:

In one embodiment, A is a C _3-6 cycloalkyl group (i.e., 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 pharmaceutically acceptable salt thereof:

In another embodiment, A is a C _3-6 cycloalkyl group (i.e., g is 1, 2, or 3), t is 1, s is 1, and R ^x and R ^y are 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 pharmaceutically acceptable salt thereof:

In one embodiment, A is a cyclopropyl or cyclobutyl group (i.e., 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 its tautomer or solvate or pharmaceutically acceptable salt:

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:

In one embodiment, A is a C _3-6 cycloalkyl group (i.e., g is 1), t is 1, s is 1, and X is -C(=O)NH ₂ , and a compound of formula (I) is a compound of formula (In) or a tautomer or solvate or pharmaceutically acceptable salt thereof:

where n is 0 or 1. In one embodiment of compound (In), q is 0.

In one embodiment, A is a C _3-6 cycloalkyl group (i.e., g is 1), t is 1, s is 1, and X is -CN, and a compound of formula (I) is a compound of formula (In ') or a tautomer or solvate or pharmaceutically acceptable salt thereof:

where q is 0 or 1. In one embodiment of compound (In), q is 0.

In one embodiment of formula (I) and its subformulas, the hydrogen atoms in the -(CR ^x R ^y )-group R ³ are ² H (ie deuterium, D). In one embodiment, the hydrogen atoms in the -CH ₂ -O group are ² H (ie, deuterium, D). In one embodiment, the hydrogen atoms in the -(CR ^x R ^y )- and -CH ₂ -O groups are ² H (ie, deuterium, D).

In one embodiment, q is 0 or 1 and R ^x and R ^y are hydrogen or deuterium.

In one embodiment, A is cyclopropyl (i.e., g is 1), t is 1, s is 1, and the hydrogens in -(CR ^x R ^y )- and -CH ₂ -O are ² H ( or D), and the compound of formula (I) is a compound of formula (Io) or a tautomer or solvate or pharmaceutically acceptable salt thereof:

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:

In one embodiment, R ³ is -(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):

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

In another embodiment, A is a C _3-6 cycloalkyl group or a saturated heterocyclic group containing 3-6 ring members, where 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 :

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

In one embodiment of compound (Iq'), q is 1 and R ^x and R ^y are hydrogen.

In one embodiment of compound (Iq'), q is 1, R ^x and R ^y are hydrogen, and X is hydroxy.

In one embodiment of compound (Iq'), q is 1, R ^x and R ^y are hydrogen, and X is fluoro.

In one embodiment of compound (Iq'), q is 0. In one embodiment of compound (Iq'), q is 0 and X is fluoro.

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

In one embodiment of compound (Iq') or compound (Iq''), g is 1, i is 1, and Y is O.

In one embodiment, g is 1, i is 1, Y is O, 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:

In one embodiment, i is 1 and Y is O or SO ₂ , specifically O. In one embodiment, a compound of formula (Iq) is a compound of formula (Iq'''') or a tautomer or solvate or pharmaceutically acceptable salt thereof. :

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.

In one embodiment, -(CH ₂ ) _s R ³ is selected from the following table (the point of attachment to the oxygen atom is indicated by a dotted bond or a bond end point indicated by "*"):

In one embodiment, -(CH ₂ ) _s R ³ is selected from the following table (the point of attachment to the oxygen atom is indicated by a dotted bond or a bond end point indicated by "*"):

In one embodiment, A is cyclopropyl, t is 1, s is 1, R ^x and R ^y are hydrogen, and X is -OH.

In one embodiment, A is cyclopropyl, t is 1, s is 1, R ^x and R ^y are hydrogen, and X is -CN.

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

R ⁴ and a

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

In one implementation, a is 0 or 1. In another implementation, a is 0. In another implementation, a is 1.

When a is 2 or 3 (ie, the phenyl group of isoindolin-1-one is substituted by more than one R ⁴ ), the R ⁴ substituents may be the same or different (ie, independently selected from the R ⁴ definitions).

In one embodiment, a is 1 and 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 pharmaceutically acceptable salt thereof:

R ⁴ is independently selected from halo, nitrile, C _1-4 alkyl, haloC _1-4 alkyl, C _1-4 alkoxy, and haloC _1-4 alkoxy.

In one embodiment, R ⁴ is halogen. In one embodiment, R ⁴ is fluorine or chlorine. In another embodiment, R ⁴ is fluoro.

In one embodiment, a is 1, 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 pharmaceutically acceptable salt thereof :

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:

In one embodiment, R ⁴ is C _1-4 alkyl (eg, -CH ₃ ) or halogen (eg, F or Cl) and a is 1.

In one embodiment, a is 0 and R ⁴ is absent (ie, is hydrogen).

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

R ⁵ and m

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

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

R ⁵ may be attached at the ortho- (or o-), meta- (or m-), or para- (or p-) position of the phenyl group, the position being relative to the point of attachment of the phenyl group to position 3 of the isoindolin-1-one ring .

When m is 2 (ie, the phenyl group is substituted with more than one R ⁵ ), the R ⁵ substituents may be the same or different (ie, independently selected from the R ⁵ definitions).

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

R ⁵ is independently selected from halo, nitrile, C _1-4 alkyl, haloC _1-4 alkyl, C _1-4 alkoxy, and haloC _1-4 alkoxy.

In one embodiment, R ⁵ is halo, C _1-4 alkyl, haloC _1-4 alkyl, or C _1-4 alkoxy. In another embodiment, R ⁵ is halogen (eg, chlorine).

In one embodiment, R ⁵ is halo (eg, Cl or F), C _1-4 alkyl (eg, -CH ₂ CH ₃ ), nitrile, haloC _1-4 alkyl (eg, -CF ₃ or -CF ₂ CH ₃ ) or haloC _1-4 alkoxy (eg -OCF ₃ ) and m is 1 or 2.

In one embodiment, m is 1 and R ⁵ is selected from halo, nitrile, C _1-4 alkyl, haloC _1-4 alkyl, C _1-4 alkoxy, and haloC _1-4 alkoxy.

In one embodiment, m=1 and R ⁵ is -Cl (eg, p-Cl), -F (eg, 4-F), -CN (eg, p-CN), -CF ₃ (eg, p -CF ₃ ), -OCF ₃ (eg p-OCF ₃ ), CF ₂ CH ₃ (eg p-CF ₂ CH ₃ ) or -CH ₂ CH ₃ (eg p-CH ₂ CH ₃ ) or m= 2 and R ⁵ is p-F or m-F.

In one embodiment, m=1 and R ⁵ is -Cl (e.g. p-Cl)

^R6 and ^R7

R ⁶ and R ⁷ are independently selected from hydrogen, C _1-6 alkyl, haloC _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, hydroxy, hydroxyC _1-6 alkyl, -COOC _1-6 alkyl, - (CH ₂ ) _j -O-C _1-6 alkyl, -(CH ₂ ) _j -O-(hydroxyC _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 containing 3-7 ring members, -CH ₂ -heterocyclic group containing 3-7 ring members, -CH ₂ -O-heterocyclic group containing 3-7 ring members, -CH ₂ -NH-heterocyclic group containing 3-7 ring members, -CH ₂ - N(C _1-6 alkyl)-heterocyclic group containing 3-7 ring members, -C(=O)NH-heterocyclic group containing 3-7 ring members, C _3-8 cycloalkyl, -CH ₂ -C _{3- 8} cycloalkyl, -CH ₂ -O-C _3-8 cycloalkyl and C _3-8 cycloalkenyl, where said cycloalkyl, cycloalkenyl or heterocyclic groups may be optionally substituted with one or more R ^z groups, and where in each case the heterocyclic group contains one or more than (eg 1, 2 or 3) heteroatoms selected from N, O, S and their oxidized forms;

or groups R ⁶ and R ⁷ together with the carbon atom to which they are attached, can be combined to form a C _3-6 cycloalkyl or heterocyclyl group containing 3-6 ring members, where the specified heterocyclic group contains one or more (for example, 1, 2 or 3) heteroatoms selected from N, O, S and their oxidized forms, and wherein said C _3-6 cycloalkyl and heterocyclyl groups may be optionally substituted with one or more R ^z groups;

R ^x and R ^y are independently selected from hydrogen, halogen, nitro, nitrile, C _1-6 alkyl, haloC _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, hydroxy, hydroxyC _1-6 alkyl, C _{1 -6} alkoxy, -(CH ₂ ) _k -O-C _1-6 alkyl, hydroxyC _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;

or the R ^x and R ^y groups, together with the carbon or nitrogen atom to which they are attached, may combine to form a C _3-6 cycloalkyl or saturated heterocyclyl group containing 3-6 ring members which may optionally be fused to an aromatic heterocyclyl group, consisting of 3-5 ring members;

or, when located at a carbon atom, the groups R ^x and R ^y can combine to form a group =CH ₂ ;

R ^z is independently selected from halo, nitro, nitrile, C _1-6 alkyl, haloC _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, =O, hydroxy, hydroxyC _1-6 alkyl, C _1-6 alkoxy, -(CH ₂ ) _k -O-C _1-6 alkyl, hydroxyC _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 , heterocyclyl group containing 3-6 ring members, heterocyclyl group containing 3-6 ring members substituted with -C(=O)C _1-4 alkyl, heterocyclyl group , containing 3-6 ring members, substituted with -C(=O)OC _1-4 alkyl, heterocyclyl group containing 3-6 ring members, substituted with -C(=O)N(H) _e (C _1-4 alkyl) _2-e , -C(=O)heterocyclyl group containing 3-6 ring members, C _3-8 cycloalkyl and C _3-8 cycloalkenyl, where if R ⁷ is pyridine, then R ^z is not -NH ₂ ;

j, e, r and p are independently selected from 0, 1 and 2; And

k is chosen from 1 and 2.

In one embodiment, R ⁶ and R ⁷ are independently selected from hydrogen, C _1-6 alkyl, haloC _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, hydroxy, hydroxyC _1-6 alkyl, -COOC _{1- 6} alkyl, -(CH ₂ ) _j -O-C _1-6 alkyl, -(CH ₂ ) _j -O-(hydroxyC _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 containing 3- 7 ring members, -CH ₂ -heterocyclic group containing 3-7 ring members, -CH ₂ -O-heterocyclic group containing 3-7 ring members, -CH ₂ -NH-heterocyclic group containing 3-7 ring members, -CH ₂ -N(C _1-6 alkyl)-heterocyclic group containing 3-7 ring members, -C(=O)NH-heterocyclic group containing 3-7 ring members, C _3-8 cycloalkyl, -CH ₂ -C _3-8 cycloalkyl, -CH ₂ -O-C _3-8 cycloalkyl and C _3-8 cycloalkenyl, where said cycloalkyl, cycloalkenyl or heterocyclic groups may be optionally substituted with one or more R ^z groups, and where in each case the heterocyclic the group contains one or more (eg 1, 2 or 3) heteroatoms selected from N, O, S and their oxidized forms;

In one embodiment, R ⁷ is a cycloalkyl, cycloalkenyl, or heterocyclic group optionally substituted with one or more R ^z selected from C _1-6 alkyl (eg, methyl), C _1-6 alkoxy (eg, methoxy), and -C( =O)C _1-6 alkyl (for example, -C(=O)CH ₃ ).

In one embodiment, R ⁷ is a cycloalkyl or cycloalkenyl group optionally substituted with one or more R ^z groups, where R ^z is hydroxy.

R ⁶ and R ⁷ may be the same or different.

When R ⁶ and R ⁷ are different, the compound of formula (I) may exist in the form of at least two diastereisomers:

For the avoidance of doubt, general formula (I) and all sub-formulas encompass individual diastereoisomers and mixtures of diastereoisomers that are linked as epimers in the -CR ⁶ R ⁷ OH group.

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

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

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

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 pharmaceutically acceptable salt thereof:

In one embodiment, R ⁷ is selected from C _1-6 alkyl or haloC _1-6 alkyl. In one embodiment, R ⁷ is C _3-6 cycloalkyl (eg, cyclopropyl, cyclobutyl, or cyclohexyl) optionally substituted with one or more R ^z groups (eg, —OH).

In one embodiment, R ⁷ is selected from C _1-6 alkyl, hydroxyC _1-6 alkyl, -(CH ₂ ) _j -O-C _1-6 alkyl, -(CH ₂ ) _j -O-(hydroxyC _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 , heterocyclic group containing 3-7 ring members, -CH ₂ -heterocyclic group containing 3-7 ring members, -CH ₂ -NH-heterocyclic group containing 3-7 ring members, -CH ₂ -N(C _1-6 alkyl)-heterocyclic group containing 3-7 ring members, -C(=O)NH-heterocyclic group containing 3-7 ring members, C _3-8 cycloalkyl and -CH ₂ -C _3-8 cycloalkyl, where said cycloalkyl or heterocyclic groups may be optionally substituted with one or more R ^z groups, and where in each case the heterocyclic group contains one or more (for example, 1, 2 or 3) heteroatoms selected from N, O, S and their oxidized forms .

8 in one embodiment, R ⁷ is selected from C _1-6 alkyl, hydroxyC _1-6 alkyl, -(CH ₂ ) _j -O-C _1-6 alkyl, -(CH ₂ ) _j -O-(hydroxyC _1-6 alkyl ), C _1-6 alkyl-N (H) _e (C _1-4 alkyl) _2-e , heterocyclic group containing 3-7 ring members, -CH ₂ -heterocyclic group containing 3-7 ring members, -C (=O)NH-heterocyclic group containing 3-7 ring members, C _3-8 cycloalkyl and -CH ₂ -C _3-8 cycloalkyl, where said cycloalkyl or heterocyclic groups may be optionally substituted with one or more R ^z groups, and where in each case the heterocyclic group contains one or more (for example, 1, 2 or 3) heteroatoms selected from N, O, S and their oxidized forms.

In one embodiment, R ⁷ is selected from a heterocyclic group containing 3-7 ring members, -CH ₂ -heterocyclic group containing 3-7 ring members, -C(=O)NH-heterocyclic group containing 3-7 ring members, C _3-8 cycloalkyl and -CH ₂ -C _3-8 cycloalkyl, where said cycloalkyl or heterocyclic groups may be optionally substituted with one or more R ^z groups, and where in each case the heterocyclic group contains one or more (for example, 1, 2 or 3) heteroatoms selected from N, O, S and their oxidized forms.

8 in one embodiment, R ⁷ is selected from a heterocyclic group containing 3-7 ring members, a -CH ₂ -heterocyclic group containing 3-7 ring members, a -C(=O)NH-heterocyclic group containing 3-7 ring members, C _3-8 cycloalkyl and -CH ₂ -C _3-8 cycloalkyl, where said cycloalkyl or heterocyclic groups may be optionally substituted with one or more R ^z groups, and where in each case the heterocyclic group contains one or more (for example, 1 or 2 ) heteroatoms selected from N, O, S and their oxidized forms.

In one embodiment, said heterocyclic group is saturated. In one embodiment, R ⁷ is a saturated heterocyclic group containing 3-6 ring members, or -CH ₂ -(saturated heterocyclic group containing 3-6 ring members), for example, where the heterocyclic group is selected from oxetanyl, oxanyl, piperidinyl, piperazinil, morpholinyl, pyrrolidinyl, imidazolinil, azetidinyl, thiomorpholinyl such as oxanil, piperidinyl or piperazinyl.

In one embodiment, R ⁷ is selected from a saturated heterocyclic group containing 3-6 ring members and a -CH ₂ -saturated heterocyclic group containing 3-6 ring members, where said heterocyclic groups may be optionally substituted with one or more R ^z groups, and where in each case the heterocyclic group contains one or more (for example, 1, 2 or 3) heteroatoms selected from N, O, S. In one embodiment, R ⁷ is selected from a nitrogen-containing saturated heterocyclic group containing 3-6 ring members, and -CH ₂ -(nitrogen-containing saturated heterocyclic group containing 3-6 ring members), and where the specified heterocyclic group may optionally contain one or more (for example, 1, 2 or 3) additional heteroatoms selected from N, O, S.

In one embodiment, R ⁷ is selected from a nitrogen-containing saturated heterocyclic group containing 3-7 ring members, or -CH ₂ -(nitrogen-containing saturated heterocyclic group containing 3-7 ring members), where these nitrogen-containing saturated heterocyclic groups may be optionally substituted with one or more R ^z groups, and wherein, in each occurrence, said nitrogen-containing saturated heterocyclic group may optionally contain one or more (e.g., 1, 2, or 3) additional heteroatoms selected from N, O, S. In one embodiment, the nitrogen-containing saturated heterocyclic group , containing 3-7 ring members, is selected from piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, imidazolinyl, azetidinyl, thiomorpholinyl such as piperidinyl or piperazinyl.

In one embodiment, R ⁷ is selected from a nitrogen-containing aromatic heterocyclic group containing 3-6 ring members, or -CH ₂ -(nitrogen-containing aromatic heterocyclic group containing 3-6 ring members), where these heterocyclic groups may be optionally substituted with one or more R ^z groups, and where the heterocyclic group may optionally contain one or more (for example, 1, 2 or 3) additional heteroatoms selected from N, O, S.

In another embodiment, R ⁷ is selected from a nitrogen-containing aromatic heterocyclic group containing 3-6 ring members, where said heterocyclic group may be unsubstituted or substituted with one or more R ^z groups, e.g., selected from halogen (e.g., fluorine), C _{1- 6} alkyl (eg methyl), C _1-6 alkoxy (eg methoxy) and -C(=O)C _1-6 alkyl (eg -C(=O)CH ₃ ).

In one embodiment, R ⁷ is selected from an oxygen-containing aromatic heterocyclic group containing 3-6 ring members, or -CH ₂ - (an oxygen-containing aromatic heterocyclic group containing 3-6 ring members), where these heterocyclic groups may be optionally substituted with one or more R ^z groups, and where the heterocyclic group may optionally contain one or more (for example, 1, 2 or 3) additional heteroatoms selected from N, O, S.

In another embodiment, R ⁷ is selected from an oxygen-containing aromatic heterocyclic group containing 3-6 ring members, where said heterocyclic group may be unsubstituted or substituted with one or more R ^z groups, e.g., R ^z groups selected from halogen (e.g., fluorine) , C _1-6 alkyl (eg methyl), C _1-6 alkoxy (eg methoxy) and -C(=O)C _1-6 alkyl (eg -C(=O)CH ₃ ).

In one embodiment, R ⁷ is selected from heterocyclyl groups containing 5 or 6 ring members optionally substituted with one or more R ^z .

In one embodiment, R ⁷ is selected from aromatic heterocyclyl groups containing 5 ring members optionally substituted with one or more R ^z . In one embodiment, R ⁷ is selected from an aromatic nitrogen-containing (eg, diaza) heterocyclyl group containing 5 ring members optionally substituted with one or more R ^z . In one embodiment, R ⁷ is pyrazolyl (eg, pyrazol-4-yl or pyrazol-3-yl).

In one embodiment, R ⁷ is selected from a saturated heterocyclyl group containing 6 ring members optionally substituted with one or more R ^z . In one embodiment, R ⁷ is selected from a saturated oxygen or nitrogen containing heterocyclyl group containing 6 ring members optionally substituted with one or more R ^z .

In one embodiment, R ⁷ is selected from oxanyl, piperidinyl, pyrazolyl, or imidazolyl, optionally substituted with one or more R ^z . In one embodiment, R ⁷ is selected from oxanyl, piperidinyl, pyrazolyl, or imidazolyl, optionally substituted with one or more R ^z , where R ^z is selected from halo (eg, -F) or C _1-4 alkyl (eg, methyl).

In one embodiment, R ⁷ is selected from oxanyl (also known as tetrahydropyranyl) and piperidinyl, optionally substituted with one or more R ^z . In one embodiment, R ⁷ is selected from oxanyl or piperidinyl, optionally substituted with one or more R ^z , where R ^z is selected from halogen (eg, -F) or C _1-4 alkyl (eg, methyl), particularly halogen (eg , -F).

In one embodiment, R ⁷ is C _3-8 cycloalkyl, such as C _3-6 cycloalkyl (eg, cyclobutyl or cyclohexyl), optionally substituted with one or more R ^z ., for example, where R ^z is hydroxy. In one embodiment, R ⁷ is cyclohexyl optionally substituted with one or more hydroxy. In one embodiment, R ⁷ is cyclohexyl, optionally substituted with one or more hydroxyl, in trans stereochemistry (eg, trans-4-hydroxycyclohexane).

In one embodiment, R ⁷ is selected from -CH ₂ -NH-heterocyclic group containing 3-7 ring members (for example, -CH ₂ -NH-oxanyl and -CH ₂ -N(C _1-6 alkyl)-heterocyclic group, containing 3-7 ring members, (eg, -CH ₂ NCH ₃ -(piperidinyl), optionally substituted with one or more R ^z groups (eg, methyl, -COCH ₃ ).

In one embodiment, R ⁷ is -(CR ^x R ^y ) _p -CONR ^x R ^y or -C(=O)NH-heterocyclic group containing 3-7 ring members. In one embodiment, R ⁷ is a -C(=O)NH-heterocyclic group containing 4-6 ring members (eg, piperidinyl, pyrazolyl, or azetidinyl).

In one embodiment, R ⁷ is -(CR ^x R ^y ) _p -CONR ^x R ^y . In one embodiment, R ⁷ is -(CR ^x R ^y ) _p -CONH(C _1-4 alkyl), in particular -(CO)NHCH ₃ , -(CO)NHCH ₂ CH ₃ or -(CO)NH (CH(CH ₃ ) ₂ ).

In one embodiment, R ⁷ is -C(=O)NH-heterocyclic group containing 3-7 ring members (e.g., -C(=O)NH-piperidinyl, -C(=O)NH-azetidinyl, or -C (=O)NH-pyrazolyl), optionally substituted with one or more R ^z groups (eg methyl, -COCH ₃ ).

In one embodiment, R ⁷ is -C _1-6 alkyl-NR ^x R ^y (eg, -C _1-6 alkyl-N(H) _e (C _1-4 alkyl) _2-e ). In one embodiment, R ⁷ is -CH ₂ NH ₂ , -CH ₂ NHCH _{3 ,} or -CH ₂ N(CH ₃ ) ₂ . In one embodiment, R ⁷ is -C _1-6 alkyl-NR ^x R ^y , where R ^x is C _3-8 cycloalkyl. In one embodiment, R ⁷ is -C _1-2 alkyl-NH-C _3-6 cycloalkyl (eg, -CH ₂ -NH-cyclopropyl).

In one embodiment, R ⁷ is -C _1-6 alkyl-NR ^x R ^y , where the R ^x and R ^y groups, together with the nitrogen atom to which they are attached, can combine to form a C _3-6 cycloalkyl or heterocyclyl group, containing 3-6 ring members. In one embodiment, the implementation of R ^x and R ^y together form a saturated heterocyclic group containing 3-6 ring members, for example, piperazinyl.

In one embodiment, R ⁷ is -C _1-6 alkyl-NR ^x R ^y , where the R ^x and R ^y groups, together with the nitrogen atom to which they are attached, combine to form a C _3-6 cycloalkyl or saturated heterocyclyl group, containing 3-6 ring members, which may optionally be fused to form an aromatic heterocyclyl group consisting of 3-5 ring members. In one embodiment, R ⁷ is -C _1-6 alkyl-NR ^x R ^y , where the R ^x and R ^y groups, together with the nitrogen atom to which they are attached, combine to form a saturated heterocyclyl group containing 3-6 ring members , which is fused to an aromatic heterocyclyl group consisting of 3-5 ring members. R ^z is independently selected from halo, nitro, nitrile, C _1-6 alkyl, haloC _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, =O, hydroxy, hydroxyC _1-6 alkyl, C _1-6 alkoxy, -(CH ₂ ) _k -O-C _1-6 alkyl, hydroxyC _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 heterocyclyl group containing 3-6 ring members, a heterocyclyl group containing 3-6 ring members substituted with -C(=O)C _1-4 alkyl, a heterocyclyl group containing 3-6 ring members substituted with -C(=O)OC _1-4 alkyl, heterocyclyl group containing 3-6 ring members substituted with -C(=O)N(H) _e (C _1-4 alkyl) _{2- e} , -C(=O)heterocyclyl group containing 3-6 ring members, C _3-8 cycloalkyl and C _3-8 cycloalkenyl.

In one embodiment, R ⁷ is independently selected from halo (eg, fluorine), C _1-6 alkyl (eg, methyl), C _1-6 alkoxy (eg, methoxy), and -C(=O)C _1-6 alkyl ( for example, -C(=O)CH ₃ ).

In one embodiment, R ⁷ is independently selected from C _1-6 alkyl (e.g., methyl), C _1-6 alkoxy (e.g., methoxy), and -C(=O)C _1-6 alkyl (e.g., -C(=O ) CH ₃ ).

In one embodiment, R ⁷ is C _1-6 alkyl (eg, methyl or ethyl), haloC _1-6 alkyl (eg, trifluoromethyl), C _2-6 alkenyl (eg, C ₂ alkenyl), hydroxyC _1-6 alkyl (for example, -CH ₂ OH, -CH ₂ CH ₂ OH), -C _1-6 alkyl-NR ^x R ^y (for example, -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 (for example, -(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 (for example, -CH ₂ OCH ₃ , -CH ₂ OCH ₂ CH ₃ or -CH ₂ OCD ₃ ), -(CR ^x R ^y ) _p -NR ^x COR ^y (for example, -CH ₂ NHCOCH ₃ ), -(CR ^x R ^y ) _p -O-CH ₂ -CONR ^x R ^y (for example, - CH ₂ -O-CH ₂ CON(CH ₃ ) ₂ ), -(CH ₂ ) _j -O-(hydroxyC _1-6 alkyl) (for example, -CH ₂ -O-CH ₂ CH ₂ OH,), -C (=O)NH-heterocyclic group containing 3-7 ring members, C _3-6 cycloalkyl, heterocyclic group containing 3-7 ring members (for example, oxanyl), or -CH ₂ -heterocyclic group containing 3-7 members rings, where the specified cycloalkyl or heterocyclic group contains one or more (for example, 1, 2 or 3) heteroatoms selected from N, O, S and their oxidized forms, and may be optionally substituted with one or more R ^z groups (for example, selected from C _1-6 alkyl (eg methyl), C _1-6 alkoxy (eg methoxy) and -C(=O)C _1-6 alkyl (eg -C(=O)CH ₃ )). In one embodiment, R ⁶ is methyl or ethyl and R ⁷ is C _1-6 alkyl (e.g. methyl), hydroxyC _1-6 alkyl, -C _1-6 alkyl-NR ^x R ^y , -(CR ^x R ^y ) _p -CONR ^x R ^y , -(CH ₂ ) _j- O-C _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-(hydroxyC _1-6 alkyl), a heterocyclic group containing 3-7 ring members (for example, oxanil), or -CH ₂ -heterocyclic group containing 3 -7 ring members, where the specified heterocyclic group contains one or more (for example, 1, 2 or 3) heteroatoms selected from N, O, S and their oxidized forms, and may be optionally substituted with one or more R ^z groups selected from C _1-6 alkyl (eg methyl), C _1-6 alkoxy (eg methoxy) and -C(=O)C _1-6 alkyl (eg -C(=O)CH ₃ )).

In one embodiment, R ⁶ is selected from hydrogen, C _1-6 alkyl (eg, -CH ₃ , -CH ₂ CH ₃ or -CH ₂ CH ₂ CH ₃ ), C _2-6 alkenyl (eg, -CH=CH ₂ ) and haloC _1-6 alkyl (for example, -CF ₃ )..

In one embodiment, R ⁶ is selected from hydrogen or C _1-6 alkyl (eg, -CH ₃ or -CH ₂ CH ₃ ).

), -(СН₂)_j-О-С_1-6алкил (например, -СН₂ОСН₃), С_3-8циклоалкил (например, циклобутил или циклогексил), гетероциклическую группу, содержащую 3-7 членов кольца, например,In one embodiment, R ⁷ is C _1-6 alkyl (eg, -CH ₃ or -CH ₂ CH ₃ ), hydroxyC _1-6 alkyl (eg, -CH ₂ OH), -C _1-6 alkyl-NR ^x R ^y (for example, -CH ₂ N(CH ₃ ) ₂ ), -(CR ^x R ^y ) _p -CONR ^x R ^y (for example, -C(=O)N(CH ₃ ) ₂ or -C(=O )NHCH ₃ or

), -(CH ₂ ) _j -O-C _1-6 alkyl (for example, -CH ₂ OCH ₃ ), C _3-8 cycloalkyl (for example, cyclobutyl or cyclohexyl), a heterocyclic group containing 3-7 ring members, for example ,

(attachment point shown by a dotted link)

or -CH ₂ -heterocyclic group containing 3-7 ring members, for example,

(attachment point shown by a dotted link)

where when the R ⁷ moiety contains a heterocyclic or cycloalkyl group, said heterocyclic group may be optionally substituted with one or more R ^z groups selected from C _1-6 alkyl (eg methyl), hydroxy, halogen (eg fluoro), -C( \u003d O) C _1-6 alkyl (for example, -C (= O) C (CH ₃ ) ₃ ), - (CH ₂ ) _r -CO ₂ H (for example, -CH ₂ COOH or CH ₂ CH ₂ COOH or - (CH ₂ ) _r -CO ₂ C _1-6 alkyl (eg CH ₂ CH ₂ COOSH ₃ ).

In one embodiment, R ⁷ is C _1-6 alkyl (eg, methyl or ethyl), haloC _1-6 alkyl (eg, trifluoromethyl), C _2-6 alkenyl (eg, C ₂ alkenyl), hydroxyC _1-6 alkyl (for example, -CH ₂ OH, -CH ₂ CH ₂ OH), -C _1-6 alkyl-NR ^x R ^y (for example, -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 (for example, -(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 (for example, -CH ₂ OCH ₃ , -CH ₂ OCH ₂ CH ₃ or -CH ₂ OCD ₃ ), -(CR ^x R ^y ) _p -NR ^x COR ^y (for example, -CH ₂ NHCOCH ₃ ), -(CR ^x R ^y ) _p -O-CH ₂ -CONR ^x R ^y (for example, - CH ₂ -O-CH ₂ CON(CH ₃ ) ₂ ), -(CH ₂ ) _j -O-(hydroxyC _1-6 alkyl) (for example, -CH ₂ -O-CH ₂ CH ₂ OH,), -C (=O)NH-heterocyclic group containing 3-7 ring members, C _3-6 cycloalkyl, heterocyclic group containing 3-7 ring members (for example, oxanil), or -CH ₂ -heterocyclic group containing 3- 7 ring members, wherein said cycloalkyl or heterocyclic group contains one or more (e.g., 1, 2, or 3) heteroatoms selected from N, O, S, and their oxidized forms, and may be optionally substituted with one or more R ^z groups (e.g., selected from C _1-6 alkyl (eg methyl), C _1-6 alkoxy (eg methoxy) and -C(=O)C _1-6 alkyl (eg -C(=O)CH ₃ )). In one embodiment, R ⁶ is methyl or ethyl, and R ⁷ is C _1-6 alkyl (e.g., methyl), hydroxyC _1-6 alkyl, -C _1-6 alkyl-NR ^x R ^y , -(CR ^x R ^y ) _p -CONR ^x R ^y , -(CH ₂ ) _j -O-C _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-(hydroxyC _1-6 alkyl), a heterocyclic group containing 3-7 ring members (for example, oxanil), or -CH ₂ -heterocyclic group containing 3-7 ring members, where the specified heterocyclic group contains one or more (for example, 1, 2 or 3) heteroatoms selected from N, O, S and their oxidized forms, and may be optionally substituted with one or more R ^z groups selected from C _1-6 alkyl (eg methyl), C _1-6 alkoxy (eg methoxy) and -C(=O)C _1-6 alkyl (eg -C(=O)CH ₃ )).

In one embodiment, R ⁶ is selected from hydrogen or C _1-6 alkyl (eg, -CH ₃ or -CH ₂ CH ₃ ).

), -(СН₂)_j-О-С_1-6алкил (например, -СН₂ОСН₃), гетероциклическую группу, содержащую 3-7 членов кольца, например,In one embodiment, R ⁷ is C _1-6 alkyl (eg, -CH ₃ or -CH ₂ CH ₃ ), hydroxyC _1-6 alkyl (eg, -CH ₂ OH o), -C _1-6 alkyl-NR ^x R ^y (eg -CH ₂ N(CH ₃ ) ₂ ), -(CR ^x R ^y ) _p -CONR ^x R ^y (eg -C(=O)N(CH ₃ ) ₂ or

), -(CH ₂ ) _j -O-C _1-6 alkyl (for example, -CH ₂ OCH ₃ ), a heterocyclic group containing 3-7 ring members, for example,

(attachment point shown by a dotted link)

or -CH ₂ -heterocyclic group containing 3-7 ring members, for example,

(attachment point shown by a dotted link)

where when the R ⁷ moiety contains a heterocyclic group, said heterocyclic group may be optionally substituted with one or more R ^z groups selected from C _1-6 alkyl (eg, methyl).

In one embodiment of formula (I), R ⁷ is a heterocyclic group containing 3-7 ring members, optionally substituted with one or more R ^z groups, for example,

(attachment point shown by a dotted link)

In one embodiment of formula (I), R ⁷ is a heterocyclic group containing 3-7 ring members, optionally substituted with one or more R ^z groups, for example,

(attachment point shown by a dotted link)

In one embodiment, R ⁷ is a -CH ₂ -heterocyclic group containing 3-7 ring members, optionally substituted with one or more R ^z groups, for example,

(attachment point shown by a dotted link)

In one embodiment, R ⁷ is selected from:

(attachment point shown by a dotted link)

In one embodiment, R ⁷ is selected from:

(attachment point shown by a dotted link)

In one embodiment, R ⁶ is hydrogen or C _1-6 alkyl. In one embodiment, R ⁶ is C _1-6 alkyl. In one embodiment, R ⁶ is methyl or ethyl. In one embodiment, R ⁶ is ethyl.

In one embodiment, R ⁶ is C _1-6 alkyl (such as methyl or ethyl, eg methyl) and R ⁷ is selected from hydroxyC _1-6 alkyl and -(CH ₂ )-O-C _1-6 alkyl. In one embodiment, R ⁶ is methyl and R ⁷ is selected from methyl, -CH ₂ -OH, and -CH ₂ -OCH ₃ . In one embodiment, R ⁷ is methyl and R ⁷ is methyl, ethyl, or propyl. In one embodiment, R ⁷ is methyl and R ⁷ is methyl.

In one embodiment, R ⁶ is C _1-6 alkyl or haloC _1-6 alkyl (eg, methyl, -monofluoromethyl, trifluoromethyl, or ethyl).

In one embodiment, R ⁶ is C _3-8 cycloalkyl, such as C _3-6 cycloalkyl (eg, cyclopropyl).

In one embodiment, R ⁶ is C _1-6 alkyl (such as methyl or ethyl, eg ethyl) and R ⁷ is selected from:

(attachment is shown by a dotted link or link endpoint indicated by "*"):

In one embodiment, R ⁶ is C _1-6 alkyl (such as methyl or ethyl, eg ethyl) and R ⁷ is selected from:

(attachment is shown by a dotted link or link endpoint indicated by "*"):

In particular, R ⁷ is:

(the connection point is shown by the connection marked with a dotted line):

In one embodiment, R ⁶ is C _1-6 alkyl (such as methyl or ethyl, eg methyl) and R ⁷ is oxanyl and the compound of formula (I) is a compound of formula (Iw):

In one embodiment of formula (Iw), R _z is hydrogen or fluorine.

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 pharmaceutically acceptable salt thereof:

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 pharmaceutically acceptable salt thereof:

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

In one embodiment, R ⁷ is pyrazolyl optionally substituted with one or more R ^z groups (eg, methyl). In one embodiment, R ⁷ is N-methylpyrazol-3-yl or N-methylpyrazol-4-yl.

In one embodiment, R ⁷ is selected from methyl, oxanyl, pyrazolyl, imidazolyl, piperidinyl, or cyclohexyl, wherein said cycloalkyl and heterocyclic groups are optionally substituted with one or more R ^z groups (eg, methyl, fluoro, or hydroxyl).

In one embodiment, R ⁷ is selected from piperidinyl optionally substituted with one or more R ^z groups (eg methyl, fluoro or hydroxyl, eg methyl and fluoro).

In another embodiment, the compound of formula (I) is a compound of formula (Ix) and R ⁶ is C _1-4 alkyl.

In one embodiment, R ⁶ is C _1-6 alkyl (eg, -CH ₃ , -CH ₂ CH _{3 ,} or -CH ₂ CH ₂ CH ₃ , such as methyl or ethyl, eg ethyl), and R ⁷ is a heterocyclic group containing 3-7 ring members optionally substituted with one or more R ^z groups.

In one embodiment, R ⁶ is C _1-6 alkyl (eg, —CH ₃ , —CH ₂ CH _{3 ,} or —CH ₂ CH ₂ CH ₃ , such as methyl or ethyl, such as ethyl), and R ⁷ is imidazolyl optionally substituted with one or more R ^z groups (eg methyl imidazolyl).

In one embodiment, R ⁶ is C _1-6 alkyl (eg, -CH ₃ , -CH ₂ CH _{3 ,} or -CH ₂ CH ₂ CH ₃ , such as methyl or ethyl, eg ethyl), and R ⁷ is piperidinyl optionally substituted with one or more R ^z groups (eg methyl piperidinyl).

In one embodiment, R ⁶ is C _1-6 alkyl (eg, —CH ₃ , —CH ₂ CH _{3 ,} or —CH ₂ CH ₂ CH ₃ , such as methyl or ethyl, such as ethyl), and R ⁷ is C _1-4 alkyl, methoxyC _1-4 malalkyl, a heterocyclic group containing 5 or 6 ring members, or a C _3-6 cycloalkyl group optionally substituted with one or more R ^z (for example, methyl, halogen (such as fluorine), C (=O)Me or -OH).

In one embodiment, R ⁶ is C _1-6 alkyl (eg, —CH ₃ , —CH ₂ CH _{3 ,} or —CH ₂ CH ₂ CH ₃ , such as methyl or ethyl, such as ethyl), and R ⁷ is methyl, ethyl, hydroxylmethyl, hydroxyethyl, methoxymethyl, piperidinyl, oxanyl, imidazolyl, pyrazolyl, cyclobutyl, cyclohexyl optionally substituted with one or more R ^z (e.g. methyl, halogen (such as fluoro), C(=O)Me, or -OH ).

In one embodiment, R ⁶ and R ⁷ are the same. In one embodiment, R ⁶ and R ⁷ are both methyl and the compound of formula (I) is a compound of formula (Iy) or a tautomer or solvate or pharmaceutically acceptable salt thereof:

In one embodiment, the -CR ⁶ R ⁷ OH group is not -C(CH ₃ ) ₂ OH. In one embodiment, R ⁷ is selected from the group consisting of:

In one embodiment, R ⁷ is selected from the group consisting of:

In one embodiment, R ^z is independently selected from halo, nitro, nitrile, C _1-6 alkyl, haloC _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, =O, hydroxy, hydroxyC _1-6 alkyl, C _1-6 alkoxy, -(CH ₂ ) _k -OC _1-6 alkyl, hydroxyC _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 heterocyclyl group containing 3-6 ring members, a heterocyclyl group containing 3-6 ring members, substituted with -C(=O)C _{1- 4} alkyl, a heterocyclyl group containing 3-6 ring members substituted with -C(=O)OC _1-4 alkyl, a heterocyclyl group containing 3-6 ring members substituted with -C(=O)N(H) _e (C _1-4 alkyl) _2-e , -C(=O)heterocyclyl group containing 3-6 ring members, C _3-8 cycloalkyl and C _3-8 cycloalkenyl.

In another embodiment, R ^z is independently selected from halo, nitro, nitrile, C _1-6 alkyl, haloC _2-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, =O, hydroxy, hydroxyC _1-6 alkyl, C _1-6 alkoxy, -(CH ₂ ) _k -O-C _1-6 alkyl, hydroxyC _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 _1-6 alkyl-N(H) _e (C _1-4 alkyl) _{2- e} , a heterocyclyl group containing 3-6 ring members, a heterocyclyl group containing 3-6 ring members substituted with -C(=O)C _1-4 alkyl, a heterocyclyl group containing 3-6 ring members substituted with -C(= O)OC _1-4 alkyl, a heterocyclyl group containing 3-6 ring members, substituted with -C (=O)N (H) _e (C _1-4 alkyl) _2-e , -C (=O) heterocyclyl group, containing 3-6 ring members, C _3-8 cycloalkyl and C _3-8 cycloalkenyl.

In another embodiment, when R ⁷ contains a saturated heterocyclic group, then R ^z is independently selected from halo, nitro, nitrile, C _1-6 alkyl, haloC _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, = O, hydroxy, hydroxyC _1-6 alkyl, C _1-6 alkoxy, -(CH ₂ ) _k -O-C _1-6 alkyl, hydroxyC _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 _1-6 alkyl) _2-e , -(CH ₂ ) _r -CO ₂ C _1-6 alkyl, -(CH ₂ ) _r -CO ₂ H, -N (H) _e (C _1-6 alkyl) _2-e , C _1-6 alkyl-N (H) _e (C _1-4 alkyl) _2-e , heterocyclyl group containing 3-6 ring members, heterocyclyl group containing 3-6 ring members, substituted - C(=O)C _1-4 alkyl, a heterocyclyl group containing 3-6 ring members substituted with -C(=O)OC _1-4 alkyl, a heterocyclyl group containing 3-6 ring members substituted with -C(=O )N(H) _e (C _1-4 alkyl) _2-e , -C(=O) heterocyclyl group containing 3-6 ring members, C _3-8 cycloalkyl and C _3-8 cycloalkenyl.

Subformulas

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

where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , a, m and s are as defined herein.

In one embodiment, R ¹ is chlorine, nitrile, methyl, or methoxy. In one embodiment, R ¹ is hydroxy or hydroxyC _1-4 alkyl (e.g., hydroxyl).

In one embodiment, R ¹ is -O _0.1 (CR ^x R ^y ) _v COOH (eg, -COOH, -CH ₂ COOH, -OCH ₂ COOH, or -C(CH ₃ ) ₂ COOH.

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 pharmaceutically acceptable salt thereof:

where R ² , R ³ , R ⁴ , R ⁵ , R ⁷ , m and s are as defined herein. In one embodiment, R ¹ is -SO ₂ -R ^x . In particular, R ^x represents -SO ₂ -C _1-4 alkyl, for example, -SO ₂ -CH ₃ or -SO ₂ -heterocyclic group containing 5-6 ring members (for example, -SO ₂ -morpholinyl, usually -SO ₂ -(1-morpholinyl) In another embodiment, R ¹ is hydroxy or hydroxyC _1-4 alkyl (eg, -CH ₂ OH or -OH).

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 pharmaceutically acceptable salt thereof:

where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁷ , a, m and s are as defined herein.

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:

where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁷ , a, m and s are as defined herein.

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

where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁷ , a, m and s are as defined herein.

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 pharmaceutically acceptable salt thereof:

where R ¹ , R ² , R ³ , R ⁵ , R ⁷ , m and s are as defined herein.

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

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

In one embodiment, A is a C _3-6 cycloalkyl group (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 pharmaceutically acceptable salt thereof :

In one embodiment, A is a C _3-8 cycloalkyl group (g is 1, 2, or 3) and t is 1, and said cycloalkyl group is geminally disubstituted (i.e., -(CR ^x R ^y )-X and a CH ₂ group (where s is 1) or an oxygen atom (where s is 0) are both attached to the same atom of a cycloalkyl group), and the compound of formula (VII) is a compound of formula (VIIa) or a tautomer or solvate thereof, or pharmaceutically acceptable salt:

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

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:

In one embodiment, R ^x and R ^y are 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 pharmaceutically acceptable salt thereof:

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

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

In one embodiment, X is hydroxy and the compound of formula (VIId) is a compound of formula (VIIe) or a tautomer or solvate or pharmaceutically acceptable salt thereof:

In one embodiment, X is -C(=O)NH ₂ and the compound of formula (VIIe) is a compound of formula (VIIe') or a tautomer or solvate or pharmaceutically acceptable salt thereof:

where q is 0 or 1, and in particular q is 0.

In one embodiment, X is -CN and the compound of formula (VIId) is a compound of formula (VIIe'') or a tautomer or solvate or pharmaceutically acceptable salt thereof:

where q is 0 or 1, and in particular q is 0.

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 pharmaceutically acceptable salt thereof:

In one embodiment of Formulas (VIIa-e'), R ⁶ is methyl. In one embodiment of Formulas (VIIa-e'), R ⁶ is ethyl.

In one embodiment of Formula (VIIe'') or (VIIf), R ⁶ is methyl. In one embodiment of Formula (VIIe'') or (VIIf), R ⁶ is ethyl.

In one embodiment of Formula (VIIe'') or (VIIf), R ⁶ is methyl. In one embodiment of Formula (VIIe'') or (VIIf), R ⁶ is ethyl.

In one embodiment of a compound of formula (VIIa-e'), R ⁷ is selected from methyl, oxanyl, pyrazolyl, imidazolyl, piperidinyl, or cyclohexyl, wherein said cycloalkyl and heterocyclic groups are optionally substituted with one or more R ^z groups (e.g., methyl, fluoro, or hydroxy ).

In one embodiment of a compound of formula (VIIa-e'), R ⁷ is selected from oxanyl and methyl.

In one embodiment of a compound of formula (VIIe'') or (VIIf), R ⁷ is selected from methyl, oxanyl, pyrazolyl, imidazolyl, piperidinyl, or cyclohexyl, wherein said cycloalkyl and heterocyclic groups are optionally substituted with one or more R ^z groups (e.g., methyl, fluorine or hydroxy).

In one embodiment of a compound of formula (VIIe'') or (VIIf), R ⁷ is selected from oxanil and methyl.

In one embodiment of a compound of formula (VIIa-f), R ⁷ is selected from piperidinyl optionally substituted with one or more R ^z groups (eg, methyl, fluoro, or hydroxy).

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

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 .

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

where R ¹ is chlorine or nitrile, when s is 1 then X is hydroxyl, or when s is 0 then X is -CN.

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

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 .

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

where R ¹ is chlorine or nitrile, when s is 1 then X is hydroxyl, or when s is 0 then X is -CN.

In one embodiment of a compound of formula (a), R ⁷ is selected from methyl, oxanyl, pyrazolyl, imidazolyl, piperidinyl, or cyclohexyl, wherein said cycloalkyl and heterocyclic groups are optionally substituted with one or more R ^z groups (eg, methyl, fluoro, or hydroxy).

In one embodiment of a compound of formula (a), R ⁷ is oxanyl or methyl.

In one embodiment of a compound of formula (a), R ⁷ is piperidinyl optionally substituted with C _1-6 alkyl (eg, methyl) and/or halogen (eg, fluorine).

In one embodiment of a compound of formula (a'), (a'') or (a'''), R ⁷ is selected from methyl, oxanyl, pyrazolyl, imidazolyl, piperidinyl, or cyclohexyl, wherein said cycloalkyl and heterocyclic groups are optionally substituted with one or more R ^z groups (eg methyl, fluoro or hydroxy).

In one embodiment of a compound of formula (a'), (a'') or (a'''), R ⁷ is oxanyl or methyl.

In one embodiment of a compound of formula (a'), (a'') or (a'''), R7 is piperidinyl optionally substituted with C _1-6 alkyl (eg methyl) and/or halogen (eg fluoro).

In one embodiment, A is a heterocyclyl group containing 3-6 ring members, wherein said heterocyclic group contains one or more (e.g., 1, 2, or 3) heteroatoms selected from N, O, S, and their oxidized forms (t is 1; g is 1, 2, 3 or 4; Z is N, O, S and their oxides; i is 1, 2 or 3; and i + g = 2, 3, 4 or 5), and a compound of formula ( VI) is a compound of formula (b) or a tautomer or solvate or pharmaceutically acceptable salt thereof:

In one embodiment, Y is O, 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:

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:

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:

In one embodiment, compound (bc) is one in which q is 0 and X is fluoro.

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

where R ¹ is chlorine or nitrile, s is 1 and X is hydroxyl, or s is 0 and X is -C(=O)NH ₂ .

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

where R ¹ is chlorine or nitrile, s is 1 and X is hydroxyl, or s is 0 and X is -CN.

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

where R ¹ is chlorine or nitrile, s is 1 and X is hydroxyl, or s is 0 and X is -C(=O)NH ₂ .

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

where R ¹ is chlorine or nitrile, s is 1 and X is hydroxyl, or s is 0 and X is -CN.

In one embodiment of the compound of formula (c), R ⁷ is selected from methyl, oxanyl, pyrazolyl, imidazolyl, piperidinyl, or cyclohexyl, wherein said cycloalkyl and heterocyclic groups are optionally substituted with one or more R ^z groups (eg, methyl, fluoro, or hydroxy).

In one embodiment of a compound of formula (c), R ⁷ is ocean yl or methyl.

In one embodiment of a compound of formula (c), R ⁷ is piperidinyl optionally substituted with C _1-6 alkyl (eg, methyl) and/or halogen (eg, fluorine).

In one embodiment of a compound of formula (c'), (c'') or (c'''), R ⁷ is selected from methyl, oxanyl, pyrazolyl, imidazolyl, piperidinyl, or cyclohexyl, wherein said cycloalkyl and heterocyclic groups are optionally substituted with one or more R ^z groups (eg methyl, fluoro or hydroxy).

In one embodiment of a compound of formula (c'), (c'') or (c'''), R ⁷ is oxanyl or methyl.

In one embodiment of a compound of formula (c'), (c'') or (c'''), R ⁷ is piperidinyl optionally substituted with C _1-6 alkyl (e.g. methyl) and/or halogen (e.g. fluorine) .

In another embodiment of the subformulas described herein above, R ² is 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).

In another embodiment of the subformulas described herein above, R ² is selected from -(CH(CH ₃ ))-CO ₂ H and -(C(CH ₃ ) ₂ -CO ₂ H).

,

или -(С(СН₃)₂-СО₂Н.In another embodiment, R ² is selected from -(CH(CH ₃ ))-CO ₂ H and -(C(CH ₃ ) ₂ -CO ₂ H) (for example,

,

or - (C (CH ₃ ) ₂ -CO ₂ H.

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

R ¹ is independently selected from hydroxy, halogen, nitro, nitrile, C _1-4 alkyl, haloC _1-4 alkyl, hydroxyC _1-4 alkyl, C _2-6 alkenyl, C _1-4 alkoxy, haloC _1-4 alkoxy, and C _2-4 alkynyls;

R ² is selected from hydrogen, C _1-4 alkyl, C _2-6 alkenyl, hydroxyC _1-4 alkyl and -CH ₂ CO ₂ H;

R ³ is hydrogen or -(A) _t -(CR ^x R ^y ) _q -X;

s and t are independently selected from 0 and 1;

q is selected from 0, 1 and 2;

where when R ³ is -(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 equal to 1 and q is not equal to 0;

A represents a C _3-6 cycloalkyl group or a heterocyclic group containing 3-6 ring members, where the specified heterocyclic group contains one or more (for example, 1, 2 or 3) heteroatoms selected from N, O, S and their oxidized forms ;

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 ;

R ⁴ and R ⁵ are independently selected from halo, nitrile, C _1-4 alkyl, haloC _1-4 alkyl, C _1-4 alkoxy, and halo C _1-4 alkoxy;

R ⁶ and R ⁷ are independently selected from hydrogen, C _1-6 alkyl, haloC _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, hydroxy, hydroxyC _1-6 alkyl, -COOC _1-6 alkyl, heterocyclic group containing 3-7 ring members, -CH ₂ -heterocyclic group containing 3-7 ring members, -CH ₂ -O heterocyclic group containing 3-7 ring members, -CH ₂ -NH-heterocyclic group containing 3- 7 ring members, -CH ₂ -N(C _1-6 alkyl)-heterocyclic group containing 3-7 ring members, -C(=O)NH-heterocyclic group containing 3-7 ring members, C _3-8 cycloalkyl , -CH ₂ -C _3-8 cycloalkyl, -CH ₂ -O-C _3-8 cycloalkyl and C _3-8 cycloalkenyl, where said cycloalkyl, cycloalkenyl or heterocyclic groups may be optionally substituted with one or more R ^z groups, and where in each case, the heterocyclic group contains one or more (eg 1, 2 or 3) heteroatoms selected from N, O, S and their oxidized forms;

R ⁹ is selected from hydrogen, C _1-6 alkyl, haloC _1-6 alkyl, hydroxyC _1-6 alkyl, -(CH ₂ ) _k -O-C _1-6 alkyl, -(CH ₂ ) _k -O-(hydroxyC _1-6 alkyl), hydroxyC _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;

R ^x and R ^y are independently selected from hydrogen, halogen, nitro, nitrile, C _1-6 alkyl, haloC _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, hydroxy, hydroxyC _1-6 alkyl, C _{1 -6} alkoxy, -(CH ₂ ) _k -O-C _1-6 alkyl, hydroxyC _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;

R ^z is independently selected from halogen, nitro, nitrile, C _1-6 alkyl, haloC _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, =O, hydroxy, hydroxyC _1-6 alkyl, C _1-6 alkoxy, -(CH ₂ ) _k -OC _1-6 alkyl, hydroxyC _1-6 alkoxy, -C (= O) C _1-6 alkyl, -C (= O) C _1-6 alkyl-OH, -C ( \u003d 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 heterocyclyl group containing 3-6 ring members, a heterocyclyl group containing 3-6 ring members substituted with -C(=O)C _1-4 alkyl, a heterocyclyl group containing 3-6 ring members substituted with -C(=O)OC _1-4 alkyl, heterocyclyl group containing 3-6 ring members substituted with -C(=O)N(H) _e (C _1-4 alkyl) _{2- e} , -C(=O)heterocyclyl group containing 3-6 ring members, C _3-8 cycloalkyl and C _3-8 cycloalkenyl;

n, e, r and j are independently selected from 0.1 and 2;

k and m are independently selected from 1 and 2; And

v and a are independently chosen from 0 and 1.

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

R ¹ is independently selected from hydroxy, halogen, nitro, nitrile and -C _1-6 alkyl;

R ² is selected from hydrogen, C _1-4 alkyl, C _2-6 alkenyl, hydroxyC _1-4 alkyl and -CH ₂ CO ₂ H;

R ³ is hydrogen or -(A) _t -(CR ^x R ^y ) _q -X;

s and t are independently selected from 0 and 1;

q is selected from 0, 1 and 2;

where when R ³ is -(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 equal to 1 and q is not equal to 0;

A represents a C _3-6 cycloalkyl group or a heterocyclic group containing 3-6 ring members, where the specified heterocyclic group contains one or more (for example, 1, 2 or 3) heteroatoms selected from N, O, S and their oxidized forms ;

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 ;

R ⁴ and R ⁵ are independently selected from halogen, nitrile and C _1-4 alkyl;

R ⁶ is selected from hydrogen, C _1-6 kyl, haloC _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl;

R7 is selected from hydrogen, C _1-6 alkyl, haloC _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, hydroxy, hydroxyC _1-6 alkyl, -COOC _1-6 alkyl, a heterocyclic group containing 3- 7 ring members, -CH ₂ -heterocyclic group containing 3-7 ring members, -CH ₂ -O-heterocyclic group containing 3-7 ring members, -CH ₂ -NH-heterocyclic group containing 3-7 ring members, -CH ₂ -N(C _1-6 alkyl)-heterocyclic group containing 3-7 ring members, -C(=O)NH-heterocyclic group containing 3-7 ring members, C _3-8 cycloalkyl, -CH ₂ -C _3-8 cycloalkyl, -CH ₂ -O-C _3-8 cycloalkyl and C _3-8 cycloalkenyl, where said cycloalkyl, cycloalkenyl or heterocyclic groups may be optionally substituted with one or more R ^z groups, and where in each case the heterocyclic the group contains one or more (eg 1, 2 or 3) heteroatoms selected from N, O, S and their oxidized forms;

R ⁹ is selected from hydrogen, C _1-6 alkyl, haloC _1-6 alkyl, hydroxyC _1-6 alkyl, -(CH ₂ ) _k -O-C _1-6 alkyl, -(CH ₂ ) _k -O-(hydroxyC _1-6 alkyl), hydroxyC _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;

R ^x and R ^y are independently selected from hydrogen, halogen, nitro, nitrile, C _1-6 alkyl, haloC _2-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, hydroxy, hydroxyC _1-6 alkyl, C _{1 -6} alkoxy, -(CH ₂ ) _k -O-C _1-6 alkyl, hydroxyC _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;

R ^z is independently selected from halo, nitro, nitrile, C _1-6 alkyl, haloC _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, =O, hydroxy, hydroxyC _1-6 alkyl, C _1-6 alkoxy, -(CH ₂ ) _k -O-C _1-6 alkyl, hydroxyC _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 , heterocyclyl group containing 3-6 ring members, heterocyclyl group containing 3-6 ring members, substituted with -C(=O)C _1-4 alkyl, heterocyclyl a group containing 3-6 ring members substituted with -C(=O)OC _1-4 alkyl, a heterocyclyl group containing 3-6 ring members substituted with -C(=O)N(H) _e (C _1-4 alkyl ) _2-e , -C(=O)heterocyclyl group containing 3-6 ring members, C _3-8 cycloalkyl and C _3-8 cycloalkenyl;

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

k and m are independently selected from 1 and 2; And

v and a are independently chosen from 0 and 1.

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

R ¹ is independently selected from hydroxy, halogen, nitro, nitrile and -C _1-6 alkyl;

R ² is selected from hydrogen, C _1-4 alkyl, C _2-6 alkenyl, hydroxyC _1-4 alkyl and -CH ₂ CO ₂ H;

R ³ is hydrogen or -(A) _t -(CR ^x R ^y ) _q -X;

s and t are independently selected from 0 and 1;

q is selected from 0, 1 and 2;

where when R ³ is -(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 equal to 1 and q is not equal to 0;

And represents a heterocyclic group containing 3-6 ring members, where the specified heterocyclic group contains one or more (for example, 1, 2 or 3) heteroatoms selected from N, O, S and their oxidized forms;

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

R ⁴ and R ⁵ are independently selected from halogen, nitrile and C _1-4 alkyl;

R ⁶ is selected from hydrogen and -C _1-6 alkyl;

R ⁷ is selected from a heterocyclic group containing 3-7 ring members, -CH ₂ -heterocyclic group, C _3-8 cycloalkyl and -CH ₂ -C _3-8 cycloalkyl, where these cycloalkyl or heterocyclic groups may be optionally substituted with one or more groups R ^z , and where in each case the heterocyclic group contains one or more (for example, 1, 2 or 3) heteroatoms selected from N, O, S and their oxidized forms;

R ⁹ is selected from hydrogen and -C _1-6 alkyl;

R ^x and R ^y are independently selected from hydrogen and -C _1-6 alkyl;

R ^z is independently selected from halo, nitro, nitrile, C _1-6 alkyl, haloC _1-6 alkyl, C _2-6 alkenyl, hydroxy, hydroxyC _1-6 alkyl, C _1-6 alkoxy, -C(=O)C _1-6 alkyl and -N(H) _e (C _1-4 alkyl) _2-e ;

n and e are independently selected from 0,1 and 2

m is selected from 1 and 2; And

and is chosen from 0 and 1.

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

R ¹ is independently selected from halogen, hydroxy and nitrile;

R ² is selected from hydrogen, C _1-4 alkyl and -CH ₂ CO ₂ H;

R ³ is -(A) _t -(CR ^x R ^y ) _q -X;

And represents a heterocyclic group containing 3-6 ring members, where the specified heterocyclic group contains one or more (for example, 1, 2 or 3) heteroatoms selected from N, O, S and their oxidized forms;

s and t are independently selected from 0 and 1;

q is selected from 0, 1 and 2;

where (i) at least one of s, t and q is not equal to 0 and (ii) when t is equal to 0, then s is equal to 1 and q is not equal to 0;

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

R ⁴ and R ⁵ are independently selected from halogen;

R ⁶ is selected from hydrogen and -C _1-6 alkyl;

R ⁷ is selected from a heterocyclic group containing 3-7 ring members, -CH ₂ -heterocyclic group, C _3-8 cycloalkyl and -CH ₂ -C _3-8 cycloalkyl, where these cycloalkyl, cycloalkenyl or heterocyclic groups may be optionally substituted with one or more R ^z groups, and where in each case the heterocyclic group contains one or more (eg 1, 2 or 3) heteroatoms selected from N, O, S and their oxidized forms;

R ⁹ is selected from hydrogen and -C _1-6 alkyl;

R ^x and R ^y are independently selected from hydrogen and -C _1-6 alkyl;

R ⁹ is independently selected from halogen, nitro, nitrile and -C _1-6 alkyl;

n is 1 and m is 1; And

and is chosen from 0 and 1.

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

R ¹ is independently selected from halogen, hydroxy and nitrile;

R ² is selected from hydrogen, C _1-4 alkyl and -CH ₂ CO ₂ H;

R ³ is -(A) _t -(CR ^x R ^y ) _q -X;

And represents a heterocyclic group containing 3-6 ring members, where the specified heterocyclic group contains one or more (for example, 1, 2 or 3) heteroatoms selected from N, O, S and their oxidized forms;

s and t are independently selected from 0 and 1;

q is selected from 0, 1 and 2;

where (i) at least one of s, t and q is not equal to 0 and (ii) when t is equal to 0, then s is equal to 1 and q is not equal to 0;

X is selected from hydrogen, halogen and -OR ⁹ ;

R ⁴ and R ⁵ are independently selected from halogen;

R ⁶ is selected from hydrogen and -C _1-6 alkyl;

R ⁷ is a heterocyclic group containing 3-7 ring members, optionally substituted with one or more R ^z groups;

R ⁹ is selected from hydrogen and -C _1-6 alkyl;

R ^x and R ^y are independently selected from hydrogen and -C _1-6 alkyl;

R ⁹ is independently selected from halo and -C _1-6 alkyl; And

n is 1 and m is 1; And

a is equal to 1.

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

R ¹ is halogen (eg Cl), C _1-4 alkynyl (eg -C≡CH), nitrile, hydroxyC _1-4 alkyl (eg CH ₂ OH), -O _0.1 (CR ^x R ^y ) _v COOH (for example, -COOH, -CH ₂ COOH, -OCH ₂ COOH or -C (CH ₃ ) ₂ COOH, -S (O) _d -C _1-4 alkyl (for example, SCH ₃ , SOCH ₃ or SO ₂ CH ₃ ), -SO ₂ -(1-morpholinyl) or -P(=O)(R ^x ) ₂ , (for example, -P(=O)(CH ₃ ) ₂ );

n is 1 or 2;

R ₂ is hydrogen, C _1-4 alkyl (eg -CH ₃ ), hydroxyC _1-4 alkyl (eg CH ₂ OH) -(CH ₂ ) _u COOH (eg -CH ₂ COOH, -CH ₂ CH ₂ -CO ₂ H or -(CH(CH ₃ ))-CO ₂ H);

fragment -(CH ₂ )SR ³ selected from:

(attachment point shown by a dotted link or link endpoint marked *):

R ⁴ is halogen (eg F);

a is 0 or 1;

R ⁵ is halogen (eg Cl);

m is 1;

R ⁶ is hydrogen or C _1-6 alkyl (eg -CH ₃ or -CH ₂ CH ₃ );

(СН₂)_jO-С_1-6алкил (например, -СН₂ОСН₃), С_3-8циклоалкил (например, циклобутил или циклогексил), гетероциклическую группу, содержащую 3-7 членов кольца, например,R ⁷ is C _1-6 alkyl (eg -CH ₃ or -CH ₂ CH ₃ ), hydroxyC _1-6 alkyl (eg -CH ₂ OH), -C _1-6 alkyl-NR ^x R ^y (eg , -CH ₂ N(CH ₃ ) ₂ ), -(CR ^x R ^y ) _p -CONR ^x R ^y (for example, -C(=O)N(CH ₃ ) ₂ or -C(=O)NHCH ₃ or

(CH ₂ ) _j O-C _1-6 alkyl (eg -CH ₂ OCH ₃ ), C _3-8 cycloalkyl (eg cyclobutyl or cyclohexyl), a heterocyclic group containing 3-7 ring members, eg

(attachment point shown by a dotted link)

or -CH ₂ -heterocyclic group containing 3-7 ring members, for example, (attachment is indicated by a dotted bond)

where when the R ⁷ moiety contains a heterocyclic or cycloalkyl group, said heterocyclic group may be optionally substituted with one or more R ^z groups selected from C _1-6 alkyl (eg methyl), hydroxy, halogen (eg fluoro), -C( =O)C _1-6 alkyl (for example, -C(=O)C(CH ₃ ) ₃ ), -(CH ₂ ) _r -CO ₂ H (for example, -CH ₂ COOH or CH ₂ CH ₂ COOH or - (CH ₂ ) _r -CO ₂ C _1-6 alkyl (eg CH ₂ CH ₂ COOSH ₃ ).

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

R ¹ is halogen (eg Cl), C _1-4 alkynyl (eg -C≡CH), nitrile, hydroxyC _1-4 alkyl (eg CH ₂ OH), -(CH ₂ ) _v COOH (eg -COOH), -S(O) _d -C _1-4 alkyl (for example, SCH ₃ , SOCH ₃ or SO ₂ CH ₃ ), -SO ₂ -(1-morpholinyl) or -P(=O)(R ^x ) ₂ , (for example, -P (=O) (CH ₃ ) ₂ );

n is 1 or 2;

R ² is hydrogen, C _1-4 alkyl (eg -CH ₃ ), hydroxyC _1-4 alkyl (eg CH ₂ OH) -(CH ₂ ) and COOH (eg -CH ₂ COOH);

fragment -(CH ₂ ) _s R ³ selected from:

(attachment point shown by a dotted link or link endpoint marked *):

R ⁴ is halogen (eg F);

a is 0 or 1;

R ⁵ is halogen (eg Cl);

m is 1;

R ⁶ is hydrogen or C _1-6 alkyl (eg -CH ₃ or -CH ₂ CH ₃ );

), гетероциклическую группу, содержащую 3-7 членов кольца, например,R ⁷ is C _1-6 alkyl (eg -CH ₃ ), hydroxyC _1-6 alkyl (eg -CH ₂ OH), -(CH ₂ ) _j -O-C _1-6 alkyl (eg -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 containing 3-7 ring members, e.g.

(attachment point shown by a dotted link)

or -CH ₂ -heterocyclic group containing 3-7 ring members, for example, (attachment is indicated by a dotted bond)

where when R ⁷ contains a heterocyclic group, said heterocyclic group may be optionally substituted with one or more R ^z groups selected from C _1-6 alkyl (eg, methyl).

In one embodiment of formula (I), R ⁷ is a heterocyclic group containing 3-7 ring members, for example,

(attachment point shown by a dotted link)

In one embodiment of the formula, where when R ⁷ contains a heterocyclic group, said heterocyclic group may be, R ⁷ is a heterocyclic group containing 3-7 ring members, optionally substituted with one or more R ^z groups, for example,

(attachment point shown by a dotted link)

or -CH ₂ -heterocyclic group containing 3-7 ring members, optionally substituted with one or more R ^z groups, for example,

(attachment point shown by a dotted link)

In one embodiment of the formula, where when R ⁷ contains a heterocyclic group, said heterocyclic group may be, R ⁷ is a heterocyclic group containing 3-7 ring members, optionally substituted with one or more R ^z groups, for example,

(attachment point shown by a dotted link)

or -CH ₂ -heterocyclic group containing 3-7 ring members, optionally substituted with one or more R ^z groups, for example,

(attachment point shown by a dotted link)

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

R ¹ is -Cl, -CN, -OH or -OCH ₃ ;

n is 1;

R ² is hydrogen;

R ³ is hydrogen or -(A) _t -(CR ^x R ^y ) _q -X;

s is 0 or 1 and t is 1;

A is selected from cyclopropyl, oxetanyl and tetrahydrofuranyl;

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

q is 0 or 1 and R ^x and R ^y are hydrogen or deuterium;

a is 0 or 1 and R ⁴ is halogen (eg fluorine);

R ⁵ is halogen (eg Cl);

m is 1;

R ⁶ is C _1-4 alkyl (eg methyl or ethyl);

R ⁷ is C _1-4 alkyl (eg methyl or ethyl), hydroxyl C _1-4 alkyl (eg hydroxylmethyl or hydroxyl ethyl), methoxyC _1-4 alkyl (eg methoxymethyl), a heterocyclic group containing 5 or 6 ring members (e.g. piperidinyl, oxanyl, imidazolyl or pyrazolyl), or C _3-6 cycloalkyl (e.g. cyclobutyl or cyclohexyl), wherein said heterocyclic group having 5 or 6 ring members and C _3-6 cycloalkyl group may be optionally substituted with one or two R ^z groups independently selected from methyl, halogen (such as fluoro), -C(=O)Me, and -OH.

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

R ¹ is -Cl, -CN, -OH or -OCH ₃ ;

n is 1;

R ² is hydrogen -(CH ₂ ) _u -CO ₂ H, where u is independently selected from 0 and 1;

R ³ is hydrogen and s is 1, or R ³ is -(A) _t -(CR ^x R ^y ) _q -X and t is 1 and q is 1;

A is selected from cyclopropyl;

X is -OH;

R ^x and R ^y are hydrogen or deuterium;

a is 0 or 1 and R ⁴ is halogen (eg fluorine);

R ⁵ is halogen (eg Cl);

m is 1;

R ⁶ is C _1-4 alkyl (eg methyl or ethyl);

R ⁷ is C _1-4 alkyl (eg methyl or ethyl), hydroxyl C _1-4 alkyl (eg hydroxylmethyl or hydroxyl ethyl), methoxyC _1-4 alkyl (eg methoxymethyl), a heterocyclic group containing 5 or 6 ring members (eg piperidinyl, oxanyl, imidazolyl or pyrazolyl), or C _3-6 cycloalkyl (eg cyclobutyl or cyclohexyl);

where the specified heterocyclic group containing 5 or 6 ring members, and _3-8 cycloalkyl group may be optionally substituted with one or two R ^z groups independently selected from methyl, halogen (such as fluorine), -C(=O)Me and -HE.

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

R ¹ is halogen (eg Cl) or nitrile;

n is 1;

R ² is hydrogen or -(CH ₂ ) _u COOH (eg -CH ₂ COOH);

R ³ is hydrogen and s is 1, or R ³ is -(A) _t -(CR ^x R ^y ) _q -X and t is 1 and q is 1;

A is selected from cyclopropyl;

X is -OH;

R ^x and R ^y are hydrogen or deuterium (eg hydrogen);

R ⁴ is halogen (eg F);

a is 0 or 1;

R ⁵ is halogen (eg Cl);

m is 1;

R ⁶ is hydrogen or C _1-6 alkyl (eg -CH ₃ or -CH ₂ CH ₃ );

R ⁷ is C _1-4 alkyl (eg methyl), hydroxylC _1-4 alkyl (eg hydroxyl methyl), methoxyC _1-4 alkyl (eg methoxymethyl), a heterocyclic group containing 5 or 6 ring members (eg piperidinyl, oxanil, imidazolyl or pyrazolyl);

where the specified heterocyclic group containing 5 or 6 ring members may be optionally substituted with one or two R ^z groups independently selected from C _1-4 alkyl (eg, methyl).

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

R ¹ is halogen (eg Cl), nitrile, -O _0.1 (CR ^x R ^y ) _v COOH (eg -COOH, -CH ₂ COOH, -OCH ₂ COOH or -C(CH ₃ ) ₂ COOH ;

n is 1 or 2;

R ² is selected from hydrogen and -(R ^x R ^y ) _u -CO ₂ H (for example, -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).

R ³ is hydrogen and s is 1.

R ⁴ is halogen (eg F);

R ⁵ is halogen (eg Cl);

m is 1;

R ⁶ is hydrogen or C _1-6 alkyl (eg -CH ₃ or -CH ₂ CH ₃ );

R ⁷ is C _1-4 alkyl (eg methyl), hydroxyl C _1-4 alkyl (eg hydroxylmethyl), methoxyC _1-4 alkyl (eg methoxymethyl), a heterocyclic group containing 5 or 6 ring members (eg piperidinyl , oxanil, imidazolyl or pyrazolyl);

where the specified heterocyclic group containing 5 or 6 ring members may be optionally substituted with one or two R ^z groups independently selected from C _1-4 alkyl (eg, methyl).

In one embodiment, the present invention provides a compound of formula (I) which is a compound of Examples 1-137, or selected from Examples 1-137, or a tautomer, N-oxide, pharmaceutically acceptable salt, or solvate thereof.

In one embodiment, the present invention provides a compound of formula (I) which is a compound of Examples 1-97, or selected from Examples 1-97, or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof.

In one embodiment, the present invention provides a compound of formula (I) which is selected from the following compounds, or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof:

4-{[(1R)-(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

(3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(oxan-4-yl)ethyl]- 1-Methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoic acid.

In one embodiment, the present invention provides a compound of formula (I) which is a 2A diastereoisomer and is selected from the following compounds, or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof:

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

(3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(oxan-4-yl)ethyl]- 1-Methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoic acid.

In one embodiment, the present invention provides a compound of formula (I) which is a 2B diastereoisomer and is selected from the following compounds, or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof:

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

(3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(oxan-4-yl)ethyl]- 1-Methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoic acid.

In one embodiment, the present invention provides a compound of formula (I) which is 2-(5-chloro-2-{[(R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)- 1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}phenyl)-2-methylpropanoic acid, or its tautomer, N-oxide, pharmaceutically acceptable salt or solvate.

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 -[(1 S)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]-2-methylpropanoic acid , or its tautomer, N-oxide, pharmaceutically acceptable salt or solvate.

For the avoidance of ambiguity, it is to be understood that each general and specific implementation and example for one substituent may be combined with each general and specific implementation and example of one or more, in particular, all other substituents defined herein, and all such embodiments are included in this application.

SALTS, SOLVATES, TAUTOMERES, ISOMERS, N-OXIDES, ESTERS, PRODRUGS AND ISOTOPS

Mention of a compound of formula (I), its subgroups (for example, formulas (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 example also includes ionic forms, salts, solvates, isomers (including geometric and stereochemical isomers, if not indicated), tautomers, N-oxides, esters, prodrugs, isotopes and their protected forms, for example, as will be shown below; in particular salts or tautomers or isomers or N-oxides or solvates of said compound, and more specifically its salts or tautomers or N-oxides or solvates. In one embodiment, the mention of a compound of formula (I), its subgroups (e.g., formulas (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 example also includes its salts or tautomers, or solvates.

salt

Many compounds of formula (I) may exist in the form of salts, for example acid addition salts or, in certain cases, organic or inorganic base salts such as carboxylate, sulphonate and phosphate salts. All such salts are within the scope of the present invention and references to compounds of formula (I) include the salt forms of the compounds.

The salts of the present invention can be synthesized from a parent compound that contains a basic or acidic moiety using standard chemical methods such as those described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, hardcover, 388 pages, August 2002. In general, such salts can be prepared by reacting the free acid or free base forms of such compounds with the appropriate a base or acid in water or an organic solvent, or a mixture thereof; in general, a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is used.

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

One particular group of salts consists of salts derived from acetic, hydrochloric, hydroiodic, phosphoric, nitric, sulfuric, citric, lactic, succinic, maleic, malic, isethionic, fumaric, benzenesulfonic, toluenesulfonic, methanesulfonic (mesylate), ethanesulfonic, naphthalenesulfonic, valeric , acetic, propanoic, butanoic, malonic, glucuronic and lactobionic acids. One particular salt is the hydrochloride.

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

If the compound is anionic or contains a functional group which may be anionic (eg, -COOH may be -COO ^- ), then a salt with an organic or inorganic base may be formed to form the appropriate 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 ion (ie NH ₄ ⁺ ) and substituted ammonium ions (eg, NH ₃ R ⁺ , NH ₂ R ₂ ⁺ , NHR ₃ ⁺ , NR ₄ ⁺ ). Examples of some suitable substituted ammonium ions are derivatives of: methylamine, ethylamine, diethylamine, propylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine and tromethamine, as well as amino acids such as lysine and arginine . An example of a common quaternary ammonium ion is N(CH ₃ ) ⁴⁺ .

When the compounds of formula (I) contain an amine functional group, they can form ammonium salts, for example, by reaction with an alkylating agent according to methods well known to the person skilled in the art. Such quaternary ammonium compounds are within the scope of formula (I).

The compounds of the present invention may exist in the form of mono- and di-salts, depending on the ionization constant of the acid from which the salt is formed.

Salt forms of the compounds of the present invention are generally pharmaceutically acceptable salts, and examples of pharmaceutically acceptable salts are described in Berge et al., 1977, "Pharmaceutically Acceptable Salts," J. Pharm. Sc., Vol. 66, pp. 1-19. However, non-pharmaceutically acceptable salts can also be prepared as intermediates, which can then be converted to pharmaceutically acceptable salts. Such non-pharmaceutically acceptable salt forms, which can be used, for example, in the purification or separation of compounds according to the present invention, are also part of the present invention.

In one embodiment, the present invention provides a pharmaceutical composition comprising a solution (e.g., an aqueous solution) comprising a compound of formula (I), as well as its subgroups and examples described herein, in the form of a salt at a concentration above 10 mg/ml, usually above 15 mg/ml, and usually above 20 mg/ml.

N-oxides

Compounds of formula (I) containing an amine functional group can also form N-oxides. Reference herein to a compound of formula (I) containing an amine functional group also includes the N-oxide.

When a compound contains multiple amine functional groups, one or more nitrogen atoms may be oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of a tertiary amine or nitrogen atom of a nitrogen-containing heterocyclic group.

N-oxides can be formed by exposing the corresponding amine to an oxidizing agent such as hydrogen peroxide or a per-acid (e.g. peroxycarboxylic acid), see e.g. Advanced Organic Chemistry by Jerry March, ^4th Edition, Wiley Interscience, pages . More specifically, N-oxides can be prepared using the procedure described in LW Deady (Syn. Comm. 1977, 7, 509-514), in which an amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example, in inert solvent such as dichloromethane.

In one embodiment of the present invention, the compound is an N-oxide, eg, of the nitrogen atom on the R ⁶ or R ⁷ group, eg, pyridine N-oxide.

Geometric isomers and tautomers

The compounds of formula (I) may exist in a number of different geometric isomeric and tautomeric forms, and references to compounds of formula (I) include all such forms. For the avoidance of doubt, when a compound may exist in one of several geometric isomeric or tautomeric forms and only one of them is specifically described or shown, formula (I) nevertheless encompasses all other forms.

For example, specific heteroaryl rings may exist in two tautomeric forms, such as A and B, shown below. For simplicity, the formula may illustrate one form, but the formula should be considered to cover both tautomeric forms.

Other examples of tautomeric forms include, for example, keto, enol, and enolate forms, such as, for example, the following tautomeric pairs: keto/enol (shown below), imine/enamine, amide/iminoalcohol, amidine/endiamines, nitroso/oxime, thiokene /enthiol and nitro/aci-nitro.

stereoisomers

Unless otherwise mentioned or indicated, the chemical designation of compounds refers to the mixture of all possible stereochemically isomeric forms.

The stereocenters are depicted in the usual manner using "dashed" or "solid" wedge lines, for example

When a compound is described as a mixture of two diastereoisomers/epimers, the stereocenter configuration is not indicated and is represented by straight lines.

Where compounds of formula (I) contain one or more chiral centers and may exist in the form of two or more optical isomers, references to compounds of formula (I) include all of their optical isomeric forms (e.g., enantiomers, epimers, and diastereoisomers), both as individual optical isomers. isomers or mixtures (eg, racemic or scalemic mixtures), or as two or more optical isomers, unless the context dictates otherwise.

Optical isomers can be characterized and defined by their optical activity (i.e. as + and - isomers or d and I isomers), or they can be characterized in terms of their absolute stereochemistry using the "R and S" nomenclature developed by Cahn, Ingold and Prelog, see Advanced Organic Chemistry ed. Jerry March, ^4th Edition, John Wiley & Sons, New York, 1992, pages 109-114, and see also Cahn, Ingold & Prelog, Angew. Chem. Int. Ed. Engl., 1966, 5, 385-415.

Optical isomers can be separated using a number of techniques, including chiral chromatography (chromatography on a chiral support), and such techniques are well known to the person skilled in the art.

As an alternative to chiral chromatography, optical isomers can be separated by formation of diastereomeric salts with chiral acids such as (+)-tartaric acid, (-)-pyroglutamic acid, (-)-ditoluene-L-tartaric acid, (+)- mandelic acid, (-)-malic acid and (-)-camphorsulfonic acid, separation of diastereoisomers by selective crystallization and subsequent dissociation of salts to obtain a single enantiomer of the free base.

In addition, enantiomeric resolution can be accomplished by covalently linking an enantiomerically pure chiral auxiliary to a compound and then performing a diastereomeric resolution using standard techniques such as chromatography. This is followed by breaking the aforementioned covalent bond to give the appropriate enantiomerically pure product.

When the compounds of formula (I) exist in two or more optical isomeric forms, one enantiomer in an enantiomer pair may be advantageous over the other enantiomer, for example in terms of biological activity. Thus, under certain circumstances, it may be desirable to use only one of a pair of enantiomers, or only one of a plurality of diastereoisomers, as a therapeutic agent.

Accordingly, the present invention provides compositions containing a compound of formula (I) with one or more chiral centers, in which at least 55% (for example, at least 60%, 65%, 70%, 75%, 80%, 85 %, 90% or 95%) of the compound of formula (I) is present in the form of a single optical isomer (eg enantiomer or diastereoisomer). In one general embodiment, 99% or more (eg, substantially all) of the total compound of formula (I) may be present as a single optical isomer (eg, enantiomer or diastereoisomer).

Compounds containing double bonds may have E- (entgegen) or Z- (zusammen) stereochemistry at said double bond. Substituents on bivalent cyclic or (partially) saturated radicals may be in the cis or trans configuration. The terms cis and trans as used herein are in accordance with the Chemical Abstracts nomenclature (J. Org. Chem. 1970, 35(9), 2849-2867) nomenclature, and refer to the position of substituents on the ring moiety.

Of particular interest are compounds of formula (I) which are stereochemically pure. When a compound of formula (I) is designated, for example, as R, this means that the compound essentially does not contain the S isomer. If the compound of formula (I) is designated, for example, as E, this means that the compound essentially does not contain the Z-isomer. The terms cis, trans, R, S, E and Z are well known to the person skilled in the art.

Isotopic Variations

The present invention includes all pharmaceutically acceptable isotopically labeled compounds according to the present invention, i.e. compounds of formula (I) in which one or more atoms have been replaced by atoms of the same atomic number but an atomic mass or mass number different from the atomic mass or mass number normally found in nature.

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), carbon such as ¹¹ C, ¹³ C and ¹⁴ C, chlorine such as ³⁶ Cl, fluorine such as ¹⁸ F, iodine such as ¹²³ I, ¹²⁵ I and ¹³¹ I, nitrogen such as ¹³ N and ¹⁵ N, oxygen such as ¹⁵ O, ¹⁷ O and ¹⁸ O, phosphorus such as ³² P, and sulfur such as ³⁵ S.

Particular isotopically labeled compounds of formula (I), for example, including a radioactive isotope, are suitable for use in drug and/or substrate tissue distribution studies. The compounds of formula (I) may also have valuable diagnostic properties in the sense that they can be used to detect or determine complex formation between a labeled compound and other molecules, peptides, proteins, enzymes or receptors. Detection or determination methods may use compounds labeled with labeling agents such as radioisotopes, enzymes, fluorescent substances, luminous substances (eg, luminol, luminol derivatives, luciferin, aequorin, and luciferase), etc. Radioactive isotopes of tritium, i.e. ³ H(T), and carbon-14, i.e. ^14C are particularly useful for this purpose due to their ease of administration and readily available detection methods.

Substitution by heavier isotopes such as deuterium, i.e. ² H(D) may provide some therapeutic benefits resulting from greater stability, such as increased in vivo half-life or reduced dose required, and therefore such substitution may be used in some cases.

In particular, every reference to hydrogen in this application should be considered to encompass ¹ H and ² H, whether or not hydrogen is explicitly defined or is present in an implicit form to respect the valence of the relevant atom (particularly carbon).

Substitution with positron active isotopes such as ¹¹ C, ¹⁸ F, ¹⁵ O and ¹³ N can be useful in studies using positron emission tomography (PET) to study targeted employment.

Isotopically labeled compounds of formula (I) can generally be prepared using standard techniques known to those skilled in the art, or methods similar to those described in the appended Examples and Materials, using appropriate isotopically labeled reagents in place of the previously used unlabeled reagent.

Esters

Esters such as carboxylic acid esters, acyloxy esters and phosphate esters of compounds of formula (I) containing a carboxylic acid group or a hydroxyl group are also included within the scope of Formula (I). Examples of esters are compounds containing a -C(=O)OR group, where R is an ester substituent, for example, a C _1-7 alkyl group, a C _3-12 heterocyclyl group, or a C _5-12 aryl group, usually C _{1- 6} alkyl group. 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 -C(=O)OR, where R is an acyloxy substituent, for example, a C _1-6 alkyl group, a C _3-12 heterocyclyl group, or a C _5-12 aryl group, usually C _{1 -6} alkyl group. Specific examples of acyloxy groups 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. Phosphate esters are exemplified by phosphoric acid derivatives.

In one embodiment of the present invention, formula (I) includes within its scope esters of compounds of formula (I) containing a carboxylic acid group or a hydroxyl group. In another embodiment of the present invention, formula (I) does not include within its scope esters of compounds of formula (I) containing a carboxylic acid group or a hydroxyl group.

Solvates and crystalline forms

Also within the scope of formula (I) are any polymorphic forms of the compounds, as well as solvates such as hydrates, alcoholates and the like.

The compounds of the present invention may form solvates with, for example, water (ie hydrates) or common organic solvents. In the context of this document, the term "solvate" means the physical association of compounds according to the present invention with one or more solvent molecules. Such physical association includes varying degrees of ionic and covalent bonding, including hydrogen bonds. In specific cases, the solvate may be capable of isolation, for example, when one or more solvent molecules are included in the crystal lattice of a crystalline solid. The term "solvate" is intended to encompass liquid phase and separable solvates. Non-limiting examples of suitable solvates include compounds of the present invention in combination with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid or ethanolamine, and the like. The compounds of the present invention can exert their biological effects when in solution.

Solvates are well known in the field of pharmaceutical chemistry. They can be important to the preparation of a substance (for example, in terms of their purification, storage of the substance (for example, its stability) and ease of handling of the substance, and are often formed during the isolation or purification steps of chemical synthesis. A person skilled in the art can determine, using standard and long-standing techniques, whether a hydrate or other solvate has formed under the isolation or purification conditions used to prepare a particular compound.Examples of such techniques include thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray diffraction crystallography (for example , single-crystal X-ray crystallography or X-ray powder diffraction) and solid-state NMR (SS-NMR, also known as magic angle NMR, or MAS-NMR). as NMR, IS, HPLC and MS.

Alternatively, a person skilled in the art may intentionally form a solvate using crystallization conditions that include the amount of solvent required for a particular solvate. Thereafter, the standard methods described herein can be used to determine whether solvates have formed.

Moreover, the compounds of the present invention may have one or more polymorphic or amorphous crystalline forms, and as such are intended to be included within the scope of the present invention.

complexes

Formula (I) also includes within its scope complexes (eg inclusion complexes or clathrates with compounds such as cyclodextrins or metal complexes) of the compounds of the present invention.

Inclusion complexes, clathrates and metal complexes can be formed using methods well known to the person skilled in the art.

Prodrugs

Also included within the scope of formula (I) are any prodrugs of compounds of formula (I). By "prodrugs" is meant, for example, any compound which is converted in vivo to a biologically active compound of formula (I).

For example, some prodrugs are esters of the active compound (eg, a physiologically acceptable metabolically unstable ester). During metabolism, the ester group (-C(=O)OR) is cleaved off to give the active drug. Such esters can be prepared by esterification of, for example, any carboxylic acid group (-C(=O)OH) in the parent compound, with pre-protection of any reactive groups present in the parent compound where appropriate, followed by deprotection if necessary. .

Examples of such metabolically unstable esters include esters of the formula -C(=O)OR where R is:

C _1-7 alkyl (eg -Me, -Et, -nPr, -iPr, -nBu, -sBu, -iBu, -tBu);

C _1-7 aminoalkyl (eg aminoethyl; 2-(N,N-diethylamino)ethyl; 2-(4-morpholino)ethyl); and acyloxy-C _1-7 alkyl (for example, acyloxymethyl; acyloxyethyl; pivaloyloxymethyl; acetoxymethyl; 1-acetoxyethyl; 1-(1-methoxy-1-methyl)ethylcarbonyloxyethyl; 1-(benzoyloxy)ethyl; isopropoxycarbonyloxymethyl; 1-isopropoxycarbonyloxyethyl; cyclohexylcarbonyloxymethyl ; 1-cyclohexylcarbonyloxyethyl; cyclohexyloxycarbonyloxymethyl; 1-cyclohexyloxycarbonyloxyethyl; (4-oxanyloxy)carbonyloxymethyl; 1-(4-oxanyloxy)carbonyloxyethyl; (4-oxanyl)carbonyloxymethyl; and 1-(4-tetrahydropyranyl)carbonyloxyethyl).

Also, some prodrugs are activated by enzymes to produce the active compound or a compound that, after additional chemical reaction, results in the active compound (e.g., as in antigen-targeted enzyme prodrug therapy (ADEPT), gene-targeted enzyme prodrug therapy ( GDEPT) and Ligand Targeted Enzyme Prodrug Therapy (LIDEPT), etc.). For example, the prodrug may be a sugar derivative or other glycosidic conjugate, or may be an amino acid ester derivative. In one embodiment, the scope of formula (I) does not include prodrugs of the compounds of formula (I).

METHODS FOR PRODUCING COMPOUNDS OF FORMULA (I)

In this section, as in all other sections of this application, unless the context indicates otherwise, the reference to formula (I) also includes all other subformulas (for example, formulas (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 examples thereof, as defined herein, unless the context dictates otherwise.

Compounds of formula (I) may be prepared according to synthetic methods well known to the person skilled in the art.

According to a further aspect of the present invention, there is provided a process for the preparation of a compound of formula (I), or a tautomer, stereoisomer, N-oxide, pharmaceutically acceptable salt or solvate thereof, said process comprising:

According to a further aspect of the present invention, there is provided a process for preparing a compound of formula (I) as defined herein above, said process comprising:

(a) reacting a compound of formula (XV) with an organometallic reagent of formula R ⁷ M (when M is a metal), for example a Grignard reagent of formula R ⁷ MgBr:

where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , a, s, m and n are as defined herein;

(b) interconversion of a compound of formula (I) or a protected derivative thereof into an additional compound of formula (I) or a protected derivative thereof; and/or

(c) deprotection of the protected derivative of the compound of formula (I); and/or

(d) obtaining a compound of formula (I) and forming a pharmaceutically acceptable salt thereof.

The desired intermediates are available from commercial sources, are known in the literature, prepared by methods similar to those described in the literature, or prepared by methods similar to those described in the experimental procedures in the examples below. Other compounds can be obtained by interconversion of functional groups using methods well known in this field.

The general synthetic route to obtain compounds of formula XV, a key intermediate, is shown in the Schemes below.

Examples of reagents and conditions for Scheme 1: a) NaOH, H ₂ O, CHCl ₃ , 85°C; A) AcOH, CT; C) Pb(OAc) ₄ , THF, 0°C; C) NaClO ₂ , H ₂ NSO ₃ H, CH ₃ CN, H ₂ O, RT; 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; at this stage, separation and isolation of the 3(R)-enantiomer can be carried out using chiral HPLC.

In Scheme 1, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as described herein, and W is a leaving group such as, for example, halogen, such as bromine, or a carbonyl group, such as, for example, acetyl.

N-aroylhydrazone (XI) can be obtained by condensation of benzaldehyde (IX) with benzhydrazide (X). Reaction with Pb(OAc) ₄ gives the aldehyde (XII), from which the acid (XIII) is obtained by Pinnick oxidation. A suitable benzylamine can then be used to prepare 3-hydroxyisoindolinone (XIV) and the R ³ -containing side chain can be added using thionyl chloride or InBr ₃ and a suitable alcohol.

Intermediates of formula (XV) can be used as a starting point for the synthesis of compounds of the present invention containing a varying functional group at the R ³ , R ⁶ and R ⁷ positions of Formula I.

Scheme 2 below shows examples of procedures for introducing various R ⁶ moieties, starting with intermediates of formula (XVI) (which is a compound of formula (XV) in which W is Br).

Examples of reagents and conditions for Scheme 2: G) (i) toluene, 1,4-dioxane, LiCl, tributyl(1-ethoxyvinyl)tin, Pd(PPh ₃ ) ₄ , (ii) HCl, H ₂ O/THF. H) MeMgCl, in the presence of ZnCl ₂ and/or LaCl ₃ -2LiCl, THF. At any stage, separation and isolation of the 3(R)-enantiomer can be carried out using chiral HPLC.

Bromide (XVI) can be converted to methyl ketone (XVII), for example, using 1,4-dioxane, LiCl, tributyl(1-ethoxyvinyl)tin, Pd(PPh ₃ ) ₄ , and then converted to alcohol XVIII by reaction with methyl Grignard reagent.

Compounds in which R ⁶ and R ⁷ are hydrogen can also be prepared according to General Synthesis Scheme 3. When R ³ contains a hydroxyl group, it can be protected during synthesis with standard protecting groups (eg TBDMS, TBDPS). Deprotection can be done using standard conditions (eg TBAF).

Examples of 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.

The compounds of formula (XVIII), first shown in Scheme 2, in which R ⁶ and R ⁷ are methyl, can also be prepared according to the general Synthesis Scheme 4.

In Scheme 4, an intermediate of formula (XXIV) is prepared from an intermediate of formula (XXIII) according to method F (InBr ₃ with R ³ (CH ₂ ) _s -OH). An intermediate compound of formula (XXIV) is then converted to a compound of formula (XVIII) using a Grignard reaction.

Examples of reagents and conditions: F) InBr ₃ R ₃ (CH ₂ ) _S -OH, DCE, 85°C; H) MeMgCl, ZnCl ₂ , THF, 0°C. At any stage, separation and isolation of the 3(R)-enantiomer can be carried out using chiral HPLC.

Compounds of general formula XXX can also be prepared according to Schemes 5 and 6.

Examples of 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) 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; N) R ₇ MgX in the presence of ZnCl ₂ and/or LaCl ₃ -2LiCl, THF or Al(R ₇ ) ₃ , THF or EtLi, ZnEt ₂ , THF. The separation of enantiomers and/or diastereoisomers in Steps E, F and N can be carried out by chiral and/or achiral HPLC.

Intermediate XIII (where W is Br) reacts with nBuLi and an appropriate aldehyde to give alcohol XXVI, which is oxidized to the corresponding ketone (XVII) using MnO ₂ or I ₂ /KI. Intermediate XXVII is then converted to 3-hydroxyindolinone XXIX following methods D and E (or F) above.

Formula XXIX intermediates can be used as a starting point for the synthesis of compounds of the present invention containing a varying functional group at the R ⁷ position of Formula I.

Alternatively, R ⁷ substituents are introduced earlier in the synthesis as shown in Scheme 6. Formula XXVII intermediates can be reacted with organometallic reagents to give a quaternary alcohol (XXXI) which is then converted to the final compounds of Formula (I) by following methods D and E (or F) (Scheme 6).

Examples of reagents and conditions: N) R ₇ MgX in the presence of ZnCl ₂ and/or LaCl ₃ -2LiCl, THF or Al(R ₇ ) ₃ , THF or EtLi, ZnEt ₂ , 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. Separation of enantiomers and/or diastereoisomers in the N and E/F Steps can be carried out by chiral and/or achiral HPLC.

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 such a case, XVI can be converted to the appropriate boronate using, for example, Miyaur's conditions. The boronate is then treated with a suitable heterocyclic iodide (or heterocyclic bromide) in the presence of carbon monoxide, a suitable catalyst (such as Pd(dppf)Cl ₂ .) and a solvent (such as toluene or anisole).

Alternatively, compounds of formula XVI can be treated with a suitable heterocyclic stannan in the presence of carbon monoxide, a suitable catalyst [such as Pd(dppf)Cl ₂ .] and a solvent (such as DMF) to give compounds of formula XXIX (Scheme 7). At any stage, separation and isolation of the 3(R)-intermediate by chiral HPLC can be carried out. Compounds of formula XXIX can then be converted to compounds of formula XXX (as shown in Scheme 5),

Compounds of formula XVI can also be used to prepare compounds of formula XXIX using the methods indicated in Scheme 8. In this case, compounds of formula XVI can be used to prepare the Weinreb amide derivative using N,O-dimethylhydroxylamine hydrochloride in the presence of carbon monoxide, a suitable palladium catalyst (e.g. Xantphos G3 catalyst). The Weinreb amide can then be reacted with a suitable metalated heterocycle (eg, the product of 4-bromo-1-methyl-1H-pyrazole and nBuLi in THF) to give compounds of formula XXIX (Scheme 8). At any stage, separation and isolation of the 3(R)-intermediate by chiral HPLC can be carried out. Compounds of formula XXIX can then be converted to compounds of formula XXX (as shown in Scheme 5).

It should be understood that particular compounds may exist in various diastereomeric and/or enantiomeric forms, and that enantiomerically pure synthetic precursors may be used in processes for their preparation.

Alternatively, racemic precursors may be used, and mixtures of diastereoisomers obtained by such methods may be resolved using methods well known to the person skilled in the art, for example, non-chiral or chiral preparative chromatography or separation using diastereomeric derivatives: for example , crystallizing a salt formed with an enantiomerically pure acid such as L-tartaric acid (or an enantiomerically pure base such as (1R)-1-phenylethane-1-amine); or enantiomeric resolution of a diastereomeric derivative formed by covalently linking an enantiomerically pure chiral auxiliary to a compound, followed by resolution using standard techniques such as chiral or non-chiral chromatography. The above covalent bond is then cleaved to obtain the appropriate enantiomerically pure product.

One of skill in the art is aware of a wide range of well known functional group interconversions to convert a compound precursor to a compound of Formula I; such interconversions are described in Advanced Organic Chemistry ed. Jerry March, 4th edition, John Wiley & Sons, 1992. For example, possible metal-catalyzed functionalizations such as the use of organotin reagents (Still reaction), Grignard reagents, and reactions with nitrogen nucleophiles are described in 'Palladium Reagents and Catalysts' [Jiro Tsuji, Wiley, ISBN 0-470-85032-9] and Handbook of OrganoPalladium Chemistry for Organic Synthesis [volume 1, edited by Ei-ichi Negishi, Wiley, ISBN 0-471-31506-0].

If necessary, one or more reactions known to those skilled in the art are carried out before or after the reactions described above, and the reactions are carried out in the correct order to achieve the desired substitutions as defined above to give other compounds of formula (I). Non-limiting examples of such reactions, for which conditions can be found in the literature, include:

protection of reactive functional groups,

deprotection of reactive functional groups,

halogenation,

dehalogenation,

dealkylation,

alkylation or arylation of amine, aniline, alcohol and phenol,

Mitsunobu reaction on hydroxyl groups,

cycloaddition reactions on suitable groups,

reduction of nitro, esters, cyano, aldehydes,

coupling reactions catalyzed by a transition metal,

acylation,

sulfonylation/introduction of sulfonyl groups,

saponification/hydrolysis of ester groups,

amidification or transesterification of ester groups,

esterification or amidification of carboxyl groups,

halogen exchange,

nucleophilic substitution with an amine, thiol or alcohol,

reductive amination,

oxime formation on carbonyl and hydroxylamine groups,

S-oxidation,

N-oxidation,

salt formation.

It should be understood that specific compounds, for example, compounds of 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), (IIIa), (IIIb), (IVa), (IVb), (V), (VI), (Via), (VII) , (VIIa), (VIIb), (VIIc), (VIId), (VIId'), (VIIe), (VIIe'), (a), (b), (ba), (bb), (bc) or (c) may exist in various diasteromeric and/or enantiomeric forms, and that enantiomerically pure synthetic precursors may be used in the processes for their preparation.

Alternatively, racemic precursors may be used, and mixtures of diastereoisomers obtained by such methods may be resolved using methods well known to the person skilled in the art, for example, non-chiral or chiral preparative chromatography or separation using diastereomeric derivatives: for example , crystallization of a salt formed with an enantiomerically pure acid such as L-tartaric acid; or enantiomeric resolution of a diastereomeric derivative formed by covalently linking an enantiomerically pure chiral auxiliary to a compound, followed by resolution using standard techniques such as chiral chromatography. The above covalent bond is then cleaved to obtain the appropriate enantiomerically pure product.

Some of the required intermediates are available from commercial sources, are known in the literature, prepared by methods similar to those described in the literature, or prepared by methods similar to those described in the experimental procedures given in the examples below. Other compounds can be obtained by interconversion of functional groups using methods well known in this field.

In a further embodiment of the present invention, a novel intermediate is provided. In one embodiment, the present invention provides a novel intermediate (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XIX), (XX), (XXI), (XXIII) and (XXIV).

Protecting groups

In many of the reactions described herein, one or more groups may need to be protected to prevent the reaction from occurring at an undesirable position on the molecule. For examples of protecting groups and methods for protecting and deprotecting functional groups, see Protective Groups in Organic Synthesis (T. Green and P. Wuts; 3rd edition; John Wiley and Sons, 1999).

In particular, the compound can be synthesized in protected forms and the protecting groups can be removed to give the compound of formula (I).

The hydroxy group may be protected, for example, in the form of an ether (-OR) or an ester (-OC(=O)R), for example as: tert-butyl ether; tetrahydropyranyl (THP) ether; benzyl, benzhydryl (diphenylmethyl) or trityl (triphenylmethyl) ether; trimethylsilyl or tert-butylmethylsilyl ether; or acetyl ether (-OC(=O)CH ₃ ).

The aldehyde or ketone group may be protected, for example, in the form of acetal (R-CH(OR) ₂ ) or ketal (R ₂ C(OR) ₂ ), respectively, in which the carbonyl group (>C=O) is attacked, for example , primary alcohol. The aldehyde or ketone group can be easily regenerated by hydrolysis using excess water in the presence of an acid.

The amine group may be protected, for example in the form of an amide (-NRCO-R) or carbamate (-NRCO-OR), for example as: methylamide (-NHCO-CH ₃ ); benzyl carbamate (-NHCO-OCH ₂ C ₆ H ₅ , -NH-Cbz or NH-Z); as tert-butyl carbamate (-NHCO-OC(CH ₃ ) ₃ , -NH-Boc); 2-biphenyl-2-propylcarbamate (-NHCO-OC(CH ₃ ) ₂ C ₆ H ₄ C ₆ H ₅ , -NH-Bpoc) as 9-fluorenylmethyl carbamate (-NH-Fmoc) as 6-nitroveratril carbamate (-NH -Nvoc), as 2-trimethylsilylethylcarbamate (-NH-Teos), as 2,2,2-trichloroethylcarbamate (-NH-Troc), as allyl carbamate (-NH-Alloc) or as 2(-phenylsulfonyl)ethylcarbamate (-NH- psec).

Other protecting groups for amines such as cyclic amines and heterocyclic N-H groups include toluenesulfonyl (tosyl) and methanesulfonyl (mesyl) groups, benzyl groups such as the p-methoxybenzyl (PMB) group, and tetrahydropyranyl (THP) groups.

The carboxylic acid group may be protected in ester form, for example as: C _1-7 alkyl ester (eg methyl ester; tert-butyl ether); C _1-7 haloalkyl ether (eg C _1-7 trihaloalkyl ether); triC _1-7 alkylsilyl-C _1-7 alkyl ether; or C _5-20 aryl-C _1-7 alkyl ether (eg, benzyl ether; nitrobenzyl ether; para-methoxybenzyl ether. The thiol group may be protected, for example, in the form of a thioether (-SR), for example, as: benzylthioether; acetamidomethyl ether (-S-CH ₂ NHC(=O)CH ₃ ).

Isolation and purification of compounds according to the present invention

Compounds of the present invention may 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 (eg flash chromatography) and HPLC. A particularly useful technique for purifying compounds is preparative liquid chromatography using mass spectrometry as a method for detecting purified compounds appearing on a chromatographic column.

Preparative LC-MS is a standard and efficient method used to purify small organic molecules such as the compounds described herein. Liquid chromatography (LC) and mass spectrometry (MS) methods can be modified to provide better separation of crude materials and improved sample detection by MS. Optimization of a preparative gradient LC method will involve changing columns, volatile eluents and modifiers, and gradients. Techniques are well known in the art for optimizing LC-MS methods and their subsequent use to purify compounds. 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. An example of such a system for purifying compounds by preparative LC-MS is described below in the Examples section of this application (under the heading "LC-MS system for mass directed purification").

Methods for recrystallizing the compounds of formula (I) and their salts can be carried out using methods well known to the person 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). Products obtained from an organic reaction are rarely pure when isolated directly from the reaction mixture. If the compound (or its salt) is a solid, it can be purified and/or crystallized by recrystallization from a suitable solvent. A good recrystallization solvent should dissolve a moderate amount of cleaning agent at elevated temperatures, but only a small amount of cleaning agent at lower temperatures. It should easily dissolve impurities at low temperatures or not dissolve them at all. Finally, said solvent must be easily removed from the purified product. This usually means that the solvent has a relatively low boiling point, and one skilled in the art will know which solvents to use to recrystallize a particular substance or, if such information is not available, will test several solvents. To ensure a good yield of purified material, a minimum amount of hot solvent is used to dissolve all of the crude material. In practice, 3-5% more solvent is used than necessary to ensure that the solution is not saturated. If the crude compound contains an impurity that is insoluble in the solvent, it can be further removed by filtration, after which the solution is left to crystallize. In addition, if the crude compound contains traces of a colored substance that is not native to the compound, it can be removed by adding a small amount of a decolorizing agent, such as activated charcoal, to the hot solution, filtering it, and allowing the solution to crystallize. Usually, crystallization occurs spontaneously after cooling the solution. If this does not occur, crystallization can be induced by cooling the solution below room temperature or by adding a single crystal of the pure substance (seed crystal). Recrystallization can also be carried out and/or yield optimized by using an anti-solvent or co-solvent. In this case, the compound is dissolved in a suitable solvent at an elevated temperature, filtered, and then an additional solvent is added in which the desired compound is sparingly soluble to facilitate crystallization. The crystals are then usually isolated by vacuum filtration, washed and then dried, for example in an oven or by drying.

Other examples of purification methods include sublimation, which includes a vacuum heating step, such as using a "cold finger", and melt crystallization (Crystalization Technology Handbook 2nd Edition, edited by A. Mersmann, 2001).

BIOLOGICAL EFFECTS

The use of the compound of the present invention in medicine or therapy is contemplated. Compounds of the present invention, subgroups and examples thereof have been shown to inhibit the interaction of p53 with MDM2. Such inhibition leads to arrest of cell proliferation and apoptosis, which may be suitable for use in the prevention or treatment of the disease states described herein, for example, the diseases and conditions discussed below, and the diseases and conditions described in the "Prior Art" 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 used to alleviate or reduce the incidence of cancer.

The compounds of the present invention may be suitable for use in the treatment of adult patients. The compounds of the present invention may be suitable for use in the treatment of pediatric patients.

The compounds of the present invention have been shown to be effective inhibitors of the formation of the MDM2-p53 complex. The antagonistic compounds of formula (I) are capable of binding to MDM2 and exhibit activity against MDM2. The efficacy of the compounds of the present invention was determined against MDM2/p53 using the assay protocol described herein and other methods known in the art. More specifically, the compounds of formula (I) and its subgroups have an affinity for MDM2/p53.

Particular compounds according to the present invention are compounds having an IC ₅₀ value of less than 0.1 μM, in particular less than 0.01 or 0.001 μM.

MDM2/p53 function has been implicated in many diseases due to the role it plays in a number of processes, such as vascular remodeling and anti-angiogenic processes, and regulation of metabolic pathways, as well as in oncogenesis. Due to the affinity of the compounds of the present invention for MDM2, it is contemplated that they may be useful in the treatment or prevention of a number of diseases or conditions, including autoimmune diseases; diabetes; chronic inflammatory diseases, eg, lupus nephritis, systemic lupus erythematosus (SLE), autoimmune-mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, autoimmune diabetes mellitus, eczema hypersensitivity reaction, asthma, COPD, rhinitis, and upper respiratory disease; hyperkeratotic diseases such as autosomal recessive congenital ichthyosis (ARVI); kidney disease, including glomerular disorders, chronic kidney disease (CKD), kidney inflammation, podocyte loss, glomerulosclerosis, proteinuria, and progressive kidney disease; cardiovascular diseases, for example, cardiac hypertrophy, restenosis, arrhythmias, atherosclerosis; myocardial infarctions associated with ischemic injury, vascular injury, stroke and reperfusion injury; vascular proliferative diseases; eye diseases such as age-related macular degeneration, in particular wet age-related macular degeneration, ischemic proliferative retinopathies such as retrolethal fibroplasia (RF) and diabetic retinopathy, and hemangioma.

Due to the affinity of the compounds of the present invention for MDM2, it is believed that they may be useful in the treatment or prevention of proliferative diseases such as cancers.

Examples of cancers (and their benign counterparts) that may be treated (or inhibited) include, but are not limited to, tumors of epithelial origin (adenomas and carcinomas of various types, including adenocarcinomas, squamous cell carcinomas, transitional cell carcinomas, and other carcinomas), such as carcinomas of the bladder and urinary tract, breast, gastrointestinal tract (including the esophagus, stomach (gastric), small intestine, large intestine, intestine, colon, rectum, and anus), liver (hepatocellular carcinoma), gallbladder, and biliary tract system, exocrine pancreas, kidney (eg, renal cell carcinoma), lung (eg, adenocarcinomas, small cell lung carcinomas, non-small cell lung carcinomas, bronchoalveolar carcinomas, and mesotheliomas), head and neck (eg, cancers of the tongue, oral cavity, larynx, pharynx, nasopharynx, palatine tonsils, salivary glands, nasal cavity, and paranasal sinuses), ovary, fallopian tubes, peritoneum, vagina, vulva, penis, testis, cervix, myometrium, endometrium, thyroid gland (eg, follicular thyroid carcinoma) , brain, adrenals, prostate, skin and adjacent organs (eg, melanoma, basal cell carcinoma, squamous cell carcinoma, keratoacanthoma, dysplastic nevus); hematologic malignancies (i.e., leukemias, lymphomas) and precancerous hematologic and borderline disorders, including hematologic malignancies and similar conditions of lymphoid origin (eg, acute lymphoblastic leukemia [ALL], chronic lymphocytic leukemia [CLL], B- cellular lymphomas such as diffuse large B-cell lymphoma [DLBCL], follicular lymphoma, Burkitt's lymphoma, mantle cell lymphoma, T-cell lymphomas and leukemias, natural killer cell [NK] lymphomas, Hodgkin's lymphomas, hairy cell leukemia, monoclonal gammopathy of unknown origin, plasmacytoma, multiple myeloma, and post-transplant lymphoproliferative syndromes) and blood system malignancies and related conditions of myeloid origin (eg, 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 soft tissue, bone, or cartilage sarcomas, such as osteosarcomas, fibrosarcomas, chondrosarcomas, rhabdomyosarcomas, malignant leiomyomas, liposarcomas, angiosarcomas, Kaposi's sarcoma, Ewing's sarcoma, synovial sarcomas, epithelioid sarcomas, gastrointestinal stromal tumors, benign and malignant histiocytomas and elevated dermatofibrosarcoma; tumors of the central and peripheral nervous system (eg, astrocytomas (eg, gliomas), neuromas and glioblastomas, meningiomas, ependymomas, pineal tumors, and schwannomas); endocrine tumors (eg, pituitary tumors, adrenal tumors, islet cell tumors, parathyroid tumors, carcinoid tumors, and medullary thyroid cancer); tumors of the eyes and their appendages (for example, retinoblastoma); embryonic cell and trophoblastic tumors (eg, teratomas, seminomas, dysgerminomas, chorioadenomas, and choriocarcinomas); as well as pediatric and fetal tumors (eg, medulloblastoma, neuroblastoma, Wilms' tumor, and primitive neuroectodermal tumors); or syndromes, concomitant or otherwise, that make the patient vulnerable to malignant tumors (eg, xeroderma pigmentosa).

Cell growth is a carefully controlled function. Cancer, a condition of abnormal cell growth, occurs when cells divide in an uncontrolled manner (increase in number), grow out of control (increase in size), and/or undergo a reduction in cell death through apoptosis (programmed cell death), necrosis, or anoicosis. In one embodiment, the abnormal cell growth is selected from uncontrolled cell proliferation, excess cell growth, or reduced programmed cell death. In particular, the abnormal cell growth condition or disease is a cancerous disease.

Thus, in pharmaceutical compositions, methods of use or methods according to the present invention for the treatment of a disease or condition involving abnormal cell growth (i.e., uncontrolled and/or rapid cell growth), said disease or condition involving abnormal cell growth, in one embodiment is a cancer.

Many diseases are characterized by persistent and unregulated angiogenesis. Chronic proliferative diseases are often accompanied by marked angiogenesis, which can influence or maintain an inflammatory and/or proliferative state, or which leads to tissue destruction through invasive proliferation of blood vessels. Tumor growth and metastasis have been found to be dependent on angiogenesis. Therefore, the compounds of the present invention can be used to prevent or stop the initiation of tumor angiogenesis.

Angiogenesis is usually used to describe the development of new or replacement blood vessels, or neovascularization. This is a necessary and physiologically normal process by which the vascular system is laid in the embryo. In general, angiogenesis does not occur in most normal tissues of the adult body, with the exception of the sites of ovulation, menstruation, and wound healing. However, many diseases are characterized by persistent and unregulated angiogenesis. For example, in arthritis, new capillary blood vessels grow into the joint and destroy the cartilage. In diabetes (and many different eye diseases), new blood vessels grow into the macula or retina or other structures of the eye and can lead to blindness. The process of atherosclerosis is associated with angiogenesis. Tumor growth and metastasis have been found to be dependent on angiogenesis. The compounds of the present invention may be effective in the treatment of diseases such as cancer and metastasis, eye diseases, arthritis and hemangioma.

Therefore, the compounds of the present invention may be suitable for use in the treatment of metastasis and metastatic cancers. Metastasis or metastatic disease is the spread of a disease from one organ or part to another non-contiguous organ or part. Cancers that can be treated with the compounds of the present invention include primary tumors (i.e., cancer cells at their site of origin), focal invasion (cancer cells that invade and infiltrate surrounding normal tissues at the site), and metastatic (or secondary) tumors, i.e. Tumors formed from malignant cells that have circulated in the bloodstream (hematogenous spread) either through the lymphatic system or through body cavities (transcoelomically) to other parts and tissues of the body. In particular, the compounds of the present invention may be suitable for use in the treatment of metastasis and metastatic cancers.

In one embodiment, the blood system cancer is leukemia. In one embodiment, the blood system cancer is lymphoma. In one embodiment, the cancer is AML. In another embodiment, the cancer is CLL.

In one embodiment, a compound of the present invention is suitable for use in the prevention or treatment of leukemia, such as acute or chronic leukemia, in particular acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), or chronic myeloid leukemia. (CML). In one embodiment, the compound of the present invention is suitable for use in the prevention or treatment of lymphoma, such as acute or chronic lymphoma, in particular Burkitt's lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, or diffuse large B cell lymphoma.

In one embodiment, a compound of the present invention is suitable for use in the prevention or treatment of acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL).

One embodiment includes a compound of the present invention for use in the prevention or treatment of cancer in a patient selected from a subset of cancers with wild-type p53 or MDM2 amplification.

Cancers may be cancers susceptible to treatment with MDM2 inhibitors. Cancers may be cancers in which MDM2 is overexpressed. The cancers may be wild-type p53 cancers.

Particular cancers include diseases with MDM2 amplification and/or overexpression of MDM2, such as hepatocellular carcinoma, lung sarcomas, osteosarcomas, and Hodgkin's disease.

Specific cancers include those with wild-type p53. Specific cancers include wild-type p53 cancer cells, more specifically, but not exclusively, if MDM2 is highly expressed.

In one embodiment, the cancer is p53 functional tumors. In one embodiment, the disease to be treated is p53-functional solid and hematologic malignancies. In another embodiment, the patient to be treated has a p53 mutant tumor, for example, AML patients with a p53 mutant tumor.

In one embodiment, the cancer is a brain tumor, such as a glioma or neuroblastoma.

In one embodiment, the cancer is a skin cancer, such as melanoma.

In one embodiment, the cancer is lung cancer, such as mesothelioma. In one embodiment, said mesothelioma is malignant peritoneal mesothelioma or malignant pleural mesothelioma. In one embodiment, the cancer is a cancer of the gastrointestinal tract, such as a stromal tumor of the gastrointestinal tract, stomach, colorectal cancer, or colon cancer.

In one embodiment, the cancer is osteosarcoma.

In one embodiment, the cancer is a liposarcoma.

In one embodiment, the cancer is Ewing's sarcoma.

In one embodiment, the cancer is liposarcoma, soft tissue sarcoma, osteosarcoma, esophageal cancer, and certain childhood cancers, including B cell cancers.

In one embodiment, the cancer is colorectal, breast, lung, and brain cancer.

In one embodiment, the cancer is childhood cancer.

Whether a particular cancer is susceptible to MDM2 inhibitors can be determined using the method described in the section titled "Diagnostic Methods".

According to a further aspect, the use of a compound for the manufacture of a medicament for the treatment of a disease or condition described herein, in particular a cancer, is provided.

Certain cancers are resistant to treatment with specific drugs. This may depend on the type of tumor (the most common epithelial malignancies are essentially chemoresistant, and prostate cancer is relatively resistant to currently available chemotherapy or radiation therapy regimens), or resistance may arise spontaneously as the disease progresses or as a result of treatment. In this regard, references to prostate cancer include prostate cancer resistant to antiandrogen therapy, in particular abiraterone or enzalutamide, or prostate cancer resistant to castration. Similarly, references to multiple myeloma include bortezomib-resistant multiple myeloma or refractory multiple myeloma, and references to chronic myeloid leukemia include imitanib-resistant chronic myeloid leukemia and refractory chronic myeloid leukemia. In this regard, references to mesothelioma include mesothelioma with resistance to topoisomerase poisons, alkylating agents, antitubulins, antifolates, platinum compounds, and radiation therapy, in particular cisplatin-resistant mesothelioma.

The compounds may also be suitable for use in the treatment of tumor growth, pathogenesis, resistance to chemotherapy and radiation therapy by sensitizing cells to chemotherapy, and as an anti-metastatic agent.

Therapeutic anticancer interventions of all types inevitably increase stress on target tumor cells. MDM2/p53 inhibitors are a class of chemotherapeutic agents with the ability to: (i) sensitize cancer cells to anticancer drugs and/or treatments; (ii) facilitating or reducing the emergence of resistance to anticancer drugs and/or treatments; (iii) reversal of resistance to cancer drugs and/or treatments; (iv) enhancing the activity of anti-cancer drugs and/or treatments; (v) slowing down or preventing the onset of resistance to anticancer drugs and/or treatments.

In one embodiment, the present invention provides a compound for use in the treatment of a disease or condition mediated by MDM2. In a further embodiment, the MDM2 mediated disease or condition is a cancer that is characterized by overexpression and/or increased activity of MDM2, or a high copy number of MDM2 and/or wild type p53.

According to a further aspect, the use of a compound for the manufacture of a medicament for the treatment of a disease or condition described herein, in particular a cancer, is provided.

In one embodiment, the present invention provides a compound for use in the prevention or treatment of a disease or condition mediated by MDM2/p53. In one embodiment, a compound is provided for inhibiting the interaction between the MDM2 protein and p53.

In one embodiment, a pharmaceutical composition is provided that contains an effective amount of at least one compound as defined herein. According to a further aspect of the present invention, there is provided a compound as defined herein.

In one embodiment, a method for preventing or treating cancer is provided, comprising the steps of administering to a mammal a medicament containing at least one compound as defined herein.

DIAGNOSIS METHODS

Prior to administration of a compound of formula (I), a patient may be screened to determine if the disease or condition the patient is or may be suffering from is susceptible to treatment with an Mdm2/p53 inhibitory compound. The term "patient" includes human and veterinary subjects such as primates, in particular human patients.

For example, a biological sample taken from a patient can be analyzed to determine whether a condition or disease, such as cancer, that the patient is or may be suffering from is characterized by genetic disorders or abnormal protein expression that results in upregulation of MDM2 levels or upregulation of the biochemical pathway downstream from MDM2/p53.

Examples of such disorders that result in 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 the receptor or ligands. Tumors with upregulation of MDM2/p53, in particular overexpression of MDM2, or expressed wild-type p53, may be particularly sensitive to inhibitors of MDM2/p53. For example, amplification of MDM2 and/or removal of its negative regulator, such as p14ARF, has been established in a number of cancers, as discussed in the Introduction section.

The term "upregulation" includes upregulation or overexpression, including gene amplification (ie, multiple copies of a gene), cytogenetic aberration, and overexpression by transcriptional or post-translational manipulation. Thus, the patient may be subjected to a diagnostic test to detect a marker indicative of MDM2 upregulation. The term "diagnosis" includes screening. The term "marker" includes genetic markers, including, for example, analysis of DNA composition to determine the presence of mutations in p53 or MDM2 amplification or deletion (loss) of p14ARF. The term "marker" also includes markers indicative of MDM2/p53 upregulation, including protein levels, protein state, and mRNA levels of the aforementioned proteins. Gene amplification includes more than 7 copies, as well as a gain of 2 to 7 copies.

Diagnostic tests and screenings are usually performed on a biological sample (i.e. body tissue or body fluids) selected from tumor biopsy samples, blood samples (isolation and expansion of isolated tumor cells), cerebrospinal fluid, blood plasma, blood serum, saliva, biopsies stool, sputum, chromosome analysis, pleural fluid, peritoneal fluid, cheek swabs, skin or urine biopsy.

Methods for identifying and analyzing cytogenetic aberration, gene amplification, mutations, and upregulation of proteins are known to those skilled in the art. Screening methods may include, but are not limited to, standard methods such as DNA sequence analysis using standard Sanger or next generation sequencing methods, reverse transcriptase polymerase chain reaction (RT-PCR), RNA sequencing (RNAseq), RNA assays (nanostring hybridization proximity RNA nCounter assays) or in-situ hybridizations such as fluorescent in-situ hybridization (FISH) or allele-specific polymerase chain reaction (PCR).

In RT-PCR screening, the level of mRNA in a tumor is measured by making a cDNA copy of the mRNA, followed by amplification of the cDNA by PCR. PCR amplification methods, primer selection and amplification conditions are known to the person skilled in the art. Nucleic acid manipulation and PCR are performed using standard methods described, for example, in Ausubel, FM et al., eds. (2004) Current Protocols in Molecular Biology, John Wiley & Sons Inc., or Innis, MA et al., eds. (1990) PCR Protocols: a guide to methods and applications, Academic Press, San Diego. Reactions and manipulations involving nucleic acid techniques are also described in Sambrook et al., (2001), ^3rd Ed, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press. Alternatively, a commercially available RT-PCR kit (eg, Roche Molecular Biochemicals) or the techniques set forth in US Pat. Nos. 4,666,828; 4683202; 4801531; 5192659, 5272057, 5882864 and 6218529, which are incorporated herein by reference. An example of an in-situ hybridization technique for measuring mRNA expression would be fluorescent in-situ hybridization (FISH) (see Angerer (1987) Meth. Enzymol., 152: 649).

In general, in situ hybridization includes the following main steps: (1) fixing the tissue to be analyzed; (2) pre-hybridization processing of the sample to increase the availability of the target nucleic acid and to reduce non-specific binding; (3) hybridization of a mixture of nucleic acids relative to the specified nucleic acid in a biological structure or tissue; (4) post-hybridization washes to remove nucleic acid fragments not bound by hybridization; and (5) detection of hybridized nucleic acid fragments. Samples used in such methods are usually labeled with, for example, radioisotopes or fluorescent reporters. Specific probes are sufficiently long, eg, from about 50, 100, or 200 nucleotides to about 1000 or more nucleotides, to allow specific hybridization to the target nucleic acid(s) under stringent conditions. Standard FISH methods are described in Ausubel, F.M. et al., eds. (2004) Current Protocols in Molecular Biology, John Wiley & Sons Inc and Fluorescence In Situ Hybridization: Technical Overview by John M. S. Bartlett in Molecular Diagnosis of Cancer, Methods and Protocols, 2nd ed.; ISBN: 1-59259-760-2; March 2004, pp. 077-088; Series: Methods in Molecular Medicine.

Methods for profiling gene expression are described in (DePrimo et al. (2003), BMC Cancer, 3:3). Briefly, the protocol is as follows: double-stranded cDNA is synthesized from whole RNA using a (dT)24-oligomer to initiate first-strand cDNA synthesis from polyadenylated mRNA followed by second-strand cDNA synthesis with random hexamer primers. Double-stranded cDNA is used as a template for in vitro transcription of cRNA using biotinylated ribonucleotides. cRNA is subjected to chemical fragmentation according to the protocols described by Affymetrix (Santa Clara, CA, USA) and then hybridized overnight in gene-specific oligonucleotide assays on Human Genome Arrays. Alternatively, sets of single nucleotide polymorphisms - snips (SNPs), such as DNA microsets, can be used to detect polymorphisms in a population.

Alternatively, protein products that have been expressed from mRNA can be analyzed by immunohistochemistry of tumor samples, microtiter plate solid phase immunoassay, Western blotting, 2D denaturing polyacrylamide gel electrophoresis, enzyme-linked immunosorbent assay (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. One of skill in the art will appreciate that all such well known techniques can be used to detect upregulation of MDM2 and p53, detection of MDM2 or p53 variants or mutants, or loss of MDM2 negative regulators in this case.

Abnormal levels of proteins such as MDM2 or p53 can be measured using standard protein assays, such as those described herein. Increased levels or overexpression can also be detected in a tissue sample, such as tumor tissue, by measuring protein levels using an assay, for example, from Chemicon International. The target protein will be immunoprecipitated from the lysate sample and levels will be measured. Analysis methods also include the use of markers.

In other words, p53 and MDM2 overexpression can be measured by tumor biopsy.

Methods for evaluating changes in gene copies include those commonly used in cytogenetic laboratories such as MLPA (Multiplex Ligation-dependent Probe Amplification), multiplex PCR that detects abnormal copy number, or other PCR techniques that can detect amplification, gains and deletions in genes.

If necessary, exfunctional assays may be used, such as measuring the number of circulating leukemic cells in a cancer patient to evaluate the response that would be elicited by an MDM2/p53 inhibitor.

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.

Therefore, a further aspect of the present invention includes the use of a compound of the present invention for the manufacture of a medicament for the treatment or prevention of a disease state or condition in a patient who has been screened and determined to have or is at risk of having a disease or condition that would be responsive to treatment with an inhibitor. MDM2/p53.

Another aspect of the present invention includes a compound of the present invention for use in the prevention or treatment of cancer in a patient selected from the subpopulation with MDM2 amplification.

Another aspect of the present invention includes a compound of the present invention for use in the prevention or treatment of cancer in a patient selected from a wild-type p53 subpopulation.

Another aspect of the present invention includes a compound of the present invention for use in the prevention or treatment of cancer in a patient deficient in an MDM2 negative regulator such as p14ARF.

MRI determination 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 who may be eligible for compound treatment. according to the present invention.

Thus, a further aspect of the present invention includes a method for diagnosing and treating a disease or condition mediated by MDM2/p53, said method comprising (i) screening a patient to determine if the disease or condition the patient is or may be suffering from is susceptible to treatment with an MDM2/p53 inhibitor; and (ii) in the event that said disease or condition afflicted by the patient is found to be susceptible, then administering to said patient a compound of formula (I) and its subgroups or examples as defined herein.

Advantages of the compounds according to the present invention

The compounds of formula (I) offer a number of advantages over compounds known in the art. Compounds according to the present invention may have a particular advantage in one or more of the following aspects:

(i) Superior activity;

(ii) Superior in vivo efficacy

(iii) Superior FC;

(iv) Superior metabolic stability;

(v) Superior oral bioavailability; And

(vi) Superior physiochemical properties.

Superior potency and efficacy in vivo

The compounds of formula (I) have an increased affinity for MDM2 and in particular an increased activity against cell lines known to be sensitive to MDM2 antagonists.

Improved target binding is a highly desirable property for a pharmaceutical compound, as it allows for dosage reduction and a sufficient separation ("therapeutic window") between MDM2 activity and toxic effects.

The compounds of formula (I) have improved cell activity and/or improved selectivity for wild-type p53 cell lines compared to mutant p53 cell lines. Due to increased activity against MDM2, the compounds of the present invention may have increased in vivo efficacy in cancer cell lines and in vivo models. In addition, these compounds show selectivity for MDM2 over MDMX, despite the sequence, structural and functional similarity between these genetic paralogs.

Superior PK and metabolic stability

Compounds of formula (I) may have favorable ADMET properties (absorption, distribution, metabolism, excretion and toxicity), for example, better metabolic stability (for example, according to mouse liver microsomes), a better P450 profile, a shorter half-life and/ or favorable ground clearance (eg, high or low ground clearance). It has also been found that many compounds of formula (I) have an improved PK profile.

Such characteristics may provide the advantage of having more drug available in the systemic circulation to achieve the desired site of action for its therapeutic effect. Elevated concentrations for pharmacological action in tumors potentially lead to improved efficacy, making it possible to administer reduced doses. Thus, the compounds of formula (I) should show reduced dosage requirements as well as easier formulation and administration.

This results in a sufficient separation ("therapeutic window") between MDM2 activity and toxic effects. Many compounds of formula (I) have the reduced Cmax required for efficacy (due to improved MDM2 and/or FA activity).

Superior oral bioavailability

Potentially, the compounds of the present invention have physiochemical properties suitable for oral exposure (oral exposure or AUC (area under the pharmacokinetic curve)). In particular, compounds of formula (I) may exhibit improved oral bioavailability or improved reproducibility of oral absorption. Oral bioavailability can be defined as the ratio (F) of the blood plasma level of a compound when dosed by the oral route to the blood plasma level of the compound when dosed by the intravenous (i.v.) route, expressed as a percentage.

Compounds having an oral bioavailability value (F-value) greater than 10%, 20% or 30%, more specifically greater than 40%, are particularly advantageous in that they can be administered orally rather than, or as well, parenterally.

Superior physiochemical properties

The compounds of formula (I) may have advantageous physiochemical properties, in particular chemical stability under acidic conditions and reduced lipophilicity.

Lipophilicity can be measured using the partition coefficient (logP) or the partition coefficient (logD). The partition coefficient is the ratio of the concentrations of the non-ionized compound between two immiscible phases (n-octanol and water) in equilibrium, while the partition coefficient is the ratio of the sum of the concentrations of all forms of the compound (ionized and non-ionized) in each of these two phases. High lipophilicity is associated with poor drug-like properties such as low water solubility, poor pharmacokinetic properties (low oral bioavailability), unwanted drug metabolism and high heterogeneity. Compounds with optimal lipophilicity may have a greater chance of success in drug development. However, reduced logP (or calculated logP, clogP) may be difficult to achieve while maintaining an acceptable level of activity to inhibit protein-protein interactions (PPI) due to the lipophilic nature of the targets involved.

PHARMACEUTICAL COMPOSITIONS

Although it is possible to administer the active compound in pure form, it is usually presented in the form of a pharmaceutical composition (eg formulation).

Thus, the present invention further provides pharmaceutical compositions as defined above and methods for preparing a pharmaceutical composition comprising (for example, adding) at least one compound of formula (I) (and its subgroups as defined herein) together with one or more pharmaceutically acceptable excipients and optionally with other therapeutic or prophylactic agents described herein.

Said pharmaceutically acceptable excipients may be selected, for example, from carriers (e.g. a solid, liquid or semi-solid carrier), adjuvants, diluents, excipients or bulking agents, granulating agents, coating agents, release regulators, binding agents, disintegrants, lubricating agents, preservatives, antioxidants, buffering agents, suspending agents, thickeners, flavoring agents, sweeteners, flavoring agents, stabilizers or any other excipients commonly used in pharmaceutical compositions. Examples of excipients for various types of pharmaceutical compositions are set out in more detail below.

The term "pharmaceutically acceptable" as used herein refers to compounds, substances, compositions and/or dosage forms which, within the limits of sound medical judgment, are suitable for use in contact with the tissues of a subject (e.g., a human subject) without causing undue toxicity, irritation, allergic reaction, or other problem or complication, with a reasonable benefit/risk ratio. Each excipient must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation.

Pharmaceutical compositions containing compounds of formula (I) may be formulated according to known techniques, see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA.

The pharmaceutical compositions may be in any form suitable for oral, parenteral, topical, intranasal, intrabronchial, sublingual, ophthalmic, otic, rectal, intravaginal, or transdermal administration. When the compositions are intended for parenteral administration, they may be formulated for intravenous, intramuscular, intraperitoneal, subcutaneous administration, or for direct delivery to a target organ or tissue by injection, infusion, or other delivery methods. Delivery can be by bolus injection, short term infusion, or long term infusion, and can be done passively or through the use of a suitable infusion pump or syringe pump.

Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injectable solutions which may contain antioxidants, buffers, bacteriostatic agents, co-solvents, surfactants, mixtures of organic solvents, cyclodextrin complexing agents, emulsifiers (to form and stabilize emulsion formulations), liposome components for forming liposomes, gelling polymers for forming polymer gels, protective agents for lyophilization, and combinations of agents for, inter alia, stabilizing the active ingredient in soluble form and maintaining the isotonicity of the formulation with the blood of the intended recipient. Pharmaceutical formulations for parenteral administration may also be in the form of aqueous and non-aqueous sterile suspensions which may contain suspending agents and thickening agents (R.G. Strickly, Solubilizing Excipients in oral and injectable formulations, Pharmaceutical Research, Vol 21(2) 2004, pp. 201-230 ).

Formulations may be presented in single-dose or multi-dose containers, such as sealed ampoules, vials, and pre-filled syringes, and may be stored in a freeze-dried (lyophilized) state requiring only the addition of a sterile liquid carrier, such as water for injection, immediately prior to use. In one embodiment, the formulation is presented as an active pharmaceutical ingredient in a bottle for reconstitution with a suitable diluent.

The pharmaceutical composition may be prepared by lyophilizing a compound of formula (I) or subgroups thereof. Lyophilization refers to the process of drying a composition by sublimation. Sublimation and lyophilization are therefore used interchangeably herein.

Solutions and suspensions for extemporaneous injections can be prepared from sterile powders, granules and tablets.

Pharmaceutical compositions of the present invention for parenteral injection may also contain pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution in sterile injectable solutions or dispersions immediately prior to use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or carriers include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), carboxymethyl cellulose and suitable mixtures thereof, vegetable oils (such as sunflower oil, safflower oil, corn oil or olive oil) and injectable organic esters such as ethyl oleate. Suitable fluidity can be maintained, for example, by using thickeners such as lecithin, by maintaining the required particle size in the case of dispersions, and also by using surfactants.

Compositions according to the present invention may also contain adjuvants such as preservatives, wetting agents, emulsifiers and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include tonicity adjusting agents such as sugars, sodium chloride and the like. Prolonged absorption of an injectable pharmaceutical form can be achieved by the inclusion of absorption delaying agents such as aluminum monostearate and gelatin.

In one typical implementation of the present invention, the pharmaceutical composition is in a form suitable for intravenous administration, for example, by injection or infusion. For intravenous administration, the solution may be administered as is or may be injected into an infusion bag (containing a pharmaceutically acceptable excipient such as 0.9% saline or 5% dextrose) prior to administration.

In another exemplary embodiment of the present invention, the pharmaceutical composition is in a form suitable for subcutaneous (SC) administration.

Pharmaceutical dosage forms suitable for oral administration include tablets (coated or uncoated), capsules (hard or soft shell), caplets, pills, lozenges, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, cachets or patches such as buccal patches.

Thus, compositions in the form of tablets may contain a single dose of the active compound together with an inert solvent or carrier such as sugar or a sugar alcohol, for example lactose, sucrose, sorbitol or mannitol; and/or a non-sugar diluent such as sodium carbonate, calcium phosphate, calcium carbonate or cellulose or a derivative thereof such as microcrystalline cellulose (MCC), methylcellulose, ethylcellulose, hydroxypropyl methylcellulose and starches such as cornstarch. Tablets may also contain common ingredients such as binders and granulating agents such as polyvinylpyrrolidone, disintegrants (eg swellable crosslinked polymers such as crosslinked carboxymethyl cellulose), lubricating agents (eg stearates), preservatives (eg parabens), antioxidants ( eg BHT), buffering agents (eg phosphate or citrate buffers) and effervescent agents such as citrate/bicarbonate mixtures. Such excipients are well known and need not be discussed in detail herein.

Tablets can be designed to release the drug either upon contact with gastric juice (immediate release tablets) or to release it in a controlled manner (controlled release tablets) over an extended period of time or in a specific area of the gastrointestinal tract.

Capsule formulations may be made from a variety of hard gelatins or soft gelatins, and may contain the active ingredient in solid, semi-solid, or liquid form. Gelatin capsules may be formulated from animal gelatin or its synthetic or vegetable equivalents.

Solid dosage forms (eg tablets, capsules, etc.) may or may not be coated. Envelopes may act as a protective film (eg, polymer, wax, or glazing) or as a drug release control mechanism, or serve aesthetic or identification purposes. The shell (eg a polymer of the Eudragit™ type) can be designed to release the active ingredient at the desired site in the gastrointestinal tract. Accordingly, the shell may be chosen to break down in the gastrointestinal tract under certain pH conditions, thereby releasing the compound into the stomach or ileum, duodenum, jejunum, or colon.

Instead of or in addition to a coating, the drug may be presented in a solid matrix containing a release controlling agent, eg a delayed release agent, which can be adapted to release the compound in a controlled manner in the gastrointestinal tract. Alternatively, the drug may be presented in a polymer shell, for example a polymethacrylate polymer shell, which can be adapted to selectively release the compound under varying acidity or alkalinity conditions in the gastrointestinal tract. Alternatively, the matrix material or retarding shell may be in the form of an erodible polymer (eg, maleic anhydride polymer) that is substantially permanently eroded as the dosage form passes through the gastrointestinal tract. As another alternative, the casing can be designed to be broken down by microbes in the gut. As yet another alternative, the active compound may be formulated as a delivery system that provides osmotic control of compound release. Osmotic release or other delayed or sustained release formulations (eg, ion exchange resin based formulations) can be prepared according to methods well known to those skilled in the art.

The compound of formula (I) may be formulated with a carrier and administered in the form of nanoparticles, the increased surface area of the nanoparticles aiding their absorption. In addition, nanoparticles provide the possibility of direct penetration into the cell. Nanoparticle drug delivery systems are described in "Nanoparticle Technology for Drug Delivery", edited by Ram B Gupta and Uday B. Kompella, Informa Healthcare, ISBN 9781574448573, published March 13, 2006. Nanoparticles for drug delivery are also described in J .control. Release, 2003, 91 (1-2), 167-172, and in Sinha et al., Mol. Cancer Ther. August 1, (2006) 5, 1909

Pharmaceutical compositions typically contain from about 1% (w/w) to about 95% of the active ingredient and from 99% (w/w) to 5% (w/w) of a pharmaceutically acceptable excipient or combination of excipients. . Typically, the compositions are typically about 20% (w/w) to about 90% (w/w) active ingredient and 80% (w/w) to 10% of a pharmaceutically acceptable excipient or combination of excipients. Pharmaceutical compositions contain from about 1% to about 95%, usually from about 20% to about 90% of the active ingredient. Pharmaceutical compositions according to the present invention may be, for example, in unit dosage form, for example, in the form of ampoules, vials, suppositories, pre-filled syringes, dragees, tablets or capsules.

Pharmaceutically acceptable excipients may be selected based on the desired physical form of the formulation and may, for example, be selected from diluents (e.g. solid diluents such as fillers or bulking agents; and liquid diluents such as solvents and co-solvents), disintegrants, buffering agents , lubricating agents, flow agents, release controlling agents (e.g. retarding or delaying the release of polymers or waxes), binding agents, granulating agents, pigments, emollients, antioxidants, preservatives, flavoring agents, drug taste correctors, regulators tonicity and coating agents.

One skilled in the art is skilled enough to select appropriate amounts of ingredients for use in the formulations. For example, tablets and capsules typically contain 0-20% disintegrants, 0-5% lubricants, 0-5% flow agents, and/or 0-99% (w/w) fillers or bulking agents (depending on drug dose). They may also contain 0-10% (w/w) polymeric binders, 0-5% (w/w) antioxidants, 0-5% (w/w) pigments. Tablets with delayed release will also contain 0-99% (wt./mass.) polymers (depending on the dose). Film shell tablets or capsules typically contain 0-10% (wt./wt.) polymers that control (for example, slowing down) the release, 0-3% (wt./wt.) pigments and/or 0-2% (wt. /mass.) softeners.

Parenteral formulations typically contain 0-20% (w/w) buffers, 0-50% (w/w) cosolvents, and/or 0-99% (w/w) Water for Injection. for Injection, WFI) (depending on the dose and whether they are lyophilized or not). Intramuscular depot formulations may also contain 0-99% (w/w) oils.

Pharmaceutical compositions for oral administration can be prepared by combining the active ingredient with solid carriers, granulating the resulting mixture, if necessary, and processing the mixture, if desired or necessary - after the addition of suitable excipients - into tablets, dragees or capsules. It is also possible to include them in a polymeric or waxy matrix which will allow the active ingredients to spread or be released in metered amounts.

The compounds of the present invention may also be formulated as solid dispersions. Solid dispersions are very fine homogeneous dispersed phases of two or more solids. Solid solutions (molecular dispersion systems), one type of solid dispersion, are well known for use in pharmaceutical technology (see (Chiou and Riegelman, J. Pharm. Sci., 60, 1281-1300 (1971)) and are suitable for increasing the speed dissolution and increasing the bioavailability of poorly water-soluble drugs.

The present invention also provides solid dosage forms comprising the solid solution described herein. Solid dosage forms include tablets, capsules, chewable tablets, and dispersible or effervescent tablets. Known excipients may be combined with the solid solution to provide the desired dosage form. For example, a capsule may contain a solid solution combined with (a) a disintegrant and a lubricant or (b) a disintegrant, a lubricant and a surfactant. In addition, the capsule may contain a bulking agent such as lactose or microcrystalline cellulose. The tablet may contain a solid solution combined with at least one disintegrant, lubricant, surfactant, bulking agent and glidant. A chewable tablet may contain a solid solution combined with a bulking agent, a lubricating agent and, if necessary, an additional sweetener (such as an artificial sweetener) and suitable flavors. Solid solutions can also be formed by spraying solutions of the drug and a suitable polymer onto the surface of inert carriers such as sugar beads ("nonpareil grains"). Such beads may then be filled into capsules or compressed into tablets.

Pharmaceutical formulations may be provided to the patient in "patient packs" containing the entire course of treatment in a single package, usually a blister pack. Patient packs have an advantage over traditional prescription drugs, where the pharmacist separates the volume of the pharmaceutical for the patient from the total volume of the pharmaceutical, in that the patient always has access to the instructions for use of the medicine found in the patient pack, which is usually not available. prescription drugs. Inclusion of instructions for use of the drug has been shown to improve patient compliance with physician instructions.

Compositions for topical and nasal delivery include ointments, creams, sprays, patches, gels, liquid drops, and inserts (eg, ophthalmic inserts). Such compositions may be formulated according to known methods.

Examples of formulations for rectal or intravaginal administration include pessaries and suppositories, which may, for example, be made from molded plastic or waxy material containing the active compound. Solutions of the active compound can also be used for rectal administration.

Compositions for administration by inhalation may be in the form of powder compositions for inhalation or liquid or powder sprays, and may be administered in unit form using powder inhalers or aerosol dispensers. Such devices are well known. For administration by inhalation, powder formulations typically contain the active compound together with an inert solid powder diluent such as lactose.

Compounds of formula (I) will typically be presented in unit dosage form and by themselves will typically contain a sufficient amount of the compound to provide the desired level of biological activity. For example, the composition may contain from 1 nanogram to 2 grams of the active ingredient, for example, from 1 nanogram to 2 milligrams of the active ingredient. Within these ranges, specific compound subranges are 0.1 milligram to 2 grams of active ingredient (more commonly 10 milligram to 1 gram, e.g., 50 milligram to 500 milligram) or 1 microgram to 20 milligram (e.g., 1 microgram to 10 milligram, for example, from 0.1 milligram to 2 milligram of the active ingredient).

For oral compositions, a unit dosage form may contain 1 milligram to 2 grams, more typically 10 milligrams to 1 gram, eg 50 milligrams to 1 gram, eg 100 milligrams to 1 gram of the active compound.

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.

TREATMENT METHODS

The compounds of formula (I) and its subgroups as defined herein may be suitable for use in the prevention or treatment of a number of disease states or pathological conditions mediated by MDM2/p53. Examples of such disease states and pathological conditions are given above.

In general, the compounds are administered to a subject in need of such administration, eg, a human or animal patient, usually a human.

Typically, the compounds will be administered in amounts that are therapeutically or prophylactically useful and generally non-toxic. However, in particular situations (for example, 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 desirable to administer compounds of formula (I) in amounts that are associated with some toxicity.

The compounds may be administered over a long period of time to maintain beneficial therapeutic effects, or they may be administered for only a short period. Alternatively, they can be administered in a continuous manner or in an intermittent manner (eg, in a pulsatile manner).

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 commonly 5 nanograms to 25 milligrams per kilogram of body weight, and more commonly 10 nanograms to 15 milligrams per kilogram (e.g., 10 nanograms to 10 milligrams, and more commonly from 1 microgram per kilogram to 20 milligrams per kilogram, for example, from 1 microgram to 10 milligrams per kilogram) of body weight, although higher or lower doses may be administered if necessary. The compound of formula (I) can be administered daily or in repetitions, for example every 2 or 3 or 4 or 5 or 6 or 7 or 10 or 14 or 21 or 28 days.

Dosages 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 range from 3700 pg/m ² to 3700 mg/m ² , more commonly from 185 ng/m ² to 925 mg/m ² , and more commonly from 370 ng/m ² to 555 mg / m ² (for example, from 370 ng / m ² to 370 mg / m ² , and more often from 37 mg / m ² to 740 mg / m ² , for example, from 37 mg / m ² to 370 mg / m ² ), although higher or lower doses may be administered if necessary. The compound of formula (I) can be administered daily or in repetitions, for example every 2 or 3 or 4 or 5 or 6 or 7 or 10 or 14 or 21 or 28 days.

The compounds of the present invention may be administered orally in a dosage range of, for example, 0.1 to 5000 mg, or 1 to 1500 mg, 2 to 800 mg, or 5 to 500 mg, such as 2 to 200 mg or 10 to 1000 mg, with specific examples of dosages including 10, 20, 50 and 80 mg. The compound can be administered once or more than once a day. The compound can be administered continuously (ie taken every day without interruption during the treatment regimen). Alternatively, the compound can be administered in an intermittent manner (i.e., taken continuously for a set period, e.g., a week, then discontinued for a period, e.g., a week, and then taken continuously for another period, e.g., a week , and so on during the application of the treatment regimen). Examples of treatment regimens that include intermittent administration include regimens in which administration is carried out in cycles with one week on and one week off; or with two weeks on and one week off; or with three weeks on and one week off; or with two weeks on and two weeks off; or with four weeks on and two weeks off; or with one week on and three weeks off - one or more cycles, such as 2, 3, 4, 5, 6, 7, 8, 9 or 10 or more cycles. Such intermittent treatment may also be based on a number of days rather than a whole week. For example, treatment may include daily dosing for 1-6 days, no dosing for 1-6 days, and this order is repeated during the course of the treatment protocol. The number of days (or weeks) in which the compounds of the present invention are not administered need not be equal to the number of days (or weeks) in which the compounds are administered.

In one embodiment, the compounds of the present invention may be administered in an amount of 3 mg/m2 to 125 mg/m2 daily. The treatment can be carried out either by continuous daily dosage administration, or, more often, it consists of many cycles of treatment, separated by breaks in treatment. One example of a single treatment cycle is the administration of 5 consecutive daily doses followed by no treatment for 3 weeks.

One particular dosing regimen is once a day (eg, orally) for a week (eg, 5 days of treatment) followed by a 1, 2, or 3 week off treatment. An alternative dosing regimen is weekly (eg, orally) for 1, 2, 3, or 4 weeks.

In one particular dosing regimen, the patient will be administered a compound of formula (I) by infusion over periods of one hour every day up to ten days, in particular up to five days in one week, and the treatment will be repeated at the desired interval, such as two -four weeks, specifically every three weeks.

More specifically, the patient may be administered a compound of formula (I) by infusion over periods of one hour every day for five days and the treatment will be repeated every three weeks.

In another particular dosage regimen, the patient is administered the compound by infusion over 30 minutes to 1 hour followed by maintenance infusions of varying duration, eg 1-5 hours, eg 3 hours.

The compounds of the present invention may also be administered by bolus or continuous infusion. The compound of the present invention can be administered at a frequency of once a day to once a week, or every two weeks, or every three weeks, or every four weeks during a treatment cycle. When administered daily during a treatment cycle, such daily dosing may be intermittent during a number of weeks of the treatment cycle: for example, administration for a week (or a number of days), no administration for a week (or a number of days), and this order is repeated in during the treatment cycle.

In yet another particular dosage regimen, the patient is administered the compound by continuous infusion over a period of 12 hours to 5 days, and in particular a continuous infusion of 24 hours to 72 hours.

Ultimately, however, the amount of compound administered and the type of composition used will be appropriate to the nature of the disease or physiological condition being treated and will be left to the discretion of the attending physician.

It may be effective to use a compound of the present invention as a single agent, or to combine a compound of the present invention with another agent that acts by a different mechanism to regulate cell growth, thereby targeting two 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.

The compounds defined herein may be administered as the sole therapeutic agent, or may be administered in combination therapy with one or more other compounds (or therapies) for the treatment of a particular disease state, e.g., a neoplastic disease, such as cancer, as defined above. in this document. For the treatment of the aforementioned conditions, the compounds of the present invention can be effectively used in combination with one or more other drugs, more specifically other anticancer agents or adjuvants (auxiliary agents in therapy) in cancer therapy. Examples of other therapeutic agents or treatments that can be administered concomitantly (simultaneously or at different time intervals) with the compounds of formula (I) include, but are not limited to:

- Topoisomerase I inhibitors

- Anti metabolites

- Agents that target tubulin

- Inhibitors of DNA binding and topoisomerase II

- Alkylating agents

- Monoclonal antibodies.

- Antihormones

- Signal transmission inhibitors

- Proteasome inhibitors

- DNA methyltransferase inhibitors

- Cytokines and retinoids

- Therapies targeting chromatin

- Radiation therapy and

- Other therapeutic or prophylactic agents.

Specific examples of anticancer agents or adjuvants (or salts thereof) include, but are not limited to, any agents selected from groups (i)-(xlviii) and optionally group (xlix) listed below:

(i) Platinum compounds, eg cisplatin (optionally in combination with amifostine), carboplatin or oxaliplatin;

(ii) Taxane compounds, eg paclitaxel, paclitaxel protein-bound particles (Abraxane™, Abraxane), docetaxel, cabazitaxel or larotaxel;

(iii) Topoisomerase I inhibitors, eg camptothecin compounds, eg camptothecin, irinotecan (CPT11), SN-38 or topotecan;

(iv) Topoisomerase II inhibitors, eg the antitumor epipodophyllotoxins or podophyllotoxin derivatives, eg etoposide or teniposide;

(v) Vinca alkaloids, eg vinblastine, vincristine, liposomal vincristine (Onco-TCS), vinorelbine, vindesine, vinflunine or vinvesir;

(vi) Nucleoside derivatives, e.g. 5-fluorouracil (5-FU, optionally in combination with leucovorin), gemcitabine, capecitabine, tegafur, UFT, S1, cladribine, cytarabine (Ara-C, cytosine arabinoside), fludarabine, clofarabine, or nonlarabine ;

(vii) Anti-metabolites, eg clofarabine, aminopterine, or methotrexate, azacitidine, cytarabine, floxuridine, pentostatin, thioguanine, thiopurine, 6-mercaptopurine, or hydroxyurea (hydroxyurea);

(viii) Alkylating agents such as chlormethine or nitrosourea, e.g. cyclophosphamide, chlorambucil, carmustine (BCNU), bendamustine, thiotepa, melphalan, treosulfan, lomustine (CCNU), altretamine, busulfan, dacarbazine, estramustine, fotemustine, ifosfamide (optionally in combinations with mesna), pipobroman, procarbazine, streptozocin, temozolomide, uracil, mechlorethamine, methylcyclohexylchloroethylnitrosourea, or nimustine (ACNU);

(ix) Anthracyclines, anthracenediones and related drugs, eg daunorubicin, doxorubicin (optionally in combination with dexrazoxane), doxorubicin liposomal formulations (eg Caelyx™, Myocet™, Doxil™), idarubicin, mitoxantrone, epirubicin, amsacrine or valrubicin;

(x) Epothilones, e.g., 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 eleuterobine;

(xi) DNA methyltransferase inhibitors, eg theozolomide, azacitidine or decitabine;

(xii) Antifolates such as methotrexate, disodium pemetrexed or raltitrexed;

(xiii) Cytotoxic antibiotics, eg antinomycin D, bleomycin, mitomycin C, dactinomycin, carminomycin, daunomycin, levamisole, plicamycin or mithramycin;

(xiv) Tubulin binding agents, eg combrestatin, colchicines or nocodazole;

(xv) Signal transduction inhibitors such as kinase inhibitors, e.g. platelet-derived growth factor receptor (PDGFR) inhibitors, Axl inhibitors, MTKIs (multi target kinase inhibitors, multi-target kinase inhibitors), Raf inhibitors, ROCK inhibitors, mTOR inhibitors, MEK inhibitors, or PI3K inhibitors), e.g. imatinib mesylate, erlotinib, gefitinib, dasatinib, lapatinib, dovotinib, axitinib, nilotinib, vandetanib, vatalinib, pazopanib, sorafenib, sunitinib, temsirolimus, everolimus (RAD 001), vemurafenib (PLX4032 or RG7204), dafrafenib, encorafenib, selumetinib (AZD624), trametinib (GSK121120212), dactolisib (BEZ235), buparlisib (BKM-120; NVP-BKM-120), BYL719, 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 CAL-101, GS 1101, GS-1101), MLN1117 (INK1117), MLN0128 (INK128), IPI-145 (INK1197), LY-3023414, ipatacertib, afuresertib, MK-2206, MK-8156, LY-3023414, LY294002, SF1126 or PI-103, sonolisib (PX-866) or AT13148.

(xvi) Aurora kinase inhibitors, eg AT9283, baracertib (AZD1152), TAK-901, MK0457 (VX680), cenisertib (R-763), danusertib (PHA-739358), alisertib (MLN-8237), or MP-470 ;

(xvii) CDK inhibitors, eg AT7519, roscovitine, seliciclib, alvocidib (flavopiridol), dinacyclib (SCH-727965), 7-hydroxystaurosporine (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);

(xviii) Inhibitors of the PKA/B and PKB (akt) pathways, e.g. TCN (triciribin), RX-0201, enzastaurin HCI (LY317615), NL-71-101, SR-13668, PX-316, or KRX-0401 (perifosin/NSC 639966);

(xix) Hsp90 inhibitors, eg onalespib (AT13387), herbimycin, geldanamycin (GA), 17-allylamino-17-desmethoxygeldanamycin (17-AAG), eg NSC-330507, Kos-953 and CNF-1010, 17-dimethylaminoethylamino -17-demethoxygeldanamycin hydrochloride (17-DMAG) e.g. NSC-707545 and Kos-1022, NVP-AUY922 (VER-52296), NVP-BEP800, CNF-2024 (BIIB-021 oral purine), ganetespib (STA-9090 ), SNX-5422 (SC-102112) or IPI-504;

(xx) Monoclonal antibodies (whether unconjugated or conjugated to radioisotopes, toxins or other agents), antibody derivatives and related agents such as anti-CD, anti-VEGFR, anti-HER2 or anti-EGFR antibodies such as rituximab (CD20), ofatumumab (CD20), ibritumumab tiuxetan (CD20), GA101 (CD20), tositumomab (CD20), epratuzumab (CD22), lintuzumab (CD33), gemtuzumab ozogamicin (CD33), alemtuzumab (CD52), galiximab (CD80), trastuzumab (HER2) -antibody), pertuzumab (HER2), trastuzumab-DM1 (HER2), ertumaxomab (HER2 and CD3), cetuximab (EGFR), panitumumab (EGFR), necitumumab (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 (ganglioside GD3), naptumomab estafenatox (5T4) or siltuximab (IL6) or immunomodulatory agents such as antibodies blocking CTLA-4 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-LI) or tremelimumab (formerly ticilimumab, CP-675,206, anti-CTLA-4);

(xxi) Estrogen receptor antagonists or selective estrogen receptor modulators (SERMs) or inhibitors of estrogen synthesis, eg tamoxifen, fulvestrant, toremifene, droloxifene, faslodex or raloxifene;

(xxii) Aromatase inhibitors and related drugs such as exemestane, anastrozole, letrazole, testolactone aminoglutethimide, mitotane or vorozol;

(xxiii) Antiandrogens (ie, androgen receptor antagonists) and related agents, eg bicalutamide, nilutamide, flutamide, cyproterone, or ketoconazole;

(xxiv) Hormones and analogues such as medroxyprogesterone, diethylstilbestrol (also known as diethylstilboestrol) or octreotide;

(xxv) Steroids, such as dromostanolone propionate, megestrol acetate, nandrolone (decanoate, fenpropionate), fluoxymestron or gossypol,

(xxvi) A steroidal cytochrome P450 17-alphahydroxylase 17,20-lyase (CYP17) inhibitor, eg abiraterone;

(xxvii) Gonadotropin-releasing hormone (GnRA) agonists or antagonists, eg abarelix, goserelin acetate, histrelin acetate, leuprolide acetate, triptorelin, buserelin or deslorelin;

(xxviii) Glucocorticoids, eg prednisone, prednisolone, dexamethasone;

(xxix) Differentiating agents such as retinoids, rexinoids, vitamin D or retinoic acid, as well as agents that block the metabolism of retinoic acid (RAMBA), for example, accutane, alitretinoin, bexarotene or tretinoin;

(xxx) Farnesyl transferase inhibitors, eg tipifarnib;

(xxxi) Chromatin-targeting therapies such as histone deacetylase (HDAC) inhibitors, e.g. sodium butyrate, hydroxamic acid suberoylanilide (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;

(xxxii) Drugs targeting the ubiquitin-proteasome pathway, including proteasome inhibitors, eg bortezomib, carfilzomib, CEP-18770, MLN-9708 or ONX-0912; NEDD8 inhibitors; HDM2 and deubiquitinase (DUB) antagonist;

(xxxiii) Photodynamic drugs such as sodium porfimer or temoporfin;

(xxxiv) Anti-cancer agents derived from marine organisms such as trabectidine;

(xxxv) Radiolabelled drugs for radioimmunotherapy, e.g. beta emitting isotope (e.g. iodine-131, yttrium-90) or alpha emitting isotope (e.g. bismuth-213 or actinium-225) , for example, ibritumomab or iodine-tositumomab, or alpha-radium 223;

(xxxvi) Telomerase inhibitors, eg telomestatin;

(xxxvii) Matrix metalloproteinase inhibitors, eg batimastat, marimastat, prinostat or metastat;

(xxxviii) Recombinant interferons (such as interferon-γ and interferon-α) and interleukins (eg interleukin 2), for example, aldesleukin, denileukin diftitox, interferon alfa-2a, interferon alfa-2b or peginterferon alfa-2b;

(xxxix) Selective immune response modulators, eg thalidomide or lenalidomide;

(xl) Therapeutic vaccines such as sipuleucel-T (Provenge) or OncoVex;

(xli) Cytokine activating agents including picibanil, romurtide, sizofiran, virulizin, or thymosin;

(xlii) Arsenic trioxide;

(xliii) G protein-coupled receptor (GPCR) inhibitors, eg atrasentan;

(xliv) Enzymes such as L-asparaginase, pegaspargase, rasburicase or pegademase;

(xlv) DNA repair inhibitors such as PARP inhibitors, eg olaparib, velaparib, iniparib, INO-1001, AG-014699 or ONO-2231;

(xlvi) Cell death agonists (eg, TNF-related apoptosis inducing ligand (TRAIL) receptor, such as mapatumumab (formerly HGS-ETR1), conatumumab (formerly AMG 655), PRO95780, lexatumumab, dulanermin , CS-1008, apomab, or recombinant TRAIL ligands such as recombinant human TRAIL/Apo2 ligand;

(xlvii) Immunotherapies such as immune checkpoint inhibitors; cancer vaccines and CAR-T cell therapy;

(xlviii) Regulators of cell death (apoptosis), including Bcl-2 (B-cell lymphoma 2) antagonists such as venetoclax (AVT-199 or GDC-0199), AVT-737, AVT-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);

(xlix) Prophylactic agents (auxiliaries); those. agents that reduce or alleviate certain side effects associated with chemotherapy agents, such as

- antiemetics;

- agents that prevent or reduce the duration of chemotherapy-associated neutropenia and prevent complications due to a decrease in platelets, red blood cells or white blood cells, for example, interleukin-11 (for example, oprelvekin), erythropoietin (EPO) and its analogues (for example, darbepoetin alpha), colony stimulating factor analogs such as granulocyte-macrophage colony stimulating factor (GM-CSF) (e.g. sargramostim) and granulocyte colony stimulating factor (G-CSF) and their analogs (e.g. filgrastim, pegfilgrastim),

- agents that inhibit bone resorption, such as denosumab or bisphosphonates, such as zoledronate, zoledronic acid, pamidronate and ibandronate,

- agents that suppress inflammatory responses such as dexamethasone, prednisone and prednisolone,

- agents used to reduce the levels of growth hormone and IGF-I (and other hormones) in the blood of patients with acromegaly or other rare hormone-producing tumors, such as synthetic forms of the hormone somatostatin, such as octreotide acetate,

- antidotes to drugs that reduce folic acid levels, such as leucovorin or folinic acid,

- agents for the treatment of pain, for example, opiates such as morphine, diamorphine and fentanyl,

- non-steroidal anti-inflammatory drugs (NSAIDs), such as COX-2 inhibitors, such as celecoxib, etoricoxib and lumiracoxib,

- agents against inflammation of the oral mucosa, for example, palifermin,

- agents for the treatment of side effects, including anorexia, cachexia, edema and episodes of thromboembolism, such as megestrol acetate.

Each compound provided in the combinations of the present invention may be administered in individually varying dosing regimens and via a variety of routes. As such, the dosage of each of the two or more agents may be different: they may each be administered at the same time or at different times. A person skilled in the art, due to his or her general knowledge, will know which dosing regimens and types of combination therapy to use. For example, a compound of the present invention may be used in combination with one or more agents administered according to their existing combination regimen. Examples of standard combination modes are shown below.

The taxane compound is preferably administered at a dosage of 50 to 400 mg per square meter (mg/m ² ) of body surface area, for example 75 to 250 mg/m ² , specifically for paclitaxel at a dosage of about 175 to 250 mg/m ² and for docetaxel at a dosage of about 75 to 150 mg/m ² per course of treatment.

The camptothecin compound is preferably administered at a dosage of 0.1 to 400 mg per square meter (mg/m ² ) of body surface area, such as 1 to 300 mg/m ² , specifically for irinotecan, at a dosage of about 100 to 350 mg/m ² and for topotecan at a dosage of about 1 to 2 mg/m ² per course of treatment.

The antitumor podophyllotoxin derivative is preferably administered at a dosage of 30 to 300 mg per square meter (mg/m ² ) of body surface area, for example 50 to 250 mg/m ² , specifically for etoposide at a dosage of about 35 to 100 mg/m ² and for teniposide at a dosage of about 50 to 250 mg/m ² per course of treatment.

The antitumor vinca alkaloid is preferably administered at a dosage of 2 to 30 mg per square meter (mg/m ² ) of body surface area, specifically for vinblastine at a dosage of 3 to 12 mg/m ² , for vincristine at a dosage of about 1 to 2 mg/m 2 m ² and for vinorelbine at a dosage of about 10 to 30 mg/m ² per course of treatment.

The antitumor nucleoside derivative is preferably administered at a dosage of 200 to 2500 mg per square meter (mg/m ² ) of body surface area, for example 700 to 1500 mg/m ² , specifically for 5-FU at a dosage of 200 to 500 mg/m ² for gemcitabine at a dosage of about 800 to 1200 mg/m ² and for capecitabine from about 1000 to 2500 mg/m ² per course of treatment.

Alkylating agents such as chlormethine or nitrosourea are preferably administered at a dosage of 100 to 500 mg per square meter (mg/m ² ) of body surface area, for example 120 to 200 mg/m ² , specifically for cyclophosphamide at a dosage of about 100 up to 500 mg/m ² , for chlorambucil at a dosage of about 0.1 to 0.2 mg/kg, for carmustine at a dosage of about 150 to 200 mg/m ² , and for lomustine at a dosage of about 100 to 150 mg/kg m ² per course of treatment.

The anthracycline antitumor derivative is preferably administered at a dosage of 10 to 75 mg per square meter (mg/m ² ) of body surface area, e.g., 15 to 60 mg/m ² of body surface area, specifically for doxorubicin, at a dosage of about 40 to 75 mg /m ² for daunorubicin at a dosage of about 25 to 45 mg/m ² and for idarubicin at a dosage of about 10 to 15 mg/m ² per course of treatment.

The antiestrogen agent is preferably administered at a dosage of from about 1 to 100 mg daily, depending on the particular agent and the condition being treated. Tamoxifen is preferably administered orally at a dosage of 5 to 50 mg, usually 10 to 20 mg twice a day, continuing therapy for a time sufficient to achieve and maintain a therapeutic effect. Toremifene is preferably administered orally at a dosage of about 60 mg once a day, continuing therapy for a time sufficient to achieve and maintain a therapeutic effect. Anastrozole is preferably administered orally at a dosage of about 1 mg once a day. Droloxifene is preferably administered orally at a dosage of about 20-100 mg once a day. Raloxifene is preferably administered orally at a dosage of about 60 mg once a day. Exemestane is preferably administered orally at a dosage of about 25 mg once a day.

Antibodies are preferably administered at a dosage of 1 to 5 mg per square meter (mg/m ² ) of body surface area, or as known in the art, if there is a difference. Trastuzumab is preferably administered at a dosage of 1 to 5 mg per square meter (mg/m ² ) of body surface area, specifically 2 to 4 mg/m ² per course of treatment.

When a compound of formula (I) is administered in combination therapy with one, two, three, four or more therapeutic agents (usually one or two, more often one), these compounds can be administered simultaneously or sequentially. In the latter case, said two or more compounds will be administered over a period and in an amount and manner sufficient to ensure that a beneficial or synergistic effect is achieved. When administered sequentially, they can be administered at small intervals (eg, over a period of 5-10 minutes) or longer intervals (eg, 1, 2, 3, 4 or more hours apart, or longer intervals if appropriate). necessary), and the specific dosage regimen is in accordance with the properties of the therapeutic agent (agents). Such dosages can be administered, for example, one, two or more times during the course of treatment, which can be repeated, for example, every 7, 14, 21 or 28 days.

It should be understood that the typical route and order of administration and the appropriate dosages and regimens for each component of the combination will depend on the particular other drug and compound of the present invention to be administered, their route of administration, the particular tumor being treated, and the particular recipient being treated. treatment. The optimal route and order of administration, dosage values and mode of administration can be readily determined by those skilled in the art using standard methods and also in view of the information provided herein.

The weight ratio of a compound of the present invention to one or more other anticancer agents when administered as a combination can be determined by one skilled in the art. The indicated ratio and the exact dose and frequency of administration depends on the specific compound of the present invention and other anticancer agent(s) used, the specific condition being treated, the severity of the condition being treated, age, body weight, sex, diet, time of administration and general the physical condition of a particular patient, the route of administration, as well as another drug that the individual may take, which is well known to specialists in this field. Moreover, it is obvious that the effective daily amount can be reduced or increased depending on the response of the subject being treated, and/or depending on the judgment of the attending physician prescribing the compounds according to the present invention. The specific weight ratio for the compound of formula (I) according to the present invention and the other anti-cancer agent may vary from 1/10 to 10/1, more specifically from 1/5 to 5/1, even more specifically from 1/3 to 3/1.

The compounds of the present invention can also be administered in conjunction with non-chemotherapeutic options such as radiation therapy, photodynamic therapy, gene therapy; surgery and controlled diet. Radiation therapy may be given for curative, palliative, adjuvant, neoadjuvant, or prophylactic purposes.

The compounds of the present invention also have therapeutic use in sensitizing tumor cells to radiotherapy and chemotherapy. On this basis, the compounds of the present invention are suitable for use as a "radiosensitizer" and/or "chemosensitizer" or may be administered in combination with another "radiosensitizer" and/or "chemosensitizer". In one embodiment, a compound of the present invention is for use as a chemosensitizer.

The term "radiosensitizer" is defined as a molecule administered to patients in therapeutically effective amounts to increase the sensitivity of cells to ionizing radiation and/or to improve the therapy of diseases that are being cured by ionizing radiation.

The term "chemosensitizer" is defined as a molecule administered to patients in therapeutically effective amounts to increase the sensitivity of cells to chemotherapy and/or to improve the therapy of diseases that are being cured by chemotherapy.

Many cancer treatment protocols currently involve the use of radiosensitizers in combination with X-ray irradiation. Examples of X-ray activated radiosensitizers include, but are not limited to, the following: metronidazole, misonidazole, desmethylmisonidazole, pimonidazole, ethanidazole, nimorazole, mitomycin C, RSU 1069, SR 4233, EO9, RB 6145, nicotinamide, 5-bromodeoxyuridine (BUdR) , 5-ioddeoxyuridine (IUdR), bromodeoxycytidine, fluorodeoxyuridine (FudR), hydroxyurea, cisplatin and therapeutically effective analogues and derivatives of these compounds.

Photodynamic therapy (PDT) for cancer involves the use of visible light as a radiation activator sensitizing agent. Examples of photodynamic radiosensitizers include, but are not limited to, hematoporphyrin derivatives, photofrin, benzoporphyrin derivatives, tin etioporphyrin, pheoborbide-a, bacteriochlorophyll-a, naphthalocyanines, phthalocyanines, zinc phthalocyanine, and therapeutically effective analogues and derivatives of these compounds.

Radiosensitizers can be administered in conjunction with a therapeutically effective amount of one or more other compounds, including, but not limited to: compounds that promote the introduction of radiosensitizers into target cells; compounds that control the flow of therapeutics, nutrients and/or oxygen to target cells; chemotherapeutic agents that act on the tumor with or without the use of additional radiation; or other therapeutically effective compounds for the treatment of cancer or other diseases.

Chemosensitizers can be administered in combination with a therapeutically effective amount of one or more other compounds, including, but not limited to: compounds that promote the introduction of chemosensitizers into target cells; compounds that control the flow of therapeutics, nutrients and/or oxygen to target cells; chemotherapeutic agents that act on a tumor, or other therapeutically effective compounds for the treatment of cancer or other disease. Calcium antagonists, such as verapamil, are considered useful in combination with antineoplastic agents for developing chemotherapy sensitivity in tumor cells resistant to accepted chemotherapeutic agents and for enhancing the efficacy of such compounds in drug-responsive malignancies.

For use in combination therapy with another chemotherapeutic agent, a compound of formula (I) and one, two, three or more other therapeutic agents may, for example, be formulated together in a dosage form containing two, three, four or more therapeutic agents, i.e. . a single pharmaceutical composition containing all components. Alternatively, the individual therapeutic agents may be formulated separately and presented together in kit form, optionally with instructions for their use.

In one embodiment, the pharmaceutical composition comprises a compound of formula I together with a pharmaceutically acceptable carrier and optionally one or more therapeutic agents.

According to another implementation variant, the present invention relates to the use of a combination according to the present invention for the preparation of a pharmaceutical composition for inhibiting the growth of tumor cells.

According to a further implementation variant, the present invention relates to a product containing a compound of formula I and one or more anticancer agents, in the form of a combined preparation for simultaneous, separate or sequential use for the treatment of patients suffering from cancer.

EXAMPLES

Hereinafter, the present invention will be illustrated, without limitation, through the specific implementation options described in the following examples. Compounds are named using an automatic naming program such as AutoNom (MDL) or ChemAxon Structure to Name, or assigned by a chemical supplier. The following abbreviations are used in the examples:

AcOH - acetic acid

Boc - tert-butyloxycarbonyl

Boc-Abu-OH - (S)-2-(Boc-amino)butyric acid

BuLi - butyllithium

CDI - 1,1-carbonyldiimidazole

DAST - Diethylaminosulfur trifluoride

DXM - dichloromethane

DCMA - Dicyclohexylmethylamine

DIPEA - N-ethyl-N-(1-methylethyl)-2-propylamine

DMC - dimethyl carbonate

DMF - N,N-dimethylformamide

DMSO - dimethyl sulfoxide

1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide

EDC - hydrochloride

Et ₃ N - triethylamine

EtOAc - ethyl acetate

EtOH - ethanol

Et ₂ O - diethyl ether

HATU - 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate)

HBTU - O-benzotriazole-N,N,N'N'-tetramethyluronium hexafluorophosphate

HCl - hydrochloric acid

HOAc - acetic acid

HOAt - 1-hydroxyazabenzotriazole

HOBt - 1-hydroxybenzotriazole

HPLC - high performance liquid chromatography

IPA - isopropyl alcohol

KHMDS - potassium hexamethyldisilazide

LiHMDS - lithium bis(trimethylsilyl)amide

MeCN - acetonitrile

MeOH - methanol

min. - minutes

MS - mass spectrometry

MB - microwaves

NaBH(OAc) ₃ - sodium triacetoxyborohydride

NaOtBu - potassium tert-butoxide

NMP - N-methyl-2-pyrrolidinone

NMR - nuclear magnetic resonance spectroscopy

Pd ₂ (dba) ₃ - tris (dibenzylideneacetone) dipalladium (o)

Pd(OAc) ₂ - palladium acetate (2)

Pd (PPh ₃ ) ₄ - tetraxis (triphenylphosphine) palladium (0)

gasoline - petroleum ether fraction with a boiling point range of 40-60°C

PyBrop - Bromo-tris-pyrrolidinophosphonium hexafluorophosphate

CT - room temperature

SiO ₂ - silicon dioxide

TBTU - N,N,N',N'-tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate

TEA - triethylamine

TFA - trifluoroacetic acid

THF - tetrahydrofuran

UV - Ultraviolet

Column chromatography

Purification by column chromatography can be carried out, for example, using Biotage's automated flash purification system with UV detection at 298 nm and collection at 254 nm. In most cases, pre-packaged silica gel cartridges for automated chromatography from Biotage were used. Where indicated, some compounds were purified using Biotage C18 reverse phase silica gel columns containing octadecyl-functionalized (endcapped) silica gel, or Biotage KP-NH cartridges using silica bonded to primary amine.

Where necessary, semi-preparative HPLC can be performed, for example, using the following tools: (i) Varian Prostar block HPLC system with binary pump system, UV detector and fraction collector controlled by Varian Star software, (ii) HPLC- Agilent 1200 system with binary pump, autosampler, fraction collector, and diode array detector controlled by Agilent ChemStation software.

Description of the LC-MS Analytical System

In the following examples, many of the resulting compounds were characterized by mass spectrometry using the systems and suitable modes of operation described below. In cases where atoms with different isotopes are present and a single mass is indicated, such mass indicated for the compound is the monoisotopic mass (ie, ³⁵ Cl; ⁷⁹ Br, etc.). Several of the systems described below may be used, and such systems may be equipped and configured to operate under very similar operating modes. Possible modes of operation are also described below.

Agilent 1200SL-6140-RAPID LC/MS system:

Shimadzu Nexera LC/MS system

Second detector: Shimadzu SPD-M20A diode array detector

Shimadzu MS Operating Conditions:

Mass Directed LC/MS Purification System

Preparative LC-MS is a standard and efficient method used to purify small organic molecules such as the compounds described herein. Liquid chromatography (LC) and mass spectrometry (MS) methods can be modified to provide better separation of crude materials and improved sample detection by MS. Optimization of a preparative gradient LC method will involve changing columns, volatile eluents and modifiers, and gradients. Techniques are well known in the art for optimizing LC-MS methods and their subsequent use to purify compounds. 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). Several systems for purifying compounds by preparative LC-MS are described below, although one skilled in the art will recognize that alternative systems and methods to those described may be used. In particular, methods based on normal phase preparative LC can be used instead of the reverse phase methods described herein. Most preparative LC/MS systems use reverse phase LC and volatile acidic modifiers because this approach is very efficient for small molecule purification and because the eluents are suitable for use in electrospray positive ionization mass spectrometry. Alternatively, other chromatographic solutions can be used to purify compounds, eg, normal phase LC, mobile phase with alternative buffers, major modifiers, etc., as described in the analytical methods above.

Description of the preparative LC-MS system:

Waters Fractionlynx System:

- Equipment:

2767 Dual Loop Autosampler/Fraction Collector

Preparative pump 2525

CFO (column fluidic organizer) for column selection

RMA (Waters Reagent Management Tool) as feed pump

Waters ZQ mass spectrometer

Waters 2996 Diode Array Photodiode Detector

Waters ZQ mass spectrometer

- Software:

Masslynx 4.1

- Operating conditions MS Waters:

Agilent 1100 Preparative LC/MS System:

- Equipment:

Autosampler: "prepALS" Series 1100

Pump: "PrepPump" series 1100 for prep flow gradient and "QuatPump" series 1100 for pump modifier in prep. flow

UV detector: "MWD" (Multi Wavelength Detector) Series 1100

MS detector: "LC-MSD VL" series 1100

Fraction collector: 2x "Prep-FC"

Charging pump "Waters RMA"

Agilent Active Splitter

- Software:

Chemstation: Chem32

- Agilent MS operating conditions:

Columns: A range of commercially available columns - both achiral and chiral - can be used so that, combined with changes in mobile phase, organic modifier and pH, they provide the best coverage in terms of a wide range of selectivity. All columns were used in accordance with the operating modes recommended by the manufacturer. Usually used columns with a particle size of 5 microns, if available. For example, Waters columns were available for screening (including but not limited to XBridge Prep Phenyl 5µ OBD 100x19mm, XBridge Prep C18 5µ OBD 100x19mm, Waters Atlantis Prep T3 OBD 5µ 100x19mm, and SunFire Prep C18 OBD 5μ 100x19 mm), Phenomenex (including but not limited to Synergy MAX-RP and LUX™ Cellulose-2), Astec (Chirobiotic™ columns including but not limited to V, V2 and T2), and Diacel® (including but not limited to Chiralpak® AD-H).

Eluents: The mobile phase eluent was selected according to the column manufacturer's recommended limitations of the stationary phase to optimize separation performance.

Methods: The most appropriate type of preparative chromatography was selected according to the analytical trace. The usual algorithm was to run analytical LC-MS using the type of chromatography (low or high pH) most appropriate for the structure of the compound. When the analytical trace showed efficient chromatography, a suitable preparative method of the same type was selected.

Solvent: All compounds were usually dissolved in 100% MeOH or 100% DMSO, or 90:10 methanol:water + 0.2% formic acid.

Supercritical liquid chromatography (SLC)

In some cases, final compounds were purified by supercritical liquid chromatography (SLC) using a Waters Thar Prep100 preparative SLC system (P200 CO2 pump, 2545 modifier pump, 2998 UV/VIS detector, 2767 Fluid Manipulator with Stacked Injection Module). A Waters 2767 liquid manipulator was used as an autosampler and fraction collector.

For preparative purification of compounds, a Diacel Chiralpak IA/IB/IC, YMC Amylose/Cellulose C or Phenomenex Lux Cellulose-4 column at 5 μm 20-21.2×250 mm was used, unless otherwise indicated.

Appropriate isocratic methods were selected based on solvent systems of methanol, ethanol or isopropanol under unchanged or basic conditions. The standard method typically used modifier 5-55%/CO2, 100 ml/min, back pressure 120 bar, column temperature 40°C.

All compounds were subjected to analytical screening before the purification step. Each sample was run under unchanged and basic conditions (5.0 μl injection, 5/95 gradient over 5 minutes) through ethanol, methanol and isopropanol. If necessary, the use of a secondary screen over expanded solvents such as acetonitrile, ethyl acetate and THF can be considered. The analyst then made a decision as to which pH and isocratic state to use depending on where the desired product eluted and the separation achieved.

The modifier used under basic conditions was diethylamine (0.1% v/v). Formic acid (0.1% v/v) can sometimes be used as an acid modifier.

The purification process was controlled using Waters Fractionlynx software by monitoring at 210-400 nm, and triggering the collection threshold at 260 nm unless otherwise noted. Collected fractions were analyzed by SLC (Waters/Thar SLC system with Waters SQD). Fractions containing the desired product were concentrated by vacuum centrifugation.

Based on the information provided, one skilled in the art will be able to purify the compounds described herein by preparative LC-MS.

Synthesis methods

Using the following methods, similar and/or analogous to the general procedures below, the compounds set forth below were obtained.

The following synthetic procedures are presented to illustrate the methods used; for a particular substance or step, the precursor used may optionally come from a separate batch synthesized according to the step in the description.

When a compound is described as a mixture of two stereoisomers/epimers, the stereocenter configuration is not indicated or is represented by straight lines.

One skilled in the art will appreciate that compounds synthesized using the protocols provided herein may exist in the form of a solvate, eg, hydrate, and/or contain residual solvent or small impurities. Compounds isolated in the form of salts may be whole stoichiometric, i.e. mono- or disalts, or have an intermediate stoichiometry.

Some of the compounds below are isolated in the form of a salt, for example, depending on the acid used in the purification method. Some compounds are isolated in the form of the free base.

Compounds containing one stereocenter (R-configuration) at position 3 are usually isolated as a single isomer by preparative chiral HPLC (as described in General Methods); at (or closer to) the final stage of the synthesis sequence. In such cases, the stereochemistry at position 3 is designated according to IUPAC, using "dashed" or "solid" wedge bonds. Unless otherwise indicated, a straight line at the stereocenter means that the compound exists as a mixture of both isomers.

Example (3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-6-(2-hydroxypropan-2-yl)- 2,3-dihydro-1H-isoindol-1-one is shown in Figure A.

Figure A: Example showing purification of the 3R isomer by chiral HPLC

Compounds containing a second stereocenter (eg, adjacent to position 6) are usually isolated as a single isomer by preparative achiral and/or chiral HPLC. In such cases, the stereochemistry at position 3 is denoted in the usual manner, using "dashed" or "solid" wedge bonds. An asterisk (*) at the second stereocenter indicates that one (or both) of the diastereoisomer associated with this position was/were isolated separately. For example, 2 isomers of (3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[1-hydroxy-1-(1-methyl-1H -pyrazol-4-yl)ethyl]-3-[(1-hydroxycyclopropyl)methoxy]-2,3-dihydro-1H-isoindol-1-one were separated by preparative achiral and/or chiral HPLC to give two separate Examples (Figure B).

Note: Depending on the specific substitution scheme, the numbering system in some analogues may differ, according to the formal naming rules.

Figure B: An asterisk (*) indicates that the two isomers were separated and isolated to give two diastereomeric examples (Examples 75 and 76)

In other cases, the isomers were separated at an intermediate stage of the synthesis, and only one isomer reached the final example. The considered isomers can be characterized by rotation of the plane of polarized light and/or relative retention time on a chiral HPLC column. In such cases, an asterisk (*) indicates that the compound has been isolated as a single isomer. This is illustrated using Example 80 (Figure C)

Figure C: Synthesis of Example 80, (3R)-2-[(4-xnop-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[1-hydroxy-1-(1- methylpiperidin-4-yl)ethyl]-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one. An example was prepared from the levorotatory enantiomer of compound (3) followed by preparative chiral HPLC in the final step.

Optical isomers can be characterized by their optical activity (ie as + and - isomers or d and l isomers). The stereocenter may also be designated "R or S" according to the nomenclature developed by Cahn, Ingold and Prelog, see Advanced Organic Chemistry et al. Jerry March, ^4th Edition, John Wiley & Sons, New York, 1992, pages 109-114, and see also Cahn, Ingold & Prelog, Angew. Chem. Int. Ed. Engl., 1966, 5, 385-415.

Optical isomers can be separated using a number of techniques, including chiral chromatography (chromatography on a chiral support), and such techniques are well known to the person skilled in the art.

As an alternative to chiral chromatography, optical isomers of basic compounds can be separated by formation of diastereomeric salts with chiral acids such as (+)-tartaric acid, (-)-pyroglutamic acid, (-)-ditoluene-L-tartaric acid, (+ )-mandelic acid, (-)-malic acid and (-)-camphorsulfonic acid, separating the diastereomeric salts by selective crystallization and subsequent dissociation of the salts to obtain the single free base enantiomer. Similarly, optical isomers of acidic compounds can be separated by formation of diastereomeric salts with chiral amines such as brucine, cinchonidine, quinine, etc.

In addition, enantiomeric resolution can be accomplished by covalently linking an enantiomerically pure chiral auxiliary to a compound and then performing a diastereomeric resolution using standard techniques such as chromatography. This is followed by breaking the aforementioned covalent bond to give the appropriate enantiomerically pure product. Examples may include the preparation of menthol esters of the acidic compound.

When the compounds of formula (I) exist in two or more optical isomeric forms, one enantiomer in an enantiomer pair may be advantageous over the other enantiomer, for example in terms of biological activity. Thus, under certain circumstances, it may be desirable to use only one of a pair of enantiomers, or only one of a plurality of diastereoisomers, as a therapeutic agent.

Accordingly, the present invention provides compositions containing a compound of formula (I) with one or more chiral centers, in which at least 55% (for example, at least 60%, 65%, 70%, 75%, 80%, 85 %, 90% or 95%) of the compound of formula (I) is present in the form of a single optical isomer (eg enantiomer or diastereoisomer). In one general embodiment, 99% or more (eg, substantially all) of the total compound of formula (I) may be present as a single optical isomer (eg, enantiomer or diastereoisomer).

Compounds containing double bonds may have E-(entgegen) or Z-(zusammen) stereochemistry at said double bond. Substituents on bivalent cyclic or (partially) saturated radicals may be in the cis or trans configuration. The terms cis and trans as used herein are in accordance with the Chemical Abstracts nomenclature (J. Org. Chem. 1970, 35(9), 2849-2867) nomenclature, and refer to the position of substituents on the ring moiety.

Of particular interest are compounds of formula (I) which are stereochemically pure. When a compound of formula (I) is designated, for example, as R, this means that the compound essentially does not contain the S isomer. If the compound of formula (I) is designated, for example, as E, this means that the compound essentially does not contain the Z-isomer. The terms cis, trans, R, S, E and Z are well known to the person skilled in the art.

EXAMPLES 1-137

Substance 1. 4-Fluoro-2-hydroxybenzaldehyde

Anhydrous triethylamine ( _1.94 ml) and paraformaldehyde (811 mg, 27.0 mmol). The mixture was heated to boiling for 4.25 hours during which time the color changed from white to pink and then to yellow. The reaction mixture was cooled to room temperature and 5% aqueous HCl (20 ml) was added. The product was extracted with EtOAc (2×50 ml) and the combined organic extracts were washed with H ₂ O (3×50 ml), brine (50 ml), dried over anhydrous MgSO ₄ and the solvent was removed under vacuum. FCC [dichloromethane-methanol (100:0)→(97:3)] of the crude precipitate afforded the title Substance 1 (367 mg, 71%) as a white solid; R _f 0.83 (10% MeOH:CH ₂ Cl ₂ ); ¹ H NMR (500 MHz, CDCl ₃ ) δ 11.35 (1H, d, J=1.6 Hz, CHO), 9.82 (1H, s), 7.55 (1H, dd, J=6, 3 and 8.6 Hz), 6.71 (1H, dt, J=2.4 and 8.3 Hz) and 6.66 (1H, dd, J=2.4 and 10.4 Hz), ¹⁹ F NMR (470.7 MHz, CDCl ₃ ) δ -97.53 (m).

Substance 2: N'-(5'-Bromo-2'-hydroxybenzylidene)-4-chlorobenzohydrazide -

Following a procedure similar to that described for the preparation of Substance 3, using 5-bromo-2-hydroxybenzaldehyde (10 g, 49.7 mmol) and 4-chlorobenzhydrazide (8.5 g, 49.7 mmol), Substance 2 was obtained as a dirty -white solid, which was used in the next step without further purification (16.5 g, 94%), δ _max /cm ^-1 1014, 1266, 1354, 1476, 1642, 3069, 3218; δ _H (500 MHz; DMSO) 6.91 (1H, d, J=8.6, 3'-H), 7.44 (1H, dd, J=2.3, 8.7, 4'-H ), 7.61-7.67 (2H, m, Ar-H), 7.81 (1H, d, J=2.3, 6'-H), 7.94-8.01 (2H, m , Ar-H), 8.62 (1H, s, 1'-CH), 11.2 (1H, br. s, NH), 12.24 (1H, br. s, OH).

Substance 3: (E)-N'-(5-Bromo-3-fluoro-2-hydroxybenzylidene)-4-chlorobenzohydrazide

To a solution of 5-bromo-3-fluoro-2-hydroxybenzaldehyde (1.06 g, 4.83 mmol) in acetic acid (23 ml) was added 4-chlorobenzhydrazide (824 mg, 4.83 mmol) at room temperature, and the resulting the mixture was stirred for 15 minutes. The suspension was poured into water (20 ml) at 0° C. and the resulting precipitate was collected by filtration. The solid was washed with water (3 x 20 ml) then with petrol (3 x 20 ml) and the product was dried overnight in a vacuum oven to give (E)-N'-(5-bromo-3-fluoro-2- hydroxybenzylidene)-4-chlorobenzohydrazide, Compound 3 (1.69 g, 94%), as a pale yellow solid which was used without further purification; R _f 0.84 (10% MeOH:CH ₂ Cl ₂ ); λ _max (EtOH)/nm 237.8, 292.6, 303.6 and 333.0; IR (cm ^-1 ) 1098, 1158, 1242, 1463, 1521, 1591, 1660, 2360 and 3261; mp 245°C (dec.); ¹ H NMR (500 MHz, DMSO) δ 12.39 (1H, br.s), 11.64 (1H, br.s), 8.63 (1H, s, HC=N), 7.98 (1H , d, J=8.5 Hz, 2 x ArH), 7.69 (1H, s, ArH), 7.65 (2H, d, J=8.5 Hz, 2 x ArH) and 7.60 ( 1H, dd, J=2.2 and 10.4 Hz, ArH). LRMS (ESI+) m/z 371.2 [M] ⁺ .

Substance 4: 5-Bromo-2-(4-chlorobenzoyl)benzaldehyde

Following a procedure similar to that described for Substance 5, N'-(5'-bromo-2'-hydroxybenzylidene)-4-chlorobenzohydrazide (Substance 2) (16.53 g, 46.7 mmol), Pb(OAc) ₄ (20.7 g, 46.7 mmol) and THF (492 ml). Purify on silica gel eluting with 20% → 85% EtOAc/Hexane to give Compound 4 as an orange solid (13.41, 88%). δ _max /cm ^-1 764, 927, 1189, 1277, 1585, 1663, 1698, 2354, 2840, 3086; δ _H (500 MHz; CDCl ₃ ) 7.37 (1H, d, J=8.2, 3-H), 7.43-7.46 (1H, m, Ar-H), 7.70-7 .73 (2H, m, Ar-H), 7.82 (1H, dd, J=2.0, 7.9, 4-H), 8.14 (1H, d, J=2.0.6 -N). m/z (ESI+) 323 (M+80%) 325 (100%).

Substance 5: 5-Bromo-2-(4-chlorobenzoyl)-3-fluorobenzaldehyde

To a suspension of (E)-N'-(5-bromo-4-fluoro-2-hydroxybenzylidene)-4-chlorobenzohydrazide (Compound 3) (1.67 g, 4.49 mmol) in THF (45 ml) was added in portions Pb(OAc) ₄ (1.99 g, 4.49 mmol). The resulting orange solution was stirred at room temperature for 2 hours and then filtered through ^Celite® eluting with EtOAc (30 ml). The organics were washed with saturated aqueous NaHCO ₃ (50 ml), brine (50 ml) dried over anhydrous Na ₂ SO ₄ and the solvent was removed under vacuum. FCC [petrol-ethyl acetate (100:0) → (95:5)] of the crude residue gave 5-bromo-2-(4-chlorobenzoyl)-3-fluorobenzaldehyde, Substance 5 (1.29 g, 84%), in in the form of a yellow solid; R _f 0.87 (40% EtOAc: Gasoline); λ _max (EtOH)/nm 201.8 and 258.4; IR (cm ^-1 ) 1095, 1249, 1271, 1586, 1649, 1710, 2920 and 3072; mp 120.6-122.0°C; ¹ H NMR (500 MHz, DMSO) δ 9.87 (1H, s, CHO), 8.27 (1H, d, J=1.6 Hz, HCCBr), 8.15 (1H, dd, J=1 .6 and 8.8 Hz, HCCF) 7.75 (2H, d, J=8.5 Hz, 2 x Ar) and 7.59 (2H, d, J=8.5 Hz, 2 x ArH). LRMS (ESI+) m/z 341.2 [M] ⁺ .

Substance 6: 5-Bromo-2-(4-chlorobenzoyl)benzoic acid

Following procedures similar to those described for Substance 7; 5-bromo-2-(4-chlorobenzoyl)benzaldehyde (Compound 4) (7.4 g, 22.9 mmol), sodium chlorite (2.9 g, 29.7 mmol), sulfamic acid (2.77 g, 30.6 mmol), acetonitrile (213 ml) and water (72 ml) gave Compound 6 as a beige solid, which was used in the next step without further purification (7.4g, 95%). δ _max /cm ^-1 1014, 1090, 1252, 1270, 1288, 1305, 1423, 1481, 1582, 1671, 2551, 2658, 2800; δ _H (500 MHz; DMSO) 7.44 (1H, d, J=8.0, 4-H), 7.56-7.60 (2H, m, Ar-H), 7.63-7, 67 (2H, m, Ar-H), 7.96 (1H, dd, J=2.0, 8.0, 4-H), 8.11 (1H, d, J=2.0, 6- H), 13.64 (1H, br s, COOH). m/z (ESI-) 337 (75%) 339 (M+ 100%) 341 (25%).

Substance 7: 5-Bromo-2-(4-chlorobenzoyl)-3-fluorobenzoic acid

To a solution of 5-Bromo-2-(4-chlorobenzoyl)-3-fluorobenzaldehyde (Compound 5) (1.27 g, 3.71 mmol) in acetonitrile (48 ml) was added a solution of sodium chlorite (436 mg, 4.82 mmol ) in water (5.4 ml) and then a solution of sulfamic acid (468 mg, 4.82 mmol) in water (5.4 ml). The resulting yellow solution was stirred at room temperature for 3 hours and then the solvent was removed in vacuo. The resulting yellow solid was dissolved in ethyl acetate (30 ml) and washed with water (30 ml), brine (30 ml), dried over anhydrous Na ₂ SO ₄ and the solvent was removed to give 5-bromo-2-(4-chlorobenzoyl) -3-fluorobenzoic acid, Substance 7 (1.33 g, 100%), as a pale yellow solid, which was used without any further purification; R _f 0.23 (10% MeOH:CH ₂ Cl ₂ ); _λmax (EtOH)/nm 207.0 and 258.0; IR (cm ^-1 ) 1087, 1269, 1397, 1590, 1678, 1711 and 3072; mp 155°C (dec.); ¹ H NMR (500 MHz, DMSO) δ 13.93 (1H, br. s, COOH), 8.07 (1H, dd, J=1.5 and 9.0 Hz, HCCF), 8.00 (1H , d, J=1.5 Hz, HCCBr), 7.74 (2H, d, J=8.5 Hz, 2 x Ar) and 7.59 (2H, d, J=8.5 Hz, 2 x ArH). LRMS (IER-) m/z 357.0 [M] ^- .

Substance 8: 6-Bromo-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-hydroxyisoindolin-1-one

The title compound was prepared from 5-bromo-2-(4-chlorobenzoyl)benzoic acid (7.4 g, 21.8 mmol) using a procedure similar to that described for Compound 9. The product was obtained as a yellow solid (6.78 d, 66%) m/z (ESI-) 462(100%) (M+H ⁺ ) ⁺

Substance 9: 6-Bromo-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-4-fluoro-3-hydroxyisoindolin-1-one

To a solution of 5-bromo-2-(4-chlorobenzoyl)-3-fluorobenzoic acid (Compound 7) (509 mg, 1.42 mmol) in anhydrous THF (7.1 ml) was added thionyl chloride (0.21 ml, 2. 85 mmol) and a catalytic amount of DMF (1 drop), and the yellow mixture was stirred at room temperature for 4 h, then concentrated under reduced pressure. The precipitate was dissolved in anhydrous THF (7.1 ml) and 4-chlorobenzylamine (0.19 ml, 1.56 mmol) and Hunig's base (0.27 ml, 1.56 mmol) were added and the mixture was stirred at room temperature for 16 hours The reaction mixture was diluted with EtOAc (20 ml), and the solution was washed with water (3×20 ml) and brine (20 ml), dried over anhydrous MgSO ₄ and concentrated under vacuum to obtain a dark orange oil. FCC [gasoline-ethyl acetate (100:0)→(95:5)→(80:20)] of the crude residue gave 6-bromo-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-4-fluoro -3-hydroxyisoindolin-1-one, Substance 9 (624 mg, 91%), as a pale yellow solid; LRMS (ESI-) m/z 480.1 [M-N] ^- .

Substance 10: 6-Bromo-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)isoindolin-1-one.

To a solution of 6-bromo-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-hydroxyisoindolin-1-one (Compound 8) (1 g, 2.1 mmol) and 1,1-Bis(hydroxymethyl )cyclopropane (0.604 ml, 6.3 mmol) in DCE (21 ml) was added InBr ₃ (76 mg, 0.21 mmol) and the resulting mixture was heated to 95°C for 3 hours. The reaction mixture was cooled to room temperature, then washed with water, brine, and the organic phase was dried (MgSO ₄ ), filtered and concentrated under vacuum. Purification on silica gel (Biotage SP4) eluting with 20% → 95% EtOAc/pet afforded Substance 10 as a brown gum (921 mg; 80%). (500 MHz, CDCl ₃ ) 0.10-0.19 (2H, m), 0.37-0.46 (2H, m), 1.53 (1H, t), 2.65 (1H, d) , 2.81(1H, d), 3.36(1H, dd), 3.50(1H, dd), 4.17(1H, d), 4.50(1H, d), 7.01( 1H, d), 7.08-7.22(8H, m), 7.63(1H, dd), 8.02(1H, d).

Substance 11: 6-Bromo-3-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-2-(4-chlorobenzyl)-3-(4-chlorophenyl)isoindolin-1-one

Substance 10 (0.8 g, 1.46 mmol), imidazole (0.370 g, 5.44 mmol), TBDMSCI (0.496 g, 3.29 mmol) in THF (10 ml/0.7 mmol) was heated at 85° C within 7 hours. After extraction, the crude material was purified by silica gel chromatography (Pet:EtOAc 1:0 to 4:1) to give the desired product, Compound 11, as a colorless oil (0.928 g, 1.403 mol) in 96 ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm) -0.02 (s, 3H), 0.00 (s, 3H), 0.06-0.15 (m, 2H), 0.30-0.43 (m, 2H ), 0.83 (s, 9H), 2.61 (d, 1H), 2.87 (d, 1H), 3.35 (d, 1H), 3.65 (d, 1H), 4.30 (d, 1H), 4.37 (d, 1H), 6.97 (d, 1H), 7.04 (d, 2H), 7.10 (d, 2H, J=8.5 Hz, Ar- H), 7.12-7.20 (m, 4H, Ar-H), 7.60 (dd, 1H), 8.02 (d, 1H); MS(ES+) m/z 456.4 [M+H] ⁺ .

Substance 12: 6-Bromo-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-4-fluoro-3-((1-(hydroxymethyl)cyclopropyl)methoxy)isoindolin-1-one

To a solution of 6-bromo-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-4-fluoro-3-hydroxyisoindolin-1-one (Compound 9) (603 mg, 1.25 mmol) in anhydrous THF ( 7 ml) was added thionyl chloride (0.18 ml, 2.50 mmol) and a catalytic amount of DMF (2 drops) and the orange mixture was stirred at room temperature for 4 h, then concentrated under reduced pressure. The precipitate was dissolved in anhydrous THF and then a solution of 1,1-bis(hydroxymethyl)cyclopropane (0.24 ml, 2.50 mmol) and K ₂ CO ₃ (345 mg, 2.50 mmol) was added and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with EtOAc (10 ml) and washed with water (3×20 ml), brine (20 ml), dried over Na ₂ SO ₄ , filtered, and the solvent was removed under vacuum. FCC [gasoline-ethyl acetate (100:0)→(80:20)] of the crude residue gave 6-bromo-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-4-fluoro-3-((1 -(hydroxymethyl)cyclopropyl)methoxy)isoindolin-1-one, Substance 12 (389 mg, 55%), as a yellow gum; ¹ H NMR (500 MHz, DMSO) δ 0.13 (2H, m), 0.34 (2H, m), 2.81 (1H, d), 2.86 (1H, d), 3.28 ( 1H, dd), 3.35(1H, dd), 4.28(1H, d), 4.34(1H, d), 7.05(2H, d), 7.19(2H, d, J = 8.5 Hz, 2 x ArH), 7.25 (2H, d, J=8.4 Hz, 2 x ArH), 7.30 (2H, d), 7.82 (1H, dd) and 7 .89 (1Н, dLRMS (ESI+) m/z 464.2 [MC ₅ H ₉ O ₂ ] ⁺

Substance 13: 2-(4-Chlorobenzyl)-3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(prop-1-en-2-yl)isoindoline-1- He

Isopenylboronic acid ester suspension (239 μl, 1.27 mmol), 6-bromo-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)isoindoline- 1-one (Compound 10) (465 g, 0.85 mmol), NaOH (35.7 mg, 0.89 mmol), and N,N-dicyclohexylmethylamine (0.191 ml, 0.894 mmol) in THF (4.63 ml ) was degassed for 10 minutes before adding Pd(dppf)Cl ₂ (62 mg, 0.09 mmol). The resulting mixture was heated to a rapid boil for 3 hours. The reaction mixture was cooled to room temperature, diluted with DCM and washed with HCl (1M), water, brine, dried (MgO ₄ ), filtered and concentrated in vacuo. Purification on silica gel eluting with 30% EtOAc/Hexanes gave Compound 13 as a white foam (316 mg; 73%); m/z (ESI+) 508.4 (10%), 406.3, 408.3 (70%).

Substance 14: 2-(4-Chlorobenzyl)-3-(4-chlorophenyl)-4-fluoro-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(prop-1-en-2-yl) isoindoline-1-one

6-bromo-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-4-fluoro-3-((1-(hydroxymethyl)cyclopropyl)methoxy)isoindolin-1-one (Substance 12) (194 mg, 0.343 mmol) was dissolved in anhydrous THF (4.6 ml) and powdered NaOH (14 mg, 0.343 mmol), DXMA (0.07 ml, 0.343 mmol) and isopropenylboronic acid pinacol ester (0.1 ml, 0.514 mmol) were added successively ) at room temperature under N ₂ atmosphere. The solution was degassed with N ₂ for 20 min, then Pd(dppf)Cl ₂ ⋅CH ₂ Cl ₂ (28 mg, 0.100 mmol) was added and the solution was heated at reflux for 3.5 h. After cooling to room temperature, the reaction mixture filtered through Celite ^® , washed with EtOAc, then transferred to a separating funnel and washed with 1M aq. HCl (20 ml), brine (20 ml), dried over Na ₂ SO ₄ , filtered and the solvent removed under vacuum. FCC [petrol-ethyl acetate (100:0)→(85:15))→(70:30)] of the crude residue followed by preparative HPLC gave 2-(4-chlorobenzyl)-3-(4-chlorophenyl)-4- fluoro-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(prop-1-en-2-yl)isoindolin-1-one, Substance 14 (150 mg, 83%), as pale yellow resins; LRMS (ESI+) m/z 426.3 [M-C ₅ H ₉ O ₂ ] ⁺ .

Substance 15: 6-Acetyl-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-((3'-(hydroxymethyl)cyclopropyl)methoxy)isoindolin-1-one

To a solution of 2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(prop-1-en-2-yl)isoindolin-1-one (Substance 13) (64 mg, 0.125 mmol) in dioxane/H ₂ O (3:1, 1.23 mL) 2,6-Lutidine (30 μL, 0.251 mmol), OsO ₄ (~1 mg , 0.0025 mmol) and NalO ₄ (106 mg, 0.5 mmol), and the resulting mixture was stirred until TLC showed complete absorption of the starting material. The reaction mixture was diluted with water and DCM and the organic phase was separated. The aqueous layer was extracted with DCM (x3) and the combined organic phases were washed with brine, dried (MgO ₄ ) and concentrated in vacuo. Purification on silica gel (Biotage SP4) eluting with 20% → 85% EtOAc/Pet afforded Substance 15 as a white foam (37 mg; 60%). HRMS (ESI+) 510, 121 (MH+).

Substance 16: 3-(4-chlorophenyl)-2-((S)-1-(4-chlorophenyl)ethyl)-3-hydroxy-6-(prop-1-en-2-yl)isoindolin-1-one

The title compound was prepared using a mixture of Compounds 25a and 25b following a procedure similar to that described for Compound 13. The crude material was purified by silica gel chromatography (Pet:EtOAc 1:0 to 2:1) to give the desired diastereoisomers as a beige solid. substances (2.255 g, 5.14 mmol).

Substance 16a R _f = 0.30 (Pet:EtOAc/9:1); MS(ES+) m/z 484.3 [M+H

Substance 16b: R _f = 0.15 (Pet:EtOAc/9:1);

Substance 17: (E)-N'-(5-acetyl-2-hydroxybenzylidene)-4-chlorobenzohydrazide

The title compound was prepared from 5-acetyl-2-hydroxybenzaldehyde (500 mg, 3.1 mmol) using a procedure similar to that described for Compound 3. The product was obtained as a yellow solid (923 mg, 96. LRMS (ES ⁺ ) m /z 317.2 [M+H

Substance 18: 5-Acetyl-2-(4-chlorobenzoyl)benzaldehyde

The title compound was prepared from (E)-N'-(5-acetyl-2-hydroxybenzylidene)-4-chlorobenzohydrazide, (Compound 17), (0.90 g, 2.8 mmol) and Pb(OAc) ₄ (2, 5 g, 5.7 mmol) using a procedure similar to that described for Substance 5. LRMS (ES ⁺ ) m/z 287.3 [M+H] ⁺ ;

Substance 19: 5-Acetyl-2-(4-chlorobenzoyl)benzoic acid

The title compound was obtained from 5-acetyl-2-(4-chlorobenzoyl)benzaldehyde,

Compound 18 (690 mg, 2.4 mmol) using a procedure similar to that described for Compound 7. The product was obtained as an off-white solid (753 mg, 100%). LRMS (ES ^- ) m/z301.2 [M-H] ^- ;

Substance 20: 6-Acetyl-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-hydroxyisoindolin-1-one

To a solution of 5-acetyl-2-(4-chlorobenzoyl)benzoic acid, Compound 19, (2.0 g, 6.6 mmol) in THF (8 ml) was added thionyl chloride (0.96 ml, 13.2 mmol) and stirred at RT for 2 h, then concentrated in vacuo. The precipitate was dissolved in THF (8 ml) and 4-chlorobenzylamine (0.89 ml, 7.3 mmol) and Hunig's base (1.3 ml, 7.3 mmol) were added and stirred at RT for 2 h, after which it was diluted EtOAc (8 ml). Washed with water (8 ml), brine (8 ml), dried (MgO ₄ ) and concentrated in vacuo. Purification (SP4, silica gel, EtOAc/petrol, 40%) afforded Compound 20 as a yellow solid (1.52 g, 54%). ¹ H NMR (500 MHz, CDCl ₃ ) δ 2.61 (3H, s, CH ₃ ), 3.21 (1H, br s, OH), 4.18 (1H, d, J=15.0 Hz, NCHH), 4.68 (1H, d, J=15.0 Hz, NCHH), 7.14-7.26 (8H, m, H-Ar), 7.31 (1H, d, J=8, 0 Hz, H-4), 8.07 (1H, dd, J=1.6, 8.0 Hz, H-5), 8.26 (1H, d, J=1.6 Hz, H-7 ). LRMS (ES ^- ) m/z 424.2 [M-H] ^- ;

Substance 21: 6-Acetyl-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-(2-hydroxyethoxy)isoindolin-1-one

The title compound was prepared in a similar manner to Compound 10, but using 0.8 mol. equiv. InBr ₃ and 20 mol. equiv. ethylene glycol. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm) 1.48-1.55 (m, 1H), 2.67 (s, 3H), 1.62 (s, 6H), 2.80- 2.92 (m, 2H), 3.32-3.52 (m, 2H), 4.11 (d, 1H), 4.67 (d, 1H), 7.14-7.19 (m, 4H), 7.20-7.27 (m), 8.14 (dd, 1H), 8.43-8.46 (m). HMS(ES+) m/z 486.3 [M+H] ⁺ ;

Substance 22: 6-Acetyl-3-(3-bromo-2,2-bis(hydroxymethyl)propoxy)-2-(4-chlorobenzyl)-3-(4-chlorophenyl)isoindolin-1-one

SOCl ₂ (0.103 ml, 1.41 mmol) was added to the 6-acetylisoindolinone derivative (Compound 20) (0.3 g, 0.704 mmol) in THF (5 ml) under dry N ₂ atmosphere. The mixture was stirred for 2 hours at room temperature, after which it was concentrated under vacuum. To the precipitate were added 2-(bromomethyl)-2-(hydroxymethyl)-1,3-propanediol (0.42 g, 2.11 mmol) and anhydrous K ₂ CO ₃ (0.194 g, 1.41 mmol) and then THF ( 5 ml) and the reaction mixture was stirred overnight. After extraction, the crude material was purified by silica gel chromatography (Pet:EtOAc 1:0 to 0:1) to give a yellow solid Substance 22 (0.186 g, 0.306 mmol. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm) 2.67 (s, 3H, COCH ₃ ), 2.78 (d, 1H, J=9.0 Hz, CCHHC), 3.00 (d, 1H, J=9.0 Hz, CCHHC), 3, 45-3.65 (m, 6H, CCH ₂ Br, C(CH ₂ OH) ₂ ), 4.41 (d, 1H, J=15.1 Hz, NCHH), 4.45 (d, 1H, J=15.1 Hz, NCHH), 7.02-7.11 (m, 4H, Ar-H), 7.13 (d, 2H, J=8.5 Hz, Ar-H), 7.18 (d, 2H, J=8.7Hz, Ar-H), 7.27 (d, 1H, J=8.0Hz, isoindolinone-H), 8.15 (dd, 1H, J=7.9 , 1.6 Hz, isoindolinone-H), 8.45 (d, 1H, J=1.2 Hz, isoindolinone-H; MS(ES+) m/z 456.4 [M+H] ⁺ ;

Substance 23: 6-Acetyl-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-((3-(hydroxymethyl)oxetan-3-yl)methoxy)isoindolin-1-one

Bromodiol (Compound 22) (0.215 g, 0.354 mmol) was dissolved in EtOH (10 ml). KOH (0.023 g, 0.407 mmol) was added and the mixture was heated to 90° C. and stirred for 6 hours. After returning to room temperature, H ₂ O (10 ml) was added, followed by the introduction of an aqueous solution of 1M HCL until a pH ~ 2-3 was reached. The mixture was extracted with EtOAc (3×20 ml), and the combined organic phases were washed with saline, dried over MgO ₄ , filtered and evaporated under vacuum. The crude material was purified by silica gel chromatography (Pet:EtOAc 1:0 to 1:3) to give the desired product as a white solid foaming Substance 23 (0.104 g, 0198 mmol) in 56 ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm) 1.73 (bs, 1H, OH), 2.67 (s, 3H,), 2.92 (d, 1H), 3.05 (d, 1H), 3.67-3, 77 (m, 2H), 4.22 (d, 1H), 4.24-4.29 (m, 2H), 4.31 (d, 1H), 4.36 (d, 1H), 4. 57 (d, 1H), 7.10 (d, 1H), 7.12-7.18 (m, 4H, H), 7.19-7.24 (m, 3H), 8.15 (dd , 1H), 8.46 (d, 1H,.); MS(ES+) m/z [M+H] ⁺ ; 456.1624.

Substance 24: (R)-3-(4-Chlorophenyl)-2-((S)-1-(4-chlorophenyl)ethyl)-3-((2-(hydroxymethyl)allyl)oxy)-6-(prop -1-en-2-yl)isoindole in-1-one

3-(4-Chlorophenyl)-2-((S)-1-(4-chlorophenyl)ethyl)-3-hydroxy-6-(prop-1-en-2-yl)isoindolin-1-one, Substance 16 , (250 mg, 0.57 mmol), 2-methylene-1,3-propanediol (0.23 ml, 2.85 mmol), InBr ₃ (305 mg, 0.86 mmol) and DCE (5 ml). Purification (SP4, silica gel, EtOAc/gasoline, 25%) afforded Substance 24 as a white glossy solid (88 mg, 30%). R _f = 0.64 (silica gel, EtOAc/gasoline. ¹ H NMR (500 MHz, CDCl ₃ ) δ 1.85 (3H, d, J=7.3 Hz, benzyl CH ₃ ), 2.17 (3H, s, isopropene CH ₃ ), 3.59 (1H, d, J=12.2 Hz, -iso-OSHH), 3.81 (1H, d, J=12.2 Hz, -iso-OSHH), 4 .16-4.23 (2H, m, CH ₂ OH), 4.40 (1H, q, J = 7.3 Hz, H-benzyl), 5.17-5.18 (1H, m, H- isopropene), 5.21-5.24 (2H, m, side chain alkene CH ₂ ), 5.44-5.45 (1H, m, H-isopropene), 6.95-7.10 (9H, m , H-Ar), 7.59 (1H, dd, J=1.7, 7.9 Hz, H-5), 7.92 (1H, d, J=1.7 Hz, H-7). LRMS (ES ⁺ ) m/z 508.4 [M+H] ⁺ .

Compound 25a and 25b: 6-Bromo-3-(4-chlorophenyl)-2-((S)-1-(4-chlorophenyl)ethyl)-3-hydroxyisoindolin-1-one

From 5-bromo-2-(4-chlorobenzoyl)benzoic acid (Compound 6) and (1S)-1-(4-chlorophenyl)ethane-1-amine, the title compounds, Compounds 25a and 25b, were prepared using procedures similar to described for Substance 9.

The products were obtained as off-white solids.

25a (S,S): MS (ES+) 477.3 [M+H] ⁺ . R _f = 0.73 (1:1 EtOAc/gasoline);

25b (R,S): MS (ES+) 477.3 [M+H] ⁺ .: R _f = 0.64 (1:1 EtOAc/gasoline

Substances 26a and 26b: 6-Bromo-3-(4-chlorophenyl)-2-((S)-1-(4-chlorophenyl)ethyl)-3-((1-hydroxymethyl)cyclopropyl)methoxy)isoindoline-1- He

Compounds 26a and 26b were prepared using procedures similar to those described for Compound 12.

26a(S,S):; MS (ES+) 460.2 [M-HOCH ₂ (c-Pr)CH ₂ O] ⁺ .): R _f = 0.51 (2:3 EtOAc/gasoline);

26b(R,S):; MS (ES+) 460.2 [M-HOCH ₂ (c-Pr)CH ₂ O, R _f = 0.42 (2:3 EtOAc/gasoline);

Substance 27: (R)-3-(4-Chlorophenyl)-2-((S)-1-(4-chlorophenyl)ethyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(prop -1-en-2-yl)isoindoline-1-one

From intermediate 26b (500 mg, 0.89 mmol) was obtained Substance 27 using procedures similar to those described for Substance 13. MS (ES+) 522.5 [M+H] ⁺ .

Substance 28: (R)-6-Acetyl-3-(4-chlorophenyl)-2-((S)-1-(4-chlorophenyl)ethyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)isoindoline -1-he

From Substance 27 was obtained Substance 28 using procedures similar to those described for Substance 15. MS (ES+) 524.5 [M+H] ⁺ .

Substance 29: (R)-3-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-3-(4-chlorophenyl)-2-((S)-1-(4-chlorophenyl )ethyl)-6-(prop-1-en-2-yl)isoindolin-1-one

To a solution of (R)-3-(4-chlorophenyl)-2-((S)-1-(4-chlorophenyl)ethyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(prop- 1-en-2-yl)isoindolin-1-one, Compound 27 (2.20 g, 4.21 mmol), TBDMSCI (1.27 g, 8.42 mmol) and imidazole ( 860 mg, 12.6 mmol), and the mixture was heated at 85°C for 5 hours. The reaction mixture was cooled to RT, extracted with EtOAc (100 ml), washed with 0.3 M aqueous HCl (150 ml), water ( 150 ml), brine (150 ml), dried over MgO ₄ and concentrated in vacuo. HPLC (95:5 gasoline in EtOAc, then 99:1 gasoline/EtOAc) gave the title compound, Substance 29, as a colorless oil (1.83 g, 68%); MS (ES+) 422.3 [M-(TBDMCOCH ₂ (c-Pr)CH ₂ O)] ⁺ .

Substance 30: (3R)-3-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-3-(4-chlorophenyl)-2-((S)-1-(4-chlorophenyl )ethyl)-6-(2-methyloxiran-2-yl)isoindolin-1-one

At 0°C to a solution of (R)-3-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-3-(4-chlorophenyl)-2-((S)-1-( 4-chlorophenyl)ethyl)-6-(prop-1-en-2-yl)isoindolin-1-one Substance 29 (500 mg, 0.79 mmol) in DCM (43 ml) mCPBA (271 mg , 1.57 mmol) and the resulting solution was stirred at RT for 18 h. The reaction mixture was quenched by adding saturated aqueous NaHCO ₃ (25 mL) and stirred at RT for 30 min. The organic layer was separated, washed with brine (40 ml), dried over MgO ₄ and concentrated in vacuo. The crude product, Compound 30, was obtained as a colorless oil and used in the next step without purification (708 mg); MS (ES+) 436.3 [M-(TBDMCOCH ₂ (c-Pr)CH ₂ O)] ⁺ .

Substance 31: (3R)-3-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-3-(4-chlorophenyl)-2-((S)-1-(4-chlorophenyl )ethyl)-6-(2-hydroxy-1-methoxypropan-2-yl)isoindolin-1-one

To a solution of sodium (249 mg, 10.8 mmol) in MeOH (1.5 ml) was added dropwise a solution of (3R)-3-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)- 3-(4-chlorophenyl)-2-((S)-1-(4-chlorophenyl)ethyl)-6-(2-methyloxiran-2-yl)isoindolin-1-one, Substances 30 (708 mg, 1, 08 mmol), in MeOH (1.5 ml), and the resulting solution was stirred at RT for 18 h, then at 65°C for 5 h. The reaction mixture was cooled to RT, NaOMe (292 mg, 5.4 mmol ), and the mixture was heated at 65°C for 2 h, then cooled to RT. The reaction mixture was quenched with water (100 ml), neutralized with aqueous 1.0 M HCl, extracted with EtOAc (2×100 ml), washed with brine (100 ml), dried over MgO ₄ and concentrated in vacuo. HPLC (3:2 gasoline/EtOAc) gave the title compound, Compound 31, as a colorless oil as a mixture of diastereoisomers (151 mg, 20; MS (ES+) 468.3 [M-(TBDMCOCH ₂ (c-Pr)CH ₂ O)] ⁺ .

Substance 32: 3-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-6-(prop-1-en- 2-yl)isoindoline-1-one

To a solution of 2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(prop-1-en-2-yl)isoindolin-1-one , Substance 13 (2.73 g, 5.37 mmol), in THF (68 ml) was added TBDMSCI (1.62 g, 10.7 mmol) and imidazole (1.10 g, 16.1 mmol), and the resulting the suspension was heated at 85°C for 5 h, then cooled to RT. The mixture was diluted with EtOAc (150 ml), washed with aqueous 0.3 M HCl (150 ml), water (150 ml), brine (150 ml) and dried over MgO ₄ . Purification with HPLC (100% gasoline to 95:5 gasoline/EtOAc) gave the title compound, Substance 32, as a colorless oil (1.12 g, 34%); _λmax (EtOH/nm) 214; IR (cm ^-1 ) 2928, 2855, 1704 (C=O), 1433; ¹ H NMR (500 MHz, CDCl ₃ ) δ -0.11 (3H, s, SiCH ₃ ), -0.09 (3H, s, SiCH ₃ ), 0.00-0.03 (2H, m, 2 x c-PrH), 0.25-0.27 (2H, m, 2 x c-PrH), 0.73 (9H, s, SiC(CH ₃ ) ₃ ), 2.08 (3H, m, CH ₃ ), 2.52 (1H, d, J=9.2 Hz, CHH'), 2.80 (1H, d, J=9.2 Hz, CHH'), 3.27 (1H, d, J =10.3 Hz, C'HH'), 3.56 (1H, d, J=10.3 Hz, C'HH'), 4.22 (1H, d, J=14.7 Hz, NCHH' ), 4.30 (1H, d, J=14.7 Hz, NCHH'), 5.08 (1H, m, alkene-CH), 5.35 (1H, s, alkene-CH'), 6, 94 (1H, d, J=8.0 Hz, ArH), 6.95-7.01 (4H, m, 4 x ArH), 7.05-7.09 (4H, m, 4 x ArH), 7.48 (1H, dd, J=1.7 and 8.0 Hz, ArH), 7.86 (1H, d, J=1.7 Hz, ArH); ¹³ C (125 MHz, CDCl ₃ ) δ -5.2, -5.3, 7.9, 8.1, 18.3, 12.9, 25.9, 42.2, 65.9, 66, 1, 94.3, 114.3, 120.4, 122.8, 128.0, 128.2, 128.4, 130.1, 130.5, 131.6, 133.0, 134.3, 136.0, 137.4, 142.1, 168.3; MS (ES+) 408.3 [M-(TBDMCOCH ₂ (c-Pr)CH ₂ O)] ⁺ .

Substance 33: 3-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-6-(2-methyloxirane-2- yl)isoindoline-1-one

At 0°C, to a solution of 3-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-6-(prop-1 -en-2-yl)isoindolin-1-one, Compound 32 (640 mg, 1.03 mmol), mCPBA (355 mg, 2.05 mmol) was added in DCM (50 ml) and the resulting solution was stirred at RT for for 18 h. The reaction mixture was quenched by adding saturated aqueous NaHCO ₃ (50 ml) and thoroughly stirred for 4 h. The organic layer was separated, washed with brine (50 ml), dried over MgO ₄ and concentrated under vacuum. The crude product, Compound 33, was used in the next step without purification (650 mg). MS (ES+) 422.3 [M-(TBDMCOCH ₂ (c-Pr)CH ₂ O)] ⁺ .

Substance 34: 3-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-6-(1-(dimethylamino)- 2-hydroxypropan-2-yl)isoindolin-1-one

In a sealed vial for a microwave reactor to a solution of 3-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-6-(2 -methyloxiran-2-yl)isoindolin-1-one, Compound 33 (1.08 g, 1.69 mmol), dimethylamine (8.45 ml, 16.9 mmol, 2, 0 M in MeOH), and the resulting solution was heated at 60°C for 4 h, then cooled to RT. The reaction mixture was diluted with water (50 ml), extracted with EtOAc (2×50 ml), washed with brine (100 ml), dried over MgO ₄ and concentrated in vacuo. Purified with Biotage using 0-30% MeOH in EtOAc as eluent to give the title compound as a colorless oil (407 mg, 35%). 1 H NMR (500 MHz, CDCl ₃ ) -0.02 (3H, m), 0.00 (3H, s), 0.03-0.12 (2H, m), 0.34-0.35 (2H , m), 0.83-0.84 (9H, m), 1.51 (3H, s), 2.19 (6H, s), 2.61-2.64 (1H, m), 2, 76-2.83(3H, m), 3.35-3.39(1H, m), 3.63-3.67(1H, m), 4.30-4.40(2H, m), 7.05-7.10(5H, m), 7.15(4H, s), 7.68-7.71(1H, m), 7.91-7.92(1H, m).

Substance 35: (S)-ethyl-3-amino-3-(4-chlorophenyl)propanoate hydrochloride

At 0°C, SOCl ₂ was added dropwise to a solution of s-beta-(p-chlorophenyl)alanine (1.00 g, 5.0 mmol) in EtOH (10 ml), and the resulting solution was heated at 78°C for 1 .5 h. The solution was cooled to RT and concentrated under vacuum to give the title compound, Substance 35, as a white solid (1.31 g, 99%); ¹ H NMR (500 MHz, DMSO) δ 1.08 (3H, t, J=7.1 Hz, CH ₃ ), 3.02 (1H, dd, J=9.5 and 16.1 Hz, CHH' C=O), 3.24 (1H, dd, J=5.4 and 16.1 Hz, CHH'C=O), 3.96-4.01 (2H, m, OCH ₂ ), 4.59 (1H, dd, J=5.4 and 9.5 Hz, NH ₂ CH), 7.49 (2H, d, J=8.5 Hz, 2 x ArH), 7.62 (2H, d, J = 8.5 Hz, 2 x ArH), 8.91 (3H, s br,)

Substance 36; (3S)-Ethyl-3-(5-bromo-1-(4-chlorophenyl)-1-hydroxy-3-oxoisoindolin-2-yl)-3-(4-chlorophenyl)propanoate

From (S)-ethyl-3-amino-3-(4-chlorophenyl)propanoate hydrochloride, Compound 35 was prepared using procedures similar to those described for Compound 9. The product was obtained as a mixture of diastereoisomers. MS (ES+) 546.2 [M-H] ^- .

Compound 37a and 37b: (3S)-Ethyl-3-(5-bromo-1-(4-chlorophenyl)-1-((1-(hydroxymethyl)cyclopropyl)methoxy)-3-oxoisoindolin-2-yl)-3 -(4-chlorophenyl)propanoate

Compounds 37a and 37b were prepared from 3-(5-bromo-1-(4-chlorophenyl)-1-hydroxy-3-oxoisoindolin-2-yl)-3-(4-chlorophenyl)propanoate using procedures similar to those described for Substances 12. Two products were isolated using SiO ₂ chromatography.

37a (S,S): R _f = 0.67 (1:1 EtOAc/gasoline); MS (ES+) 532.2 [M-HOCH ₂ (c-Pr)CH ₂ O] ⁺ .

37b (S,R): R _f = 0.52 (1:1 EtOAc/gasoline); MS (ES+) 530.3 [M-HOCH ₂ (c-Pr)CH ₂ O] ⁺ .

Substance 38: (S)-Ethyl-3-(4-chlorophenyl)-3-((R)-1-(4-chlorophenyl)-1-((1-(hydroxymethyl)cyclopropyl)methoxy)-3-oxo- 5-(prop-1-en-2-yl)isoindolin-2-yl)propanoate

From Substance 37b, Substance 38 was prepared using procedures similar to those described for Substance 13. MS (ES+) 492.4 [M-HOCH ₂ (c-Pr)CH ₂ O] ⁺ .

Substance 39: (S)-Ethyl-3-((R)-5-acetyl-1-(4-chlorophenyl)-1-((1-(hydroxymethyl)cyclopropyl)methoxy)-3-oxoisoindolin-2-yl) -3-(4-chlorophenyl)propanoate

From Substance 38, Substance 39 was prepared using procedures similar to those described for Substance 15. MS (ES+) 494.3 [M-HOCH ₂ (c-Pr)CH ₂ O] ⁺ .

Substance 40: (S)-3-((R)-5-Acetyl-1-(4-chlorophenyl)-1-((1-(hydroxymethyl)cyclopropyl)methoxy)-3-oxoisoindolin-2-yl)-3 -(4-chlorophenyl)propanoic acid

To a solution of (S)-ethyl-3-((R)-5-acetyl-1-(4-chlorophenyl)-1-((1-(hydroxymethyl)cyclopropyl)methoxy)-3-oxoisoindolin-2-yl)- 3-(4-chlorophenyl)propanoate, Compound 39 (130 mg, 0.22 mmol), in THF/water (1.9 ml/3.0 ml) was added LiOH.H ₂ O (183 mg, 4.36 mmol ), and the resulting yellow solution was heated at 60°C for 3 h, then cooled to RT. The solution was acidified to pH 5 with aqueous 1.0 M HCl, extracted with EtOAc (3×25 ml), washed with brine (50 ml), dried over MgO ₄ and concentrated under vacuum. HPLC (1:1 gasoline/EtOAc (0.1% AcOH) to 100% EtOAc (0.1% AcOH)) provided the title compound, Substance 40, as a white solid (85 mg, 68%); MS (ES+) 566.2 [M-H] ^- .

Substance 41: 6-Acetyl-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutoxy)isoindolin-1-one

Compound 41 was prepared from 6-acetyl-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-hydroxyisoindolin-1-one using a procedure similar to that described for Compound 12.

Substance 42: 4-[(Triisopropylsilanyl)ethynyl]-benzylamine

Step 1: (4-chlorobenzyl)-carbamic acid tert-butyl ester

4-Chlorobenzylamine (10.5 ml, 86 mmol) was added to a mixture of Amberlyst 15 resin (1.8 g) and di-tert-butyl dicarbonate (18.5 g, 84.7 mmol) and the reaction mixture was stirred at room temperature for within 3 hours. The crude mixture was diluted with DCM (200 ml) and the catalyst was removed by filtration. The solvent was removed in vacuo to give the desired product as a white solid (18.9 g). MS: [M - C ₄ H ₉ ] ⁺ = 186. ¹ H NMR (400 MHz, CDCl3): 7.38-7.30 (2H, m), 7.23 (2H, d), 4.87 ( 1H, s), 4.29 (2H, s), 1.48 (9H, s).

Step 2: {4-[(triisopropylsilanyl)-ethynyl]-benzyl}-carbamic acid tert-butyl ester

Ethynyltriisopropylsilane (13.4 ml, 94.1 mmol) was added to a suspension of (4-chloro-benzyl)-carbamic acid tert-butyl ester (18.9 g, 78.4 mmol), PdCl ₂ (CH ₃ CN) ₂ ( 202 mg, 0.78 mmol), XPhos (1.1 g, 2.3 mmol) and Cs ₂ CO ₃ (53.6 g, 164.6 mmol) in MeCN (170 ml) and the reaction mixture was stirred under atmosphere N ₂ at 110°C for 20 hours. The reaction mixture was then cooled to room temperature, quenched with water (300 ml) and extracted with EtOAc (2×300 ml). The organic phases were collected, dried over Na ₂ SO ₄ . The reaction mixture was then cooled to room temperature, quenched with water (300 ml) and extracted with EtOAc (2×300 ml). The organic phases were collected, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude material was loaded onto columns (0-20% EtOAc in gasoline gradient) to give 15.7 g of a yellow oil. 1 H NMR (400 MHz, CDCl3): 7.45 (2H, d), 7.23 (2H, d), 4.83 (1H, s), 4.32 (2H, s), 1.48 (9H , s), 1.20-1.11 (21H, m).

Stage 3: 4-[(Triisopropylsilanyl)-ethynyl]-benzylamine

TFA (25 ml, 326 mmol) was added to a solution of {4-[(Triisopropylsilanyl)-ethynyl]-benzyl}-carbamic acid tert-butyl ester (15.6 g, 40.3 mmol) in DCM (50 ml). The reaction mixture was stirred for 16 hours at room temperature and then quenched with water (30 ml) and 2N. NaOH until the solution reaches pH=11. The product was extracted with DCM (3x). The organic phases were collected, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the desired product (12.5 g) as an orange oil. 1 H NMR (400 MHz, CDCl3): 7.46 (2H, d), 7.31-7.24 (2H, m), 3.87 (2H, s), 1.94 (2H, s), 1 .15 (21H, s).

Substance 43: 4-Chloro-2-(methylthio)phenyl)methanamine

To a solution of 4-chloro-2-(methylthio)benzonitrile (500 mg, 2.72 mmol) in dry THF (10 mL) was added slowly the borohydride-THF complex (1M in THF, 13.6 mL, 13.6 mmol) at 0°C, then heated under reflux for 1 h. After cooling, 1 M HCl in MeOH (10 ml) was slowly added under ice-cooling. The solvent was removed by concentration in vacuo, after which water (0.61 mmol/ml to benzonitrile) was added, then washed with Et ₂ O (0.61 mmol/ml to benzonitrile), after which it was basified with 2 M NaOH solution to pH 12. Added Et ₂ O (0.61 mmol/ml to benzonitrile), and the mixture was washed with water (3×0.61 mmol/ml to benzonitrile) and saline (0.4 mol/ml to benzonitrile). The organic layer was dried (MgO ₄ ) and concentrated in vacuo to give the product as a yellow oil (400 mg, 78%). LCMS (ESI ⁺ ) m/z=171.1 [M-NH ₂ ] ⁺ .

Substance 44: (3R)-6-Acetyl-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-3-[(3R)-oxolan-3-yloxy ]-2,3-dihydro-1H-isoindol-1-one

The title compound was obtained using a technique similar to that described in Example 41, Stage 1 and 2; using (3R)-hydroxytetrahydrofuran instead of cyclopropan-1,1-dimethanol. The 3(R) isomer was isolated as the slower moving fraction from Step 1 using preparative chiral HPLC. MS(ES+) m/z 630 [M+H] ⁺ .

Substance 45: Ethyl-(3S)-3-[(1R)-5-acetyl-1-(4-chlorophenyl)-7-fluoro-3-oxo-1-[(3S)-oxolan-3-yloxy]- 2,3-dihydro-1H-isoindol-2-yl]-3-(4-chlorophenyl)propanoate

The title compound was prepared in a similar manner to Comp. 44, but using ethyl-(3S)-3-amino-3-(4-chlorophenyl)propanoate hydrochloride (Compound 35) instead of (4-chloro-2-(methylsulfonyl)phenyl)methanamine and (3S)-hydroxytetrahydrofuran instead of (3R)-hydroxy-tetrahydrofuran. MS(ES+) m/z 598 [M-H] ^-

Substance 46: 2-(4-Chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-methyl-ethyl)benzoic acid

The title compound was prepared in a similar manner to Example 73 and 74, Step 1; but using acetone instead of 1-methyl-1H-pyrazole-4-carboxaldehyde. MS: [M+H] ⁺ = 337.

Substance 47: (2-(Aminomethyl)-5-chlorophenyl)dimethylphosphine oxide

Step 1: 4-Chloro-2-(dimethylphosphoryl)benzonitrile

To a round bottom flask was added 4-chloro-2-iodobenzonitrile (2.5 g, 9.50 mmol), dimethylphosphine oxide (1.12 g, 14.30 mmol), Pd ₂ (dba) ₃ (435 mg, 0.48 mmol ), Xantphos (550 mg, 0.95 mmol), and the flask was purged with N ₂ . The solids were diluted in dioxane (25 ml), triethylamine (2.10 g, 20.9 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. H ₂ O (50 ml) was added to the reaction mixture and aqueous the phase was extracted with EtOAc (2×100 ml). The combined organics were dried (MgO ₄ ), filtered and concentrated in vacuo. The precipitate was purified on a 50 g SNAP column eluting with MeOH in DCM (0 to 10%) to give the title compound (1.07 g at 80% purity). ¹ H NMR (400 MHz, CDCl ₃ ) 8.33-8.29 (1H, m), 7.76-7.73 (1H, m), 7.65-7.62 (1H, m), 1 .96 (6H, d);

Step 2: (2-(Aminomethyl)-5-chlorophenyl)dimethylphosphine oxide

To a solution of 4-chloro-2-(dimethylphosphoryl)benzonitrile (960 mg, 4.50 mmol) in THF (10 ml) under N ₂ was added BH ₃ . THF (23 ml, 23.00 mmol, 1M THF) and the reaction mixture was stirred for 1 hour. The reaction mixture was quenched by careful addition of MeOH (10 ml). The solution was concentrated in vacuo, redissolved in MeOH and loaded into a 10 g SCXII cartridge. The cartridge was washed successively with MeOH (3 column volumes) and then with 2M NH ₃ MeOH (3 column volumes). The ammonia wash was concentrated in vacuo to give the title compound (770 mg). ¹ H NMR (400 MHz, CDCl ₃ ) 7.46-7.41 (3H, m), 4.14 (2H, s), 1.83 (6H, d).

Substance 48: 2-(4-Chlorobenzoyl)-3-fluoro-5-(tetrahydro-2H-pyran-4-carbonyl)benzoic acid

Stage 1 was carried out using a technique similar to that described in Examples 73 and 74; stage 1, but using tetrahydro-2H-pyran-4-carbaldehyde instead of 1-methyl-1H-pyrazole-4-carboxaldehyde. Bu ₂ Mg was also used instead of methylmagnesium chloride. MS: [M+H] ⁺ = 393.

Step 2: 2-(4-Chlorobenzoyl)-3-fluoro-5-(tetrahydro-2H-pyran-4-carbonyl)benzoic acid

2-(4-Chlorobenzoyl)-3-fluoro-5-(hydroxy(tetrahydro-2H-pyran-4-yl)methyl)benzoic acid (17.4 g, 44.4 mmol) was stirred in DCM (400 mL) at RT, then TEMPO (0.69 g, 4.44 mmol) and tetra-n-butylammonium chloride (5.72 g, 17.8 mmol) were added followed by OKCONE®, a monopersulfate compound (30 g, 97.7 mmol ). The reaction mixture was left to stir at RT for 18 hours. TEMPO (0.69 g, 4.44 mmol) was added and the reaction mixture was left to stir at RT for an additional 48 hours. Solids were removed by filtration and the filter cake was washed DCM (2×100 ml). The combined filtrates were concentrated under reduced pressure and the resulting residue was dissolved in EtOAc (500 ml). The combined organic layers were washed with aqueous 2M HCl (2×500 ml) and brine (200 ml), dried (MgO ₄ ), filtered and concentrated to give the title compound as a pale yellow foam (16 g, 92% yield). MS: [M-N] ^- = 389.

Substance 49: 4-[(1R)-1-Amino-2-(prop-2-en-1-yloxy)ethyl]benzonitrile

Step 1: N-[(1R)-1-(4-cyanophenyl)-2-hydroxyethyl]-2,2,2-trifluoroacetamide

TFUA (3.6 ml, 25.2 mmol) was added to a solution of 4-[(1R)-1-amino-2-hydroxyethyl]benzonitrile (5.0 g, 25.2 mmol) in DCM (100 ml) containing TEA (10.9 ml, 75.6 mmol) and the solution was stirred for 10 minutes at room temperature. The reaction mixture was partitioned between DCM and 2N. HCl. The aqueous phase was extracted with DCM (2x) and EtOAc (2x). The organic phases were collected, dried over MgO ₄ , filtered and concentrated in vacuo to give the desired product as a white solid (4.8 g, 74% yield). LCMS: [M-N] ^- = 257.

Stage 2: N-[(1R)-1-(4-cyanophenyl)-2-(prop-2-en-1-yloxy)ethyl]-2,2,2-trifluoroacetamide

NaH (60% dispersion in oil, 1.5 g, 36.9 mmol) was added portionwise to a solution of N-[(1R)-1-(4-cyanophenyl)-2-hydroxyethyl]-2,2,2-trifluoroacetamide (4.76 g, 18.4 mmol) in DMF (15 ml) at 0°C under an inert atmosphere, and the resulting mixture was then stirred for 10 min at room temperature. Then 3-iodoprop-1-ene (1.7 ml, 18.4 mmol) was added dropwise, the reaction mixture was stirred for 10 min at room temperature and then quenched with water. The product was extracted with EtOAc (3x), the organic phase was washed 3x with brine and the solvent was removed in vacuo.The crude material was purified by silica gel flash chromatography (0-30% EtOAc gradient in gasoline) to give the title compound as a colorless liquid (3.5 g, 64% yield).LCMS: [M +H] ⁺ = 299.

Stage 3: 4-[(1R)-1-Amino-2-(prop-2-en-1-yloxy)ethyl]benzonitrile

2 n. NaOH (10 ml) was added to a solution of N-[(1R)-1-(4-cyanophenyl)-2-(prop-2-en-1-yloxy)ethyl]-2,2,2-trifluoroacetamide (3.5 g, 11.7 mmol) in MeOH (10 ml).

The reaction mixture was stirred for 16 hours at room temperature, after which 4 ml of 2N hydrochloric acid was added to the mixture. NaOH, and stirring was continued for another 2 hours at 45°C. The solvent was removed under vacuum, and the residue was divided between EtOAc and NaHCO ₃ . The organic phase was dried over MgO ₄ , filtered and concentrated in vacuo to give 2.3 g (96% yield) of the desired compound as a pale yellow oil. LCMS: [M+H] ⁺ = 203.

Substance 50: 2-(4-Chlorobenzoyl)-3-fluoro-5-(1-methyl-1H-imidazole-4-carbonyl)benzoic acid

Step 1: 2-(4-chloroenzoyl)-3-fluoro-5-(hydroxy(1-methyl-1H-imidazol-4-yl)methyl)benzoic acid

5-Bromo-2-(4-chlorobenzoyl)-3-fluorobenzoic acid (178.25 g; 0.5 mol) was added to a 10 L round bottom flask equipped with an overhead stirrer with a large paddle and anhydrous THF (2610 mL) was added. . This solution was cooled to -5°C<T<0°C, and a 3 M solution of methylmagnesium chloride in THF (183 ml; 0.55 mol) was added dropwise at such a rate that the internal temperature remained below 0°C. After completion of the addition, the mixture was stirred at 0°C for 15 minutes and then cooled to -78°C. A solution of 2.5 M n-butyllithium in hexanes (259 ml; 0.647 mol) was added dropwise at such a rate that the internal temperature remained below -70°C. The reaction mixture became much darker and thicker, eventually acquiring the consistency of a precipitate. After completion of the addition, the mixture was stirred at -78°C for 30 minutes, after which a solution of 1-methyl-1H-imidazole-4-carbaldehyde (71.3 g; 0.648 mol) in anhydrous THF (500 ml) was added dropwise at this speed to keep the internal temperature below -70°C. After completion of the addition, the mixture was stirred at -78°C for 30 minutes, the cooling bath was removed, and the mixture was left to reach room temperature. The mixture was quenched with 1 M HCl, the pH was adjusted to 7 and the whole was evaporated under reduced pressure. The precipitate was divided into 4 equal portions and each portion was chromatographed on silica gel (300 g) eluting with a gradient of 0-30% MeOH in DCM to give the title compound as a yellow solid (151 g; 78%). MS [M+H] ⁺ = 389

Step 2: 2-(4-Chlorobenzoyl)-3-fluoro-5-(1-methyl-1H-imidazole-4-carbonyl)benzoic acid

To a stirred mixture of 2-(4-chlorobenzoyl)-3-fluoro-5-(hydroxy(1-methyl-1H-imidazol-4-yl)methyl)benzoic acid (24.6 g; 63.4 mmol) in 1, 4-dioxane (600 ml) was added activated manganese dioxide (55g; 634 mmol) and the mixture was heated at 110° C. for 1 h. LCMS indicated completion of the reaction. The reaction mixture was cooled, filtered through Celite and GFA filter paper, washed with MeOH. The filtrate and washing precipitate were combined and evaporated under reduced pressure to give a dark solid (24g). MS [M+H] ⁺ = 387.

Substance 51: 3-((allyloxy)methyl)-4-(aminomethyl)benzonitrile hydrochloride (4)

Stage 1: tert-butyl-N-[(2-bromo-4-cyanophenyl)methyl]-N-tert-butoxycarbonylcarbamate (2)

3-Bromo-4-(bromomethyl)benzonitrile (1) (8 g, 29.1 mmol) was dissolved in THF (80 ml) and DMF (80 ml) and the solution was stirred at room temperature under nitrogen atmosphere. Di-tert-butyliminocarboxylate (9.48 g, 43.6 mmol) and potassium carbonate (6.0 g, 43.6 mmol) were added and the reaction mixture was heated at 100° C. overnight. The mixture was diluted with EtOAc (250 ml) and water (250 ml). The organic phase was collected and the aqueous phase was extracted with EtOAc (250 ml). The combined organic extracts were washed with brine (120 ml), dried (MgO ₄ ), filtered and evaporated to dryness. The crude product was purified by trituration with minimal methanol (~20 mL) and the solid was collected by filtration to give the desired product (10.3 g, 86%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ): 7.84 (1H, d), 7.59 (1H, dd), 7.23 (1H, d), 4.88 (2H, s), 1.46 (18H, s)

Stage 2: tert-butyl-N-[[2-(Allyloxymethyl)-4-cyanophenyl]methyl]-N-tert-butoxycarbonylcarbamate (3)

tert-Butyl-N-[(2-bromo-4-cyanophenyl)methyl]-N-tert-butoxycarbonylcarbamate (2) (5 g, 12.1 mmol), RuPhos (0.569 g, 1.21 mmol), [( potassium allyloxy)methyl]trifluoroborate (2.6 g, 14.6 mmol) and cesium carbonate (11.9 g, 36.1 mmol) were dissolved in dioxane (90 ml) and water (10 ml). The mixture was purged with nitrogen for 5 minutes and then palladium acetate (136 mg, 0.61 mmol) was added. The mixture was purged with nitrogen for another 5 minutes and then heated at 100° C. for 24 hours. The mixture was concentrated under reduced pressure and the resulting residue was partitioned between EtOAc (150 ml) and water (150 ml). The organic layer was collected and the aqueous phase was extracted with additional EtOAc (150 ml). The combined organic extracts were passed through a hydrophobic inlet filter on a column and evaporated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (gradient elution with 0 to 20% EtOAc in iso-hexane) to give the pure product (3 0 g, 53%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ): P 7.68 (1H, d), 7.59-7.56 (1H, m), 7.29 (1H, d), 5.99-5.89 (1H, m), 5.35-5.22 (2H, m), 4.86 (2H, s), 4.56 (2H, s), 4.07-4.04 (2H, m), 1.44 (18H, s), 0.95-0.82 (1H, m)

Step 3: 3-((allyloxy)methyl)-4-(aminomethyl)benzonitrile hydrochloride (4)

tert-Butyl-N-[[2-(allyloxymethyl)-4-cyanophenyl]methyl]-N-tert-butoxycarbonylcarbamate (3) (2.6 g, 6.46 mmol) was dissolved in DCM (83 ml) and added 4 n. HCl in dioxane (28.6 ml). The mixture was stirred at room temperature for 4 hours. Solvents were removed under vacuum and any remaining traces of solvents were removed by co-evaporation from chloroform. The desired product (1.6 g) was isolated as a white solid and considered pure enough to be used in subsequent steps. ¹ H NMR (400 MHz, DMSO): 8.51-8.51 (3H, m), 7.93 (1H, dd), 7.88 (1H, d), 7.71 (1H, d), 6.02-5.92(1H, m), 5.33(1H, ddd), 5.22(1H, dd), 4.65(2H, s), 4.16(2H, s), 4 .06 (2H, d);

Substance 52: (S)-2-(4-chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-(tetrahydro-2H-pyran-4-yl)propyl)benzoic acid

Step 1: 2-(4-Chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-(tetrahydro-2H-pyran-4-yl)propyl)benzoic acid

Diethylzinc (62 ml, 1M solution in hexanes, 62.0 mmol) and ethyllithium (36 ml, 1.72 M solution in dibutyl ether, 62.0 mmol) were added to 50 ml of THF at -50° C. under nitrogen atmosphere. The mixture was stirred at -50°C for 1 hour and then 2-(4-chlorobenzoyl)-3-fluoro-5-(tetrahydro-2H-pyran-4-carbonyl)benzoic acid (Substance 48, 9.7 g, 24.0 mmol) as a solution in THF (100 ml). The mixture immediately turned dark orange and the internal temperature reached -22°C. The mixture was stirred at -50° C. for 20 min, after which it was quenched by the slow addition of 2 N sodium hydroxide. HCl (500 ml) (carefully). After stirring for 1 h, the pH was adjusted to 1-2 with 2M HCl and the aqueous phase was extracted with ethyl acetate (200 ml), washed with 2M HCl (75 ml), dried over magnesium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (gradient elution from 0 to 100% EtOAc in isohexane) to give the title compound (9.03 g, 90%) as a colorless foam. MS: [M+H] ⁺ = 421

Step 2: Methyl-(S)-2-(4-chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-(tetrahydro-2H-pyran-4-yl)propyl)benzoate

To a round bottom flask containing crude 2-(4-chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-(tetrahydro-2H-pyran-4-yl)propyl)benzoic acid (6.32 g, 15 mmol ), K ₂ CO ₃ (2.69 g, 19 mmol) and DMF (50 ml) were added methyl iodide (0.934 ml, 16 mmol). The reaction mixture was stirred for 1.5 h at room temperature, after which LCMS showed complete conversion to the desired product. The mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate (150 ml) and washed with water (100 ml) then 4% aqueous LiCl solution (2×100 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated to give a pale yellow foam. The enantiomers were separated by chiral SLC to give the title compound (8.1 g) as a colorless solid.

Methyl-(S)-2-(4-chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-(tetrahydro-2H-pyran-4-yl)propyl)benzoate: Fast moving MS isomer: [M+ H] ⁺ = 435. [α] _D ²⁰ = -1.83 (c 1.0, MeOH).

Methyl-(R)-2-(4-chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-(tetrahydro-2H-pyran-4-yl)propyl)benzoate: MS slow moving isomer: [M+ H] ⁺ = 435. [α] _D ²⁰ = +1.48 (c 1.0, MeOH).

Step 3: (S)-2-(4-Chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-(tetrahydro-2H-pyran-4-yl)propyl)benzoic acid

Methyl-(S)-2-(4-chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-(tetrahydro-2H-pyran-4-yl)propyl)benzoate (8.2 g, 18.86 mmol) was dissolved in THF (250 ml), methanol (30 ml) and water (50 ml). Anhydrous LiOH (2.26 g, 94.3 mmol) was added and the mixture was stirred at room temperature for 2 hours. The resulting solution was concentrated to a volume of about 60 ml, diluted with water (500 ml) and washed with diethyl ether (400 ml). The aqueous layer was then acidified with 2N HCl. HCl and extracted with DCM (3×200 ml). The combined extracts were dried (MgO ₄ ) and evaporated to give the title compound (8.1 g, quant) as a colorless foam. ¹ H NMR (400 MHz, CDCl ₃ ) 7.86 (1H, s), 7.71 (2H, d), 7.49-7.41 (3H, m), 4.05 (1H, dd), 3.98-3.93(1H, m), 3.43-3.28(2H, m), 1.97-1.89(2H, m), 1.77-1.74(1H, m ), 1.52-1.40 (2H, m), 1.20-1.13 (1H, m), 0.75 (3H, dd), OH and COOH were not observed. MS: [M-H ⁺ ] ^- = 419. [α] _D ²⁰ = -2.3 (c 1.0, MeOH).

Substance 52b: (R)-2-(4-chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-(tetrahydro-2H-pyran-4-yl)propyl)benzoic acid

The title compound was prepared in a similar manner to Example 52, but using (R)-2-(4-chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-(tetrahydro-2H-pyran-4-yl)propyl) benzoate in Step 3. MS: [M-H+] ^- = 419. [α] _D ²⁰ = +1.8 (c 10, MeOH).

Substance 53: 2-(4-chlorobenzoyl)-3-fluoro-5-(4-fluorotetrahydro-2H-pyran-4-carbonyl)benzoic acid

Step 1: Ethyl 2-(4-chlorobenzoyl)-3-fluoro-5-(tetrahydro-2H-pyran-4-carbonyl)benzoate

Potassium carbonate ( 54.8 g, 396 mmol) and then iodoethane (26.8 ml, 334 mmol). The mixture was stirred for 18 hours at RT and then evaporated to dryness under reduced pressure. The precipitate was triturated with water (1 L) and the solid was collected by filtration, washing with additional water (3×500 ml). The solid was dissolved in DCM (750 ml), dried (MgO ₄ ), filtered and evaporated under reduced pressure to give the title compound (107 g, 99%) as a pale yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) 8.43 (1H, d), 7.90 (1H, dd), 7.75-7.72 (2H, m), 7.47-7.44 (2H , m), 4.21 (2H, q), 4.11-4.05 (2H, m), 3.63-3.48 (3H, m), 1.97-1.79 (4H, m ), 1.13 (3H, dd).

Step 2: Ethyl 2-(4-chlorobenzoyl)-3-fluoro-5-(4-fluorotetrahydro-2H-pyran-4-carbonyl)benzoate

A three-necked flask was equipped with a nitrogen supply tube, a thermometer, and an addition funnel for pressure equalization. Ethyl 2-(4-chlorobenzoyl)-3-fluoro-5-(tetrahydro-2H-pyran-4-carbonyl)benzoate (54.0 g, 129 mmol) and dry THF (560 ml) were placed in the flask. The mixture was then cooled to -78°C and LHMDS (170 ml, 170 mmol, 1M in THF) was added at a uniform rate so that the internal reaction temperature did not exceed -60°C. The mixture was stirred at -78°C for 20 min, and then a solution of N-fluorobenzenesulfonimide (53.14 g, 169 mmol) in THF (560 ml) was added evenly so that the internal temperature did not exceed -60°C. The mixture was stirred at -78°C for 20 min and then left to warm to room temperature (~1 h). The reaction mixture was quenched with water (500 ml) and then extracted with ethyl acetate (3×250 ml). The combined organic extracts were dried (MgO ₄ ), filtered and evaporated under reduced pressure to give a crude residue which was purified by silica gel column chromatography (340 g cartridge, gradient elution with 0 to 40% EtOAc in isohexane) to give the title compound (46 .2 g, 82%) as a colorless solid. MS: [M+H] ⁺ = 437.

Step 3: 2-(4-Chlorobenzoyl)-3-fluoro-5-(4-fluorotetrahydro-2H-pyran-4-carbonyl)benzoic acid

To 2-(4-chlorobenzoyl)-3-fluoro-5-(4-fluorotetrahydro-2H-pyran-4-carbonyl)benzoate (46.2 g, 105 mmol) in THF (260 ml) and methanol (260 ml) 2M NaOH solution (530 ml) was added. The resulting orange solution was stirred at room temperature for 1 hour. Diethyl ether (500 ml) was added and the layers were separated. The aqueous phase was adjusted to pH 1 with concentrated HCl and the resulting mixture was extracted with ethyl acetate (2×500 ml). The combined organic extracts were dried (MgO ₄ ), filtered and evaporated under reduced pressure to give the title compound (37.4 g, 87%) as a colorless solid. The product was considered pure enough to be used in the next step. ¹ H NMR (400 MHz, CDCl ₃ ) 8.62 (1H, s), 8.08 (1H, dd), 7.71 (2H, d), 7.46-7.43 (2H, m), 4.01-3.84(4H, m), 2.41-2.22(2H, m), 2.04-1.96(2H, m).

Substance 54: (R)-2-(4-chlorobenzoyl)-3-fluoro-5-(1-(4-fluorotetrahydro-2H-pyran-4-yl)-1-hydroxypropyl)benzoic acid

From 2-(4-chlorobenzoyl)-3-fluoro-5-(4-fluorotetrahydro-2H-pyran-4-carbonyl)benzoic acid (Compound 53). The title compound was prepared using procedures similar to those described for Compound 52. ¹ H NMR (400 MHz, CDCl ₃ ) 7.97 (1H, s), 7.71 (2H, d), 7.57 (1H, d), 7.43 (2H, d), 3.86 (2H , ddd), 3.71-3.59 (3H, m), 2.28-2.18 (1H, m), 2.03-1.60 (5H, m), 0.76 (3H, t ). [α] _D ²⁰ = +16.06 (from 1.04, MeOH).

Substance 55: 2-(4-Chlorobenzoyl)-5-(cyclobutanecarbonyl)-3-fluorobenzoic acid

The title compound was prepared from cyclobutylaldehyde using procedures similar to those described in Example 73 steps 1 and 2. MS: [M-H] ^- = 359

Substance 56: trans-4-((tert-butyldiphenylsilyl)oxy)cyclohexanecarbaldehyde

Stage 1: trans-4-Hydroxy-N-methoxy-N-methylcyclohexanecarboxamide

DIPEA ( 91 ml, 520 mmol) and the mixture was stirred for 20 h. aqueous HCl (50 ml), separated with water (400 ml), the layers were shaken and separated, the aqueous layer was re-extracted with DCM (2×150 ml). The combined organic extracts were dried (MgO ₄ ), filtered and concentrated under reduced pressure to give the desired product (21 g) as a thick pale yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) 3.70 (3H, s), 3.68-3.59 (1H, m), 3.18 (3H, s), 2.70-2.55 (1H , m), 2.10-2.02 (2H, m), 1.88-1.80 (2H, m), 1.63-1.53 (2H, m), 1.38-1.26 (2Н, m), OH is absent.

Stage 2: trans-4-((tert-butyldiphenylsilyl)oxy)-N-methoxy-N-methylcyclohexane-1-carboxamide

Grans-4-hydroxy-N-methoxy-N-methylcyclohexanecarboxamide (12.2 g, 65 mmol) was dissolved in DMF (200 ml) and stirred at room temperature under nitrogen atmosphere. tert-Butyl(chloro)diphenylsilane (19.7 g, 71 mmol) was added followed by imidazole (4.88 g, 71 mmol). The reaction mixture was stirred for 18 hours. DMF was evaporated under reduced pressure and the resulting residue was redissolved in EtOAc (250 ml). The organic layer was washed with 4% LiCl aqueous solution (2×150 ml) and then dried (MgO4), filtered, and evaporated under reduced pressure. The crude residue was purified by silica gel column chromatography (gradient elution from 0 to 60% EtOAc in iso-hexane) to give the pure product as a colorless oil which crystallized after settling (19.0 g, 69% yield). MS: [M+H] ⁺ = 426.

Stage 3: trans-4-((tert-butyldiphenylsilyl)oxy)cyclohexanecarbaldehyde

Trans-4-((tert-butyldiphenylsilyl)oxy)-N-methoxy-N-methylcyclohexanecarboxamide (0.5 g, 1.17 mmol) was dissolved in dry THF (7.5 ml) under nitrogen atmosphere. The solution was cooled to -78° C. and then DIBAL (1M in hexane, 2.11 ml, 2.11 mmol) was added dropwise. The mixture was stirred at -78° C. for 1.5 h and then quenched with 10% aqueous potassium sodium tartrate solution (10 ml). The mixture was allowed to warm to room temperature and then further diluted with EtOAc (40 ml) and potassium sodium tartrate solution (15 ml). The mixture was stirred for 20 minutes, after which it was transferred to a separating funnel. The organic phase was collected and the aqueous phase was extracted with EtOAc (2×30 ml). The combined organic extracts were dried (MgO ₄ ), filtered and evaporated under reduced pressure to give a crude precipitate which was used in the next step without further purification. ¹ H NMR (400 MHz, CDCl ₃ ) 9.56 (1H, s), 7.67-7.65 (4H, m), 7.43-7.34 (6H, m), 3.64-3 .55 (1H, m), 2.20-2.13 (1H, m), 1.95-1.80 (4H, m), 1.48-1.37 (2H, m), 1.28 -1.20 (2H, m), 1.05 (9H, s).

Substance 57: (-)-5-(1-(1-(tert-Butoxycarbonyl)-4-fluoropiperidin-4-yl)-1-hydroxypropyl)-2-(4-chlorobenzoyl)-3-fluorobenzoic acid (*both isomers were separated and isolated)

Step 1: 5-(1-(tert-butoxycarbonyl)-4-fluoropiperidine-4-carbonyl)-2-(4-chlorobenzoyl)-3-fluorobenzoic acid

A mixture of 5-(1-(tert-butoxycarbonyl)piperidine-4-carbonyl)-2-(4-chlorobenzoyl)-3-fluorobenzoic acid (Example 80, step 2, 50 g, 0.102 mol) and NaOH (4.32 g , 0.108 mol) was stirred in anhydrous THF (250 ml) and anhydrous MeOH (90 ml) until all NaOH was dissolved. The solution was evaporated under reduced pressure and the residue was dissolved in anhydrous THF (400 ml) and added over 1 minute to a stirred solution of 1M LHMDS in hexanes (125 ml) in anhydrous THF (100 ml) at -40° C. under nitrogen. The mixture was stirred for 20 minutes at -40° C. before a solution of N-fluorobenzenesulfonimide (48.6 g, 0.154 mol) in anhydrous THF (400 ml) was added in a steady stream over 1 minute. After completion of the addition, the mixture was stirred with cooling in a -40° C. bath for 20 minutes. The mixture was quenched with water (500 ml), stirred at room temperature for 30 minutes, the pH was adjusted to pH 2 with 2N hydrochloric acid. HCl, and then the aqueous phase was extracted with EtOAc (2×750 ml). The combined organics were dried (MgO ₄ ) and the solvent was evaporated. The precipitate was triturated with DCM (500 ml) and the solid was filtered, washed with DCM and dried to give the title compound as a colorless solid (31.3 g, 60%). MS [M-N] ^- = 506.

Step 2: (-)-5-(1-(1-(tert-butoxycarbonyl)-4-fluoropiperidin-4-yl)-1-hydroxypropyl)-2-(4-chlorobenzoyl)-3-fluorobenzoic acid

To anhydrous THF (130 ml) at -50° C. under nitrogen atmosphere was added a 1.72 M solution of EtLi in dibutyl ether (38.4 ml, 65.96 mmol) and then 1 M diethylzinc in hexanes (66.4 ml). The mixture was stirred at -50°C for 70 minutes before adding a solution of 5-(1-(tert-butoxycarbonyl)-4-fluoropiperidine-4-carbonyl)-2-(4-chlorobenzoyl)-3-fluorobenzoic acid (13.4 g, 26.38 mmol) in anhydrous THF (130 ml) in a gentle stream over 1 minute. After the addition was complete, the mixture was stirred at -50° C. for 20 minutes, quenched with careful addition of water (200 ml), warmed to room temperature, acidified with 1M HCl and extracted with EtOAc (2×500 ml). The combined extracts were dried (MgO ₄ ) and the solvent was evaporated under reduced pressure. The precipitate was triturated with isohexane (500 ml), the solvent was poured into another vessel and the colorless solid was dried to give the title compound as a racemate. (13.9 g, 99%). MS [M-H] ^- = 536. The racemate (11.2 g) was separated by SLC to give the title compound as the slow moving isomer (5.11 g, 45% yield).

(+)-5-(1-(1-(tert-butoxycarbonyl)-4-fluoropiperidin-4-yl)-1-hydroxypropyl)-2-(4-chlorobenzoyl)-3-fluorobenzoic acid: Fast moving isomer* ¹ H NMR (400 MHz, CDCl ₃ ) 7.97 (1H, s), 7.72 (2H, d), 7.54 (1H, d), 7.43 (2H, d), 4.01-4 .01 (2H, m), 3.00-2.89 (2H, m), 2.28-2.19 (1H, m), 2.08-1.98 (2H, m), 1.81 -1.50 (3H, m), 1.43 (9H, s), 0.75 (3H, dd), no exchangeable protons were observed. [α] _D ²⁰ = +31.41° (s 1, MeOH).

(-)-5-(1-(1-(tert-butoxycarbonyl)-4-fluoropiperidin-4-yl)-1-hydroxypropyl)-2-(4-chlorobenzoyl)-3-fluorobenzoic acid: Slow moving isomer* ¹ H NMR (400 MHz, CDCl ₃ ) 7.97 (1H, s), 7.72 (2H, d), 7.54 (1H, d), 7.43 (2H, d), 4.01-4 .01 (2H, m), 3.00-2.89 (2H, m), 2.28-2.19 (1H, m), 2.08-1.98 (2H, m), 1.81 -1.50 (3H, m), 1.43 (9H, s), 0.75 (3H, dd), no exchangeable protons were observed. [α] _D ²⁰ = -31.33° (with 1, MeOH).

Substance 58: (2-Bromo-4-methylphenyl)methanamine

Received received in a manner similar to that described in Example 33, Stage 1; from 2-bromo-4-methylbenzonitrile. ¹ H NMR (400 MHz, CDCl ₃ ) 7.37 (1H, s), 7.25 (1H, d), 7.08 (1H, d), 3.86 (2H, s), 2.31 ( 3H, s).

Substance 59: (2-Bromo-4-methoxyphenyl)methanamine

Received in a manner similar to that described in Example 33, Stage 1; from 2-bromo-4-methylbenzonitrile. ¹ H NMR (400 MHz, CDCl ₃ ) 7.26 (1H, d), 7.11 (1H, d), 6.84 (1H, dd), 3.85 (2H, s), 3.79 ( 3H, s), 1.5 (2H, brs).

Substance 60: (S)-5-(1-(1-(tert-Butoxycarbonyl)piperidin-4-yl)-1-hydroxypropyl)-2-(4-chlorobenzoyl)-3-fluorobenzoic acid

Stages 1-2. From piperidine ketone (Examples 80 and 81, Step 2, 11.0 g, 23 mmol), Steps 1 and 2 were performed using a procedure similar to that described for Compound 52, Step 1-2, The racemic mixture was separated by chiral SLC to give (-)-tert-butyl-(S)-4-(1-(4-(4-chlorobenzoyl)-3-fluoro-5-(methoxycarbonyl)phenyl)-1-hydroxypropyl)piperidine-1-carboxylate (3 g ). MS: [M+H] ⁺ =534, [α] _D20 =-34.15 (c 1.18, MeOH) ^.

And

(+)-tert-butyl-(S)-4-(1-(4-(4-chlorobenzoyl)-3-fluoro-5-(methoxycarbonyl)phenyl)-1-hydroxypropyl)piperidine-1-carboxylate (3, 6 g). MS: [M+H] ⁺ =534, [α] _D20 =+24.46 (c 1.02, MeOH) ^.

Step 3: (S)-5-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1-hydroxypropyl)-2-(4-chlorobenzoyl)-3-fluorobenzoic acid

Using procedures similar to those described for Compound 52, step 3, from (-)-tert-butyl-(S)-4-(1-(4-(4-chlorobenzoyl)-3-fluoro-5-(methoxycarbonyl) phenyl)-1-hydroxypropyl)piperidine-1-carboxylate (3.0 g, 5.6 mmol) gave 3.1 g of the title compound. MS: [M+H] ⁺ =518, [α] _D20 =-37.51 (0.97 g/100 ml) ^.

Substance 61: 2-(4-Chlorobenzoyl)-3-fluoro-5-(pyridine-2-carbonyl)benzoic acid

The title compound was prepared using procedures similar to those described in Example 73 (step 1-2) but using pyridine-2-carboxaldehyde in step 1. As alternative oxidation conditions in step 2, iodine (2 mol. equiv.) was used, K ₂ CO ₃ (2 mol. equiv.), Ki (0.25 mol. equiv.) in water (90 ° C). MS: [M+H] ⁺ =384.

Substance 62: Prop-2-en-1-yl-(2S,3S)-3-amino-3-(4-chlorophenyl)-2-methylpropanoate

Step 1: N-[(1Z)-(4-Chlorophenyl)methylidene]-2-methylpropane-2-(R)sulfinamide. (R)-2-methylpropane-2-sulfinamide (18.1 g, 150 mmol), 4-chlorobenzaldehyde (20.0 g, 143 mmol) and Cs ₂ CO ₃ (51.0 g, 157 mmol) were suspended in DCM (150 ml) and stirred at room temperature for 16 hours. The mixture was then filtered through Celite and the volatiles removed in vacuo to give the desired product as a white solid (26.0 g, 75% yield). LCMS: [M+H] ⁺ =244.

Step 2: (4-Methoxyphenyl)methyl-(2S,3S)-3-(4-chlorophenyl)-2-methyl-3-[(2-methylpropan-2-(R)-sulfinyl)amino]propanoate. n-BuLi (2.5 M in hexane, 16.8 ml, 45 mol) was slowly added to a solution of diisopropylamine (6.3 ml, 45 mmol) in THF (20 ml) at 0°C and the reaction mixture was stirred for 30 min. at the same temperature. The mixture was then cooled to -78°C and slowly added, (4-methoxyphenyl)methylpropanoate (7.2 ml, 40 mmol) while maintaining the temperature below -70°C. After 30 min. chlorotriisopropoxytitanium(IV) (1M in hexane, 80 ml, 84 mmol) was added to the reaction mixture and stirring was continued for another 30 minutes. at -78°C. Finally a solution of N-[(1Z)-(4-chlorophenyl)methylidene]-2-methylpropane-2-(R)sulfinamide (5.0 g, 20 mmol) in THF (15 mL) was added slowly and the reaction mixture stirred for another 2 h at -78°C. NH ₄ Cl (aq.), water and EtOAc were added to the reaction mixture, the mixture was warmed to room temperature and stirred thoroughly for 30 minutes. to dissolve most of the solid. The organic phase was separated and the aqueous phase was extracted with EtOAc (3x). The organic phases were collected, dried over Na ₂ SO ₄ and concentrated in vacuo. The precipitate was purified using silica gel columns (0-100% EtOAc in gasoline gradient) to give the desired product as a yellow oil (5.1 g, 58% yield). 1H NMR (400 MHz, DMSO-d6): 7.39-7.27 (2H, m), 7.24 (2H, d), 7.00 (2H, t), 6.91-6.80 ( 2H, m), 5.72-5.63(1H, m), 4.88-4.73(2H, m), 4.24(1H, t), 3.75(3H, s), 2 .99-2.87 (1H, m), 1.28 (3H, d), 1.02-0.90 (9H, m).

Step 3: (2S,3S)-3-(4-Chlorophenyl)-2-methyl-3-[(2-methylpropan-2-(R)-sulfinyl)amino]propanoic acid. TFA (12 ml) was added to a solution of (4-methoxyphenyl)methyl-(2S,3S)-3-(4-chlorophenyl)-2-methyl-3-[(2-methylpropane-2-(R)-sulfinyl)amino ]propanoate (6.0 g, 13.7 mmol) in DCM (20 ml) and the reaction mixture was stirred at room temperature for 1 h. The volatiles were removed in vacuo and the residue was partitioned between 1M HCl and EtOAc. The aqueous phase was extracted with EtOAc (3x), the organic phases were collected, dried over Na ₂ SO ₄ and concentrated under vacuum to obtain the desired product as a light brown solid, which was used in the next step without further purification. LCMS: [M+H] ⁺ =318.

Step 4: Prop-2-en-1-yl-(2S,3S)-3-(4-chlorophenyl)-2-methyl-3-[(2-methylpropan-2-(R)-sulfinyl)amino]propanoate . Allyl bromide (2.3 ml, 26 mmol) was added to a suspension of (2S,3S)-3-(4-chlorophenyl)-2-methyl-3-[(2-methylpropan-2-(R)-sulfinyl)amino]propanoic acid (impure from the previous step, approx. 13 mmol) and K ₂ CO ₃ (5.4 g, 39 mmol) in DMF. The reaction mixture was stirred at room temperature for 2 h, quenched with water and extracted with EtOAc. The organic matter was dried over Na ₂ SO ₄ and concentrated under vacuum. The precipitate was purified using silica gel columns (0-100% EtOAc in gasoline gradient) to give the desired product as a yellow oil (2.8g, 57% yield over 2 steps). 1H NMR (400 MHz, DMSO-d6): 7.40-7.32 (2H, m), 7.29 (2H, d), 5.74-5.58 (2H, m), 5.15- 5.02(2H, m), 4.41-4.31(2H, m), 4.27(1H, t), 3.00-2.88(1H, m), 1.28(3H, d), 1.01 (9H, s).

Step 5: Prop-2-en-1-yl-(2S,3S)-3-amino-3-(4-chlorophenyl)-2-methylpropanoate. HCl (4M in dioxane, 15 ml) was added to a solution of prop-2-en-1-yl-(2S,3S)-3-(4-chlorophenyl)-2-methyl-3-[(2-methylpropan-2- (R)-sulfinyl)amino]propanoate (2.8 g, 7.8 mmol) in EtOH (20 mL) and the suspension was stirred at room temperature for 30 minutes. The volatiles were removed under vacuum and the residue was partitioned between NaHCO ₃ and EtOAc. The organic matter was collected, dried over Na ₂ SO ₄ and concentrated in vacuo to give the desired product as a yellow oil (1.7 g, 86% yield). 1H NMR (400 MHz, DMSO-d6): 7.34 (4H, s), 5.81-5.68 (1H, m), 5.22-5.06 (2H, m), 4.46- 4.33(2H, m), 4.07-3.94(1H, m), 2.76-2.60(1H, m), 1.96(2H, s), 1.09(3H, d).

Substance 63: Ethyl 2-[2-(aminomethyl)-5-chlorophenoxy]acetate hydrochloride

Stage 1: tert-butyl-N-[(4-chloro-2-hydroxyphenyl)methyl]carbamate

To a stirred solution of 4-chloro-2-hydroxybenzonitrile (1.57 g, 10.0 mmol) in dry methanol (70 ml) cooled to 0°C was added Boc ₂ O (4.36 g, 20.0 mmol) and NiCl ₂ ⋅6H ₂ O (0.24 g, 1.0 mmol). NaBH ₄ (2.65 g, 70.0 mmol) was then added in small portions over 30 minutes. The reaction was exothermic and proceeded with evolution of gas. The resulting reaction mixture, containing a fine black precipitate, was allowed to warm to room temperature and allowed to stir for another 1 h, after which diethylenetriamine (1.1 mL, 20.0 mmol) was added. The mixture was allowed to stir for 30 minutes before the solvent was evaporated. The precipitate was dissolved in DCM (50 ml), piperidine (2 ml) was added and stirred for 30 minutes, then the organic phase was washed with water and saturated NaHCO ₃ . The organic layer was dried (MgO ₄ ) and the solvent was removed in vacuo and the crude product was purified by column chromatography to give the title compound (1.47 g, 57%). MS: [M+H] ⁺ =256.

Step 2: Ethyl 2-[2-({[(tert-butoxy)carbonyl]amino}methyl)-5-chlorophenoxy]acetate

K ₂ CO ₃ (0.95 g, 6 .9 mmol) and the mixture was stirred for 30 min. Ethyl bromoacetate (1.4 ml, 8.55 mmol) was added and stirring was continued for 2 h. Water was added, the reaction mixture was extracted with EtOAc, the organic phase was washed with brine (3X), dried and the solvent was evaporated. The crude material was purified by column chromatography eluting with petroleum ether-EtOAc 0-40% to give the title compound (1.64 g, 84%). MS: [M+H] ⁺ =243 (M-Boc).

Step 3: Ethyl 2-[2-(aminomethyl)-5-chlorophenoxy]acetate hydrochloride

To a solution of ethyl 2-[2-({[(tert-butoxy)carbonyl]amino}methyl)-5-chlorophenoxy]acetate (1.8 g, 5.25 mmol) in dioxane (20 ml) was added 4M dioxane - HCl and the mixture was stirred for 16 h. The solvent was evaporated to give a white solid (1.3 g, 89%). MS: [M+H] ⁺ =244.

Compound 64: 2-(4-chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-trans-4-hydroxycyclohexyl)propyl)benzoic acid (*both isomers were separated and isolated)

Stage 1: 5-(trans-4-((tert-butyldiphenylsilyl)oxy)cyclohexane-1-carbonyl)-2-(4-chlorobenzoyl)-3-fluorobenzoic acid

From trans-4-((tert-butyldiphenylsilyl)oxy)cyclohexanecarbaldehyde (Compound 56), the title compound was prepared using procedures similar to those described in Example 73, steps 1 and 2. MS: [MH] ^- =641.

Stage 2: 5-(1-(trans-4-((tert-butyldiphenylsilyl)oxy)cyclohexyl)-1-hydroxypropyl)-2-(4-chlorobenzoyl)-3-fluorobenzoic acid

The title compound was prepared using the procedure described for Compound 52, step 1, and the enantiomers were separated by chiral SLC.

(+)-5-(1-(trans-4-((tert-6utildiphenylsilyl)oxy)cyclohexyl)-1-hydroxypropyl)-2-(4-chlorobenzoyl)-3-fluorobenzoic acid: *fast moving ¹ H NMR isomer (400 MHz, CDCl ₃ ) 7.8 (1H, s), 7.70-7.63 (6H, m), 7.43-7.34 (9H, m), 3.55-3.46 ( 1H, m), 1.94-1.78(5H, m), 1.43-1.24(3H, m), 1.03(9H, s), 0.96-0.83(3H, m), 0.69 (3H, t) Exchangeable was not observed. MS: [MH] ^- =671. [α] _D ²⁰ =+27.65 (with 1.0 MeOH).

(-)-5-(1-(trans-4-((tert-butyldiphenylsilyl)oxy)cyclohexyl)-1-hydroxypropyl)-2-(4-chlorobenzoyl)-3-fluorobenzoic acid: *slow moving ¹ H NMR isomer (400 MHz, CDCl ₃ ) 7.79 (1H, s), 7.70-7.63 (6H, m), 7.44-7.33 (9H, m), 3.54-3.48 ( 1H, m), 1.96-1.75(5H, m), 1.46-1.16(3H, m), 1.03(9H, s), 0.96-0.85(3H, m), 0.69 (3H, t) Exchangeable was not observed. MS: [MH] ^- =671. [α] _D ²⁰ = -24.62 (c 1.0, MeOH).

Step 3: 2-(4-chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-trans-4-hydroxycyclohexyl)propyl)benzoic acid

(-)-5-1-(trans-4-((tert-butyldiphenylsilyl)oxy)cyclohexyl)-1-hydroxypropyl)-2-(4-chlorobenzoyl)-3-fluorobenzoic acid (3.5 g, 5.2 mmol) was dissolved in THF (70 ml) and the mixture was treated with TBAF (1M in THF, 20.7 ml, 20.7 mmol) and heated overnight at 60°C. The reaction mixture was quenched with saturated aqueous NaHCO ₃ and was extracted with ethyl acetate (2×75 ml). The combined organic layers were dried (MgO ₄ ), filtered and evaporated to dryness under reduced pressure to give the crude product. The residue was purified by column chromatography (gradient elution, 20 to 100% ethyl acetate in isohexane (with 0.1% formic acid)) to give the title compound (1.92 g, 85%) as a colorless oil. MS: [MH] ^- =433.

Substance 65: 2-(4-chlorobenzoyl)-3-fluoro-5-(1-methyl-1H-pyrazole-3-carbonyl)benzoic acid

The title compound was prepared using procedures similar to those described in Example 72, Step 1 and Step 2, but using 1-methyl-1H-pyrazole-3-carbaldehyde instead of 1-methyl-1H-pyrazole-4-carboxaldehyde in step 1; and manganese dioxide in 1,4-dioxane at 100°C instead of TEMPO/sodium hypochlorite in step 2. MS [M+H] ⁺ =387

Example 1: (3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-6-(2-hydroxypropan-2-yl )-2,3-dihydro-1H-isoindol-1-one

To a solution of MeMgBr (3M THF, 0.97 ml, 2.91 mmol) in THF (4.0 ml) at room temperature was added Zn(II)Cl ₂ (30 mg, 0.22 mmol) and the resulting solution was stirred at this temperature for 1 hour. The solution was cooled to 0°C before adding a cool solution of 6-acetyl-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-((3'-(hydroxymethyl)cyclopropyl)methoxy)isoindolin-1-one ( Substance 15) (573 mg, 1.12 mmol) in THF (4.0 ml), and the resulting mixture was stirred at 0°C for 2 hours. The reaction mixture was quenched by adding a saturated solution of NH ₄ Cl, and the resulting mixture was extracted with EtOAc (x3). The combined organic phases were washed with brine, dried (MgO ₄ ), filtered and concentrated in vacuo. Purification on silica gel (Biotage SP4) eluting with 20% → 80% EtOAc/Pet gave the product as a clear gum (320 mg; 54%). Separation by chiral HPLC (Chrialpak IA 250×10 mm id, 75% heptane, 2-propanol, 4.5 ml/min) gave the title compound (Example 1) (R)-2-(4-Chlorobenzyl)-3 -(4-chlorophenyl)-3-((3'-(hydroxymethyl)cyclopropyl)methoxy)-6-(2-hydroxypropan-2-yl)isoindolin-1-one. δ _H (500 MHz, CD ₃ OD) 0.12-0.23 (2H, m, 3'-CH ₂ ), 0.37-0.45 (2H, m, 3'-CH ₂ ' 1.56 (6H, s, (CH ₃ ) ₂ ), 2.76 (1H, d, J=9.0, 2'-H), 2.88 (1H, d, J=9.0, 2'-H '), 3.42 (1H, d, J=11.2, 4'-H), 3.58 (1H, d, J=11.2, 4'-H'), 4.40 (1H, d, J=15.1, N-CH), 4.45 (1H, d, J=15.1, N-CH'), 7.07-7.14 (4H, m, Ar-H), 7.15-7.22 (5H, m, Ar-H & 4-H), 7.76 (1H, dd, J=1.2, 8.1, 5-H), 8.02 (1H, d, J=1.2, 7-H); HRMS, Detect; M ⁺ 526, 1540/..

Example 2: (3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-4-fluoro-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-6-(2-hydroxypropane -2-yl)-2,3-dihydro-1H-isoindol-1-one

Hg(OAc) ₂ (145 mg, 0.456 mmol) and water (0.3 ml) were added to the microwave vial. After stirring for 15 min, THF (0.25 ml) was added followed by a solution of 2-(4-chlorobenzyl)-3-(4-chlorophenyl)-4-fluoro-3-((1-(hydroxymethyl)cyclopropyl)methoxy) -6-(prop-1-en-2-yl)isoindolin-1-one (Compound 14) (150 mg, 0.285 mmol) in THF (0.5 ml). The orange solution was stirred at room temperature for 1.5 h, after which perchloric acid (60%, 7.5 μl) was added, the orange color turning to yellow after 2.5 h. 1M aq. NaOH (0.8 ml) and the solution turned brown, then NaBH ₄ (22 mg, 0.570 mmol) was added and the color changed to mellac grey. The reaction mixture was allowed to stir for 16 h, then filtered through ^Celite® and then a thiol cartridge, and the solvent was removed under vacuum. FCC [petrol-ethyl acetate (100:0)→(80:20)→(50:50)→(20:80)] crude precipitate followed by preparative HPLC gave 28 mg, 20%, white solid. Separation of the two enantiomers was carried out by preparative chiral HPLC to give (R)-2-(4-Chlorobenzyl)-3-(4-chlorophenyl)-4-fluoro-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-6- (2-hydroxypropan-2-yl)isoindolin-1-one (Example 2). ¹ H NMR (500 MHz, CDCl ₃ ): 7.77 (1H, d, 7-H), 7.37 (1H, dd, ArH), 7.20-7.26 (4H, m, 4×ArH ), 7.10-7.16 (4H, m, 4×ArH), 4.55 (1H, d, NC-H'), 4.11 (1H, d, NC-H), 3.53 ( 1H, d, 4'-H'), 3.34 (1H, d, 4'-H), 2.96 (1H, d, 2'-H'), 2.69 (1H, d, 2' -H), 1.55-1.64 (6H, 2×s, 2×CH ₃ ), 0.37-0.44 (2H, m, Cy-Py-H ₂ ) and 0.08-0. 23 (2H, m, Su-Ru-H). MS: [M-C ₅ H ₉ O ₂ ] ⁺ 442

Example 3: (3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-3-(2-hydroxyethoxy)-6-(2-hydroxypropan-2-yl)-2,3- dihydro-1H-isoindol-1-one

The title compound was prepared from (Compound 21) (0.062 g, 0.128 mmol), ZnCl ₂ (0.005 g, 0.035 mmol) and MeMgCl (3M in THF) (0.15 ml, 0.46 mmol) using a procedure similar to that described in Example 1. The product was obtained as a white solid foaming substance (0.030 g, 0.062 mmol, 47%). Separation by chiral preparative HPLC yielded Example 3. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm) 1.50 (s, 1H), 1.62 (s, 6H), 1.82 (s, 1H ), 2.77-2.83 (m, 1H), 2.87-2.95 (m, 1H), 3.33-3.47 (m, 2H), 4.08 (d, 1H), 4.64 (d, 1H), 7.09 (dd, 1H), 7.13-7.20 (m, 4H), 7.20-7.25 (m, 4H), 7.71 (dd, 1H), 8.0 (d, 1H); MS(ES+) m/z 486.3 [M+H] ⁺ ;

Example 4: (3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-3-{[3-(hydroxymethyl)oxetan-3-yl]methoxy}-6-(2-hydroxypropane -2-yl)-2,3-dihydro-1H-isoindol-1-one

From Substance 23. The title compound was obtained in a similar manner to Example 1, but using 4.5 mol. equiv. MeMgCl. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm) 1.60 (s, 1H, OH), 1.62 (s, 3H, C(CH ₃ ) ₂ ), 1.63 (s, 3H, C (CH ₃ ) ₂ ), 1.92 (s, 1H, OH), 2.99 (d, 1H, J=9.2 Hz, OCHHC), 3.03 (d, 1H, J=9.2 Hz , OCHHC), 3.67-3.75 (m, 2H, CCH ₂ OH), 4.18 (d, 1H, J=15.2 Hz, NCHH), 4.25 (d, 1H, J=6 .3 Hz, oxetane CHH), 4.30 (d, 1H, J=6.2 Hz, oxetane CHH), 4.33 (d, 1H, J=6.3 Hz, oxetane CHH), 4.36 ( d, 1H, J=6.2 Hz, oxetane CHH), 4.56 (d, 1H, J=15.2 Hz, NCHH), 7.07 (d, 1H, J=7.9 Hz, isoindolinone- H), 7.09-7.19 (m, 6H, Ar-H), 7.22 (d, 2H, J=8.9 Hz, Ar-H), 7.73 (dd, 1H, J= 8.0, 1.7 Hz, isoindolinone-H), 8.03 (d, 1H, J=1.7 Hz, isoindolinone-H);; MS(ES+) m/z 586.3 [M+HCOO ^- ] ^- ;

Example 5: 1-({[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-5-(2-hydroxypropan-2-yl)-3-oxo-2,3 -dihydro-1H-isoindol-1-yl]oxy}methyl)cyclopropane-1-carboxylic acid

To a solution of 2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(2-hydroxypropan-2-yl)isoindolin-1-one (Example 1) (110 mg, 0.21 mmol), RuCl ₃ ⋅H ₂ O (10 mg, 0.02 mmol) in a mixture of EtOAc (0.7 mmol / ml alcohol), MeCN (0.7 mmol / ml alcohol) and water (0.4 mmol/ml alcohol), sodium periodate (4.1 mol. equiv.) was added and stirred at RT for 15 min, after which it was diluted with EtOAc (0.04 mmol/ml alcohol) and filtered through a layer of celita. The filtrates were washed with water (0.04 mmol/ml alcohol) and the aqueous phase was extracted with EtOAc (2×0.04 mmol/ml alcohol). The combined organic phases were washed with brine (0.02 mmol/ml alcohol), dried (MgO ₄ ) and concentrated in vacuo, sodium periodate (185 mg, 0.86 mmol), MeCN (0.6 ml), EtOAc (0 .6 ml) and water (1.0 ml). Purification (SP4, silica gel, EtOAc/gasoline (0.1% AcOH), 60%) followed by semi-preparative chiral HPLC (C-18 silica gel, MeCN/0.1% aq. formic acid, 40%) gave Example 5 c as a white solid (54 mg, 48%). ¹ H NMR (500 MHz, CDCl ₃ ) δ 0.48-0.52 (1H, m, H-cyclopropane), 0.57-0.61 (1H, m, H-cyclopropane), 1.18-1 .21 (1H, m, H-cyclopropane), 1.25-1.29 (1H, m, H-cyclopropane), 1.60 (3H, s, CH ₃ ), 1.62 (3H, s, CH ₃ ), 2.71 (1H, d, J=9.6 Hz, -iso-OCHH), 3.16 (1H, d, J=9.6 Hz, -iso-OCHH), 4.19 (1H , d, J=15.1 Hz, NCHH), 4.58 (1H, d, J=15.1 Hz, NCHH), 7.09-7.19 (9H, m, H-Ar), 7, 71 (1H, dd, J=1.8, 8.0 Hz, H-5), 7.98 (1H, d, J=1.8 Hz, H-7);; LRMS (ES ^- ) m/z 538.3 [M-H] ^- ;

Example 6: (3R)-3-(4-chlorophenyl)-2-[(1S)-1-(4-chlorophenyl)ethyl]-3-(2,3-dihydroxy-2-methylpropoxy)-6-(2 -hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one

(*as mixture of isomers at positions shown)

(S)-3-(4-Chlorophenyl)-2-((S)-1-(4-chlorophenyl)ethyl)-3-((2-(hydroxymethyl)allyl)oxy)-6-(prop-1- en-2-yl)isoindolin-1-one, Substance 24, (90 mg, 0.18 mmol), Hg(OAc) ₂ (140 mg, 0.44 mmol), water (0.5 ml), THF ( 0.5 ml), 6 M NaOH (0.2 ml) and NaBH ₄ (269 mg, 7.1 mmol). Purification (SP4, silica gel, EtOAc/gasoline, 80%) provided Example 6 as a mixture of 2 isomers (27 mg, 28%). ¹ H NMR (500 MHz, CDCl ₃ ) δ mixture of diastereoisomers 0.95 (3H, s, -iso-OCH ₂ C(OHCH ₃ )CH ₂ OH), 1.00 (3H, s, -iso-OCH ₂ C (OHCH ₃ )CH ₂ OH), 1.64 (6H, s, C(CH ₃ ) ₂ OH), 1.65 (6H, s, C(CH ₃ ) ₂ OH), 1.67 (3H, d , J=7.3 Hz, NCHCH ₃ ), 1.71 (3H, d, J=7.5 Hz, NCHCH ₃ ), 1.87 (2H, br s, OH x2), 2.00 (2H, br s, OH x2), 2.65-2.73 (4H, m, -iso-OCH ₂ x2), 3.23-3.36 (4H, m, CH ₂ OH x2), 4.24 (1H , q, J=7.5 Hz, NCHCH ₃ ), 4.28 (1H, q, J=7.3 Hz, NCHCH ₃ ), 7.01 (1H, d, J=7.9 Hz, H- 4), 7.02 (1H, d, J=7.9 Hz, H-4), 7.28-7.36 (6H, m, H-Ar), 7.55-7.57 (2H, m, H-Ar), 7.71-7.74 (2H, m, H-5), 7.98-7.99 (2H, m, H-7). LRMS (ES ⁺ ) m/z 566.4 [M+Na] ⁺ .

Example 7: (3R)-3-(4-chlorophenyl)-2-[(1S)-1-(4-chlorophenyl)ethyl]-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-6-(2 -hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one

Example 7 was prepared from Compound 28 using a procedure similar to that described in Example 1. NMR (500 MHz, CDCl ₃ ) δ 0.33-0.36 (1H, m), 0.42-0.45 (1H, m ), 0.47-0.54 (2H, m), 1.53 (3H, s), 1.55 (3H, s,), 1.84 (3H, d,), 2.89 (1H, d,), 3.21 (1H, d,), 3.56 (2H,), 4.28 (1H, q,)), 6.92-6.98 (9H, m), 7.63 (1H, dd,), 7.85 (1H, d,); MS (ES+) 540.5 [M+H] ⁺

Examples 8 and 9: (3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-6-(1,2-dihydroxypropan-2-yl)-3-{[1-(hydroxymethyl )cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one

*Two separate epimers in position shown

To a solution of 2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(prop-1-en-2-yl)isoindolin-1-one , Substances 13 (1.20 g, 2.36 mmol), in acetone/water (18 ml/7.1 ml) was added methylmorpholine-N-oxide (318 mg, 2.71 mmol) and OsO ₄ (2.5% wt , in tBuOH, 0.90 ml, 0.09 mmol) and the resulting yellow/orange solution was stirred at RT for 3.5 h. The reaction mixture was diluted with DCM (125 ml), washed with saturated aqueous sodium sulfite (125 ml), dried over MgO ₄ and concentrated in vacuo. HPLC (1:1 gasoline/EtOAc to 100% EtOAc) gave the product as a white solid as a mixture of 4 diastereoisomers (592 mg, 46%). Purification by preparative chiral HPLC (324 mg, Chiralpak IA 250×10 mm, 92.5:7.5 Heptane/Ethanol) gave

Example 8 (Isomer 1): δ _H (500 MHz, CDCl ₃ ) 0.13-0.16 (2H, m, 2×s-PrH), 0.40-0.42 (2H, m, 2×s -PrH), 1.57 (3H, s, CH ₃ ), 2.64 (1H, d, J=9.4 Hz, CHH'), 2.84 (1H, d, J=9.4 Hz, CHH'), 3.35 (1H, d, J=11.3 Hz, CHH'), 3.49 (1H, d, J=11.3 Hz, CHH'), 3.69 (1H, d, J=11.0 Hz, CHH'), 3.79 (1H, d, J=11.0 Hz, CHH'), 4.19 (1H, d, J=14.9 Hz, CHH'), 4 .54 (1H, d, J=14.9 Hz, CHH'), 7.12-7.21 (9H, m, 9×ArH), 7.70 (1H, dd, J=1.7 and 7 .9 Hz, ArH), 7.97 (1H, d, J=1.7 Hz, ArH).

Example 9 (isomer 2): δH (500 MHz, CDCl3) 0.14-0.15 (2H, m, 2xc-PrH), 0.40-0.41 (2H, m, 2xc-PrH ), 1.57 (3H, s, CH3), 2.63 (1H, d, J=9.4 Hz, CHH'), 2.85 (1H, d, J=9.4 Hz, CHH') , 3.34 (1H, d, J=11.3 Hz, CHH'), 3.49 (1H, d, J=11.3 Hz, CHH'), 3.69 (1H, d, J=11 .0 Hz, CHH'), 3.81 (1H, d, J=11.0 Hz, CHH'), 4.19 (1H, d, J=14.9 Hz, CHH'), 4.54 ( 1H, d, J=14.9 Hz, CHH'), 7.13-7.21 (9H, m, 9×ArH), 7.69 (1H, d, J=7.8 Hz, ArH), 7.98 (1H, s, ArH).

Examples 10 and 11: (3R)-3-(4-chlorophenyl)-2-[(1S)-1-(4-chlorophenyl)ethyl]-6-(2-hydroxy-1-methoxypropan-2-yl)- 3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one

*Two separate epimers in position shown

At 0°C, to a solution of (3R)-3-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-3-(4-chlorophenyl)-2-((S)-1-( 4-chlorophenyl)ethyl)-6-(2-hydroxy-1-methoxy propan-2-yl)isoindolin-1-one, Compound 31 (80 mg, 0.12 mmol), TBAF was added in THF (4 mL) ( 1.0 M in THF, 0.13 ml, 0.13 mmol) and the reaction mixture was stirred at 0°C for 1 h, then at RT for 18 h. The reaction mixture was diluted with water (20 ml), neutralized with 1 0 M aq. HCl, extracted with EtOAc (2×25 ml), washed with brine (50 ml) and dried over MgO ₄ . HPLC (1:1 gasoline/EtOAc to 100% EtOAc) and semi-preparative HPLC (ACE 5 C18-AR 150×4.6 mm id, 5 µm, 55:45 Acetonitrile/Water + 0.1% v/v formic acid) gave the product as a white solid in the form of a mixture of diastereoisomers (36 mg, 53%); MS (ES+) 570.4 [M+H] ⁺ ; Purification by preparative chiral HPLC (82 mg, Chiralpak IC 250×10 mm Mobile phase: Heptane/Ethanol 87.5:12.5) gave:-

Example 11 (*isomer 1): δH (500 MHz, CDCl3) 0.32-0.36 (1H, m, c-PrH), 0.42-0.46 (1H, m, c-PrH), 0 .47-0.53 (2H, m, 2×c-PrH), 1.44 (3H, s, CH3), 1.83 (3H, d, J=7.3 Hz, CHCH3), 2.89 (1H, d, J=9.5 Hz, CHH'), 3.21 (1H, d, J=9.5 Hz, CHH'), 3.32 (3H, s, OCH3), 3.43 ( 1H, d, J=9.2 Hz, CHH'), 3.54 (1H, d, J=9.2 Hz, CHH'), 3.56 (2H, s, CH2), 4.28 (1H , q, J=7.3 Hz, CHCH3), 6.92-6.99 (9H, m, 9×ArH), 7.62 (1H, dd, J=1.7 and 8.0 Hz, ArH ), 7.81 (1H, d, J=1.7 Hz, ArH). m/z 468.4 [M-OCH2C(CH2-CH2)CH2OH] ⁺

Example 10 (*isomer 2): ¹ H-NMR δ _H (500 MHz, CDCl ₃ ) 0.32-0.36 (1H, m, c-PrH), 0.42-0.46 (1H, m, c-PrH), 0.47-0.53 (2H, m, 2xc-PrH), 1.46 (3H, s, CH ₃ ), 1.83 (3H, d, J=7.3 Hz , CHCH ₃ ), 2.87 (1H, d, J=9.5 Hz, CHH'), 3.22 (1H, d, J=9.5 Hz, CHH'), 3.32 (3H, s , OCH ₃ ), 3.41 (1H, d, J=9.2 Hz, CHH'), 3.51 (1H, d, J=9.2 Hz, CHH'), 3.56 (2H, s , CH ₂ ), 4.28 (1H, q, J=7.3 Hz, CHCH ₃ ), 6.92-6.99 (9H, m, 9×ArH), 7.64 (1H, dd, J =1.7 and 7.9 Hz, ArH), 7.79 (1H, d, J=1.7 Hz, ArH).: m/z 468.4 [M-OCH2C(CH2-CH2)CH2OH] ⁺

Examples 12 and 13: (3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-6-[1-(dimethylamino)-2-hydroxypropan-2-yl]-3-{[ 1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one

(*Two isomers in position shown)

Deprotection of Compound 34 using a procedure similar to that described in Example 10 and subsequent purification by preparative chiral HPLC yielded two diastereoisomers:

Example 12 (*isomer 1): 1H NMR (500 MHz, CDCl ₃ ) 0.12-0.20 (2H, m), 0.36-0.45 (2H, m), 1.83 (3H, s ), 2.58(1H, d), 2.68-2.29(3H, m), 2.89(1H, d), 2.99-3.00(3H, m), 3.29( 1H, d), 3.39-3.42(1H, m), 3.55(1H, d), 3.62-3.66(1H, m), 4.18(1H, d), 4 .54 (1H, d), 7.11-7.22 (9H, m), 7.86 (1H, d), 7.94 (1H, s). MS: [M+H] ⁺ =569.5.

Example 13 (*isomer 2): 1H NMR (500 MHz, CDCl3) 0.12-0.23 (2H, m), 0.36-0.42 (2H, m), 1.80 (3H, s) , 2.42(1H, d), 2.64(3H, s), 2.92(1H, d), 2.99-3.00(3H, m), 3.15(1H, d), 3.40-3.45(1H, m), 3.58-3.63(2H, m), 4.17(1H, d), 4.53(1H, d), 7.11-7, 15 (4H, m), 7.19-7.23 (5H, m), 7.85 (1H, s), 7.96 (1H, d). MS: [M+H]+=569.5.

Example 14: (3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-1-{[1-(hydroxymethyl)cyclopropyl]methoxy}-5-(2-hydroxypropane -2-yl)-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoic acid

Example 14 was prepared from Compound 40 using procedures similar to those described in Example 1. ¹ H NMR (500 MHz, MeOD) δ 0.40-0.44 (4H, m, 4xc-PrH), 1.47 ( 6H, s, 2×CH ₃ ), 2.91 (1H, d, J=9.2 Hz, CHH'), 3.09-3.21 (2H, m, CHH' and CHCHH'), 3, 51 (2H, s, CH ₂ ), 3.73 (1H, dd, J=11.1 and 16.2 Hz, CHCHH'), 4.64 (1H, dd, J=3.6 and 11.1 Hz, CHCHH'), 6.89-6.97 (8H, m, 8×ArH), 7.02 (1H, d, J=8.0 Hz, ArH), 7.65 (1H, dd, J =1.7 and 8.0 Hz, ArH), 7.89 (1H, d). MS. 582.1 (M-H ⁺ ) ^-

Example 15: (3R)-3-(4-chlorophenyl)-2-[(1S)-1-(4-chlorophenyl)ethyl]-6-(1,2-dihydroxypropan-2-yl)-3-{[ 1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one

Example 15 was prepared from (R)-3-(4-chlorophenyl)-2-((S)-1-(4-chlorophenyl)ethyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-( prop-1-en-2-yl)isoindolin-1-one (Compound 27) using procedures similar to those described in Example 8. The product was obtained as a white solid in the form of a mixture of diastereoisomers (65 mg, 31 (500 MHz, CDCl ₃ ) δ 0.34-0.36 (1H, m, c-PrH), 0.43-0.52 (3H, m, 3×c-PrH), 1.49-1.50 (3H, m, CH ₃ ), 1.82-1.84 (3H, m, NCHCH ₃ ), 2.89-2.92 (1H, m, alkyl-CH), 3.18-3.21 (1H, m , alkyl-CH), 3.51-3.56 (2H, m, 2×alkyl-CH), 3.58-3.63 (1H, m, alkyl-CH), 3.71-3.75 ( 1H, m, alkyl-CH), 4.28 (1H, q, J=7.3 Hz, NCHCH ₃ ), 6.92-6.97 (8H, m, 8×ArH), 7.00 (1H , d, J=7.9 Hz, ArH), 7.60-7.62 (1H, m, ArH), 7.84-7.85 (1H, m, ArH), MS (ES+) 454.3 [M-HOCH ₂ (c-Pr)CH ₂ O] ^- ;

Example 16: (3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-3-(3-hydroxy-3-methylbutoxy)-6-(2-hydroxypropan-2-yl)- 2,3-dihydro-1H-isoindol-1-one

Example 16 was prepared from Compound 41 using a procedure similar to that described in Example 1. Purification by chiral HPLC (Chiralpak IC 250×10 mm, Mobile phase: Heptane/Ethanol 80:20): gave Example 16: (R)- 2-(4-Chlorobenzyl)-3-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutoxy)-6-(2-hydroxypropan-2-yl)isoindolin-1-one (39 mg). ¹ H NMR (500 MHz, CDCl ₃ ) δ 0.98 (3H, s, CH ₃ ), 1.02 (3H, s, CH ₃ ), 1.13-1.19 (1H, m, CH), 1.35-1.41 (1H, m, CH), 1.55 (3H, s, CH ₃ ), 1.56 (3H, s, CH ₃ ), 2.75-2.80 (1H, m , CH), 2.86-2.91 (1H, m, CH), 3.91 (1H, d, J=14.9 Hz, NCHH'), 4.65 (1H, d, J=14, 9 Hz, NCHH'), 7.03 (1H, d, J=7.9 Hz, ArH), 7.11-7.18 (8H, m, 8×ArH), 7.65 (1H, dd, J=1.7 and 7.9 Hz, ArH), 7.93 (1H, d, J=1.7 Hz, ArH); ¹³ C (125 MHz, CDCl ₃ ) δ 29.1, 29.9, 31.9, 32.0, 41.5, 42.4, 60.0, 70.0, 72.6, 95.2, 120.0, 122.7, 127.8, 128.4, 128.8, 129.5, 130.7, 131.4, 133.3, 134.7, 136.2, 137.0, 143, 4, 151.7, 168.3; MS (ES+) 424.3 [M-(OH)C(CH ₃ ) ₂ CH ₂ CH ₂ O] ^- ;

Example 17: (3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-6-(2-hydroxypropan-2-yl)-3-[(1H-pyrazol-4-yl) methoxy]-2,3-dihydro-1H-isoindol-1-one

Example 17 Step 1: Ethyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate

NaH (80% in oil, 130 mg, 4.3 mmol, 1.5 eq.) was added to 4-ethoxycarbonyl-1H-pyrazole (400 mg, 2.86 mmol, 1 eq.) in THF (8 ml), and the mixture was stirred at rt. within 30 min. SEMCI (556 μl, 3.14 mmol, 1.1 eq.) was added and the reaction mixture was stirred at rt. within 18 hours the Mixture was divided between EtOAc (2×30 ml) and water (20 ml), the organic layers were dried (MgO ₄ ), and the solvent was removed under vacuum. The precipitate was purified by HPLC on silica gel eluting with a gradient of 5-20% EtOAc/petrol to give the title compound as a clear oil (657 mg, 85%); HRMS detect. 271.1468 MN+

Example 17 Step 2: (1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)methanol

LiAlH ₄ (1 M in THF, 1.94 ml, 1.94 mmol, 1.5 eq.) was added to ethyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate ( 350 mg, 1.29 mmol) in THF (4 ml) at 0° C. and the mixture was stirred at rt. over 4 h. Water (74 μl) was added followed by NaOH (15% water, 220 μl) and water (74 μl). The mixture was stirred at rt. for 1 h, filtered, solids washed with EtOAc and the filtrate evaporated in vacuo to give the title compound as a clear oil (330 mg, >100%); HRMS calc. for C ₁₀ H ₂₁ O ₂ N ₂ Si 229.1367, found. 229.1361. MN+

Example 17 Step 3: 6-Acetyl-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4- yl)methoxy)isoindoline-1-one

Prepared in a similar manner to Substance 12 using 6-acetyl-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-hydroxyisoindolin-1-one (Substance 20) (150 mg, 0.35 mmol, 1 eq .), SOCl ₂ (51 µl, 0.70 mmol, 2 eq.) and (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)methanol (161 mg, 0.70 mmol, 2 eq.) The title compound was obtained as a clear glass (105 mg, 47%); HRMS detect. 636.1830. MN+

Example 17 Step 4: 2-(4-Chlorobenzyl)-3-(4-chlorophenyl)-6-(2-hydroxypropan-2-yl)-3-((1-((2-(trimethylsilyl)ethoxy)methyl )-1H-pyrazol-4-yl)methoxy)isoindolin-1-one

Received in a similar manner to Example 1 using MeMgCl (151 μl, 3 M in THF, 0.45 mmol, 1.5 eq.) and ZnCl ₂ (8 mg, 0.06 mmol, 0.2 eq.) in THF ( 1 ml) and then 6-acetyl-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl )methoxy)isoindolin-1-one (192 mg, 0.30 mmol, 1 eq.). The title compound was obtained as a clear gum (78 mg, 40%); HRMS 652.2145. MN+

Example 17 Step 5: (3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-6-(2-hydroxypropan-2-yl)-3-[(1H-pyrazole-4 -yl)methoxy]-2,3-dihydro-1H-isoindol-1-one

Et ₄ NF⋅H ₂ O (149 mg, 1.0 mmol, 10 eq.) and 4 type A molecular sieves (50 mg) were added to 2-(4-chlorobenzyl)-3-(4-chlorophenyl)-6- (2-hydroxypropan-2-yl)-3-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)methoxy)isoindolin-1-one (65 mg, 0.1 mmol) in THF (2 ml), and the mixture was heated to 65°C for 3 h, left to cool to rt, and divided between EtOAc (25 ml) and water (3×20 ml). The organic layer was dried (MgO ₄ ) and the solvent removed in vacuo to give a white solid (25 mg, 48%). The enantiomers were separated by chiral HPLC (Daicel Chiralpak IA, 250×10 mm id, 5 μm, n-heptane: 2-propanol 5:1; 4.7 ml/min) to give the title compound (6 mg). ¹ H NMR (500 MHz; CDCl ₃ ) L _H 1.63 (6H, 2×s), 3.66 (1H, d), 3.76 Hz (1H, d), 4.00 (1H, d) , 4.72(1H, d), 7.08-7.27(9H, m), 7.72(1H, dd), 8.03(1H, dd); HRMS detect. 522, 1334. MH+

Example 18: 1-({[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-5-(2-hydroxypropan-2-yl)-3-oxo-2,3 -dihydro-1H-isoindol-1-yl]oxy}methyl)cyclopropane-1-carbonitrile

Example 18 Step 1: 1-(Hydroxymethyl)cyclopropanecarbonitrile

LiBH ₄ (573 mg, 26.3 mmol, 2 eq.) was added to ethyl 1-cyanocyclopropanecarboxylate (1.7 ml, 13.15 mmol, 1 eq.) in THF (18 ml) and the mixture was heated to 50° C for 18 hours the Reaction mixture was cooled to 0°C, and added NaHCO ₃ (sat. aq.) to stop gas evolution. The mixture was diluted with brine (20 ml) and extracted with EtOAc (1×60 ml), DCM (3×60 ml) and 10% MeOH/DCM (2×60 ml). The organic extracts were combined, dried (MgO ₄ ) and the solvent removed in vacuo to give the title compound as a clear oil (820 mg, 65%); ¹ H NMR (500 MHz; CDCl ₃ ): 0.96-1.01 (2H, m), 1.27-1.31 (2H, m), 3.64 (2H, s).

Example 18 Step 2: 1-(((5-Bromo-2-(4-chlorobenzyl)-1-(4-chlorophenyl)-3-oxoisoindolin-1-yl)oxy)methyl)cyclopropan-1-carbonitrile

Thionyl chloride (120 µl, 1.64 mmol, 2 eq.) was added to 6-bromo-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-hydroxyisoindolin-1-one (Substance 8) (382 mg , 0.82 mmol, 1 eq.) in THF (4 mL) and the mixture was stirred at rt. within 4 h. The solvent was removed under vacuum, the residue was redissolved in THF (2 ml), cyanoalcohol (Example 18, Step 1; 160 mg, 1.64 mmol, 2 eq.) in THF (2 ml) was added, and the mixture stirred at rt. for 18 h. The mixture was diluted with EtOAc (2×30 ml) and washed with water. The organic layers were combined, dried over MgO ₄ and the solvent was removed under vacuum. The crude mixture was purified by HPLC on SiO ₂ eluting with a gradient of 0-2% Et ₂ O/DCM to give the title compound as a clear gum (390 mg, 87%); MS (ES+) 543.3, 545.3 [M+H] ⁺ .

Example 18 Step 3 and 4: 1-({[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-5-(2-hydroxypropan-2-yl)-3- oxo-2,3-dihydro-1H-isoindol-1-yl]oxy}methyl)cyclopropane-1-carbonitrile

Using the product from Example 18, Step 2, the title compound was prepared following procedures similar to those described for Compound 13 and Example 2: 1H NMR (500 MHz; CDCl3): 0.35-0.42 (1H, m), 0 .42-0.49(1H, m), 1.09-1.20(2H, m), 1.62(2x3H, 2xs), 2.31(1H, d), 2.91 (1H, d), 4.02 (1H, d), 4.72 (1H, d), 7.15-7.22 (5H, m), 7.25-7.30 (4H, m), 7.74 (1H, dd), 8.00 (1H, d); MS (ES+) 521.4, 523.4 [M+H]+.

Example 19 N-{[1-({[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-5-(2-hydroxypropan-2-yl)-3-oxo -2,3-dihydro-1H-isoindol-1-yl]oxy}methyl)cyclopropyl]methyl}methanesulfonamide

Example 19 Step 1: 1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropanecarbonitrile

1-(Hydroxymethyl)cyclopropanecarbonitrile (1.1 g, 11.3 mmol), TBDPSCI (2.66 ml, 11.3 mmol, 1 eq.), imidazole (926 mg, 13.6 mmol, 1.2 eq. ) and DMAP (69 mg, 0.57 mmol, 0.05 eq.) were combined in DCM (15 ml) and stirred at rt. within 18 hours the Mixture was divided between EtOAc (2×20 ml) and water (20 ml), washed with saline, dried (MgO ₄ ), and the solvent was removed under vacuum. The precipitate was purified by HPLC on silica gel eluting with a gradient of 2-40% EtOAc/petrol to give the title compound as a clear oil (2.05 g, 54%); HRMS calc. for C ₂₁ H ₂₉ O ₁ N ₂ Si 353.2044, found. 353.2034.

Example 19 Step 2: (1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methanamine

1-(((tert-Butyldiphenylsilyl)oxy)methyl)cyclopropanecarbonitrile (220 mg, 0.66 mmol) was dissolved in MeOH (10 mL) and hydrogenated over a Raney nickel catalyst in a Thales H-cube flow reactor at 20°C, 20 bar , for 3 h, with constant recirculation of the reaction mixture (flow rate 1 ml/min). The solvent was removed in vacuo and the residue was purified by HPLC on silica gel eluting with a gradient of 0-20% MeOH/EtOAc to give the title compound as a clear gum (78 mg, 46%); ¹ H NMR (500 MHz; CDCl ₃ ) 0.30-0.41 (4H, m), 1.06 (9H, s), 2.38 (2H, br s), 2.72 (2H, s) , 3.57(2H, s), 7.35-7.46(6H, m), 7.62-7.69(4H, m).

Example 19 Step 3: N-((1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methyl)methanesulfonamide

MsCl (120 μl, 1.54 mmol, 1.1 eq.) was added to a mixture of (1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methanamine (480 mg, 1.4 mmol, 1 eq.) and Et ₃ N (236 μl, 1.69 mmol, 1.2 eq.) in DCM (4 ml) at 0°C and the mixture was stirred at rt. within 18 h, divided between DCM (2×30 ml) and water (20 ml), washed with saline, dried over MgO ₄ and the solvent was removed under vacuum. The precipitate was purified using HPLC on SiO ₂ with a gradient of 10-35% EtOAc/petrol to give the title compound as a white solid (520 mg, 88%); ¹ H NMR (500 MHz; CDCl ₃ ) 0.36-0.40 (2H, m), 0.49-0.54 (2H, m), 1.08 (9H, s), 2.90 (3H , s), 3.15(2H, d), 3.54(2H, s), 4.93(1H, m), 7.36-7.51(6H, m), 7.62-7, 68 (4H, m).

Example 19 Step 4: N-((1-(Hydroxymethyl)cyclopropyl)methyl)methanesulfonamide

N-((1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methyl)methanesulfonamide (500 mg, 1.2 mmol, 1 eq) and Et ₄ NF (197 mg, 1.32 mmol, 1, 1 equiv.) was combined in THF (10 ml) and stirred at rt. for 2 hours. The mixture was diluted with water (10 ml) and brine (10 ml) and was extracted with EtOAc (2×20 ml) and DCM (4×20 ml). The organic extracts were combined, dried over MgO ₄ and the solvent was removed under vacuum. Purification by HPLC on SiO ₂ with a gradient of 70-100% EtOAc/petrol afforded the title compound as a clear oil (188 mg, 88%); MS ES-178.1 [M-H] ^- .

Example 19 Step 5: N-((1-(((5-Bromo-2-(4-chlorobenzyl)-1-(4-chlorophenyl)-3-oxoisoindolin-1-yl)oxy)methyl)cyclopropyl)methyl )methanesulfonamide

Thionyl chloride (117 µl, 1.62 mmol, 2 eq) was added to 6-bromo-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-hydroxyisoindolin-1-one (Substance 8) (375 mg , 0.81 mmol, 1 eq.) and DMF (1 drop, cat.) in THF (4 ml) and stirred at rt. within 4 hours the Solvent was removed under vacuum, the precipitate was redissolved in THF (2 ml), and was added alcohol in THF (2 ml). The mixture was stirred at rt. within 96 h, divided between EtOAc (2×30 ml) and water (20 ml). The organic extracts were combined, dried over MgO ₄ and the solvent was removed under vacuum. The crude product was purified by HPLC on SiO ₂ with a gradient of 25-50% EtOAc/petrol to give the title compound as a clear gum (385 mg, 76%); MS ES-523.2 [M-N] ^- .

Example 19 Steps 6 and 7: N-{[1-({[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-5-(2-hydroxypropan-2-yl )-3-oxo-2,3-dihydro-1H-isoindol-1-yl]oxy}methyl)cyclopropyl]methyl}methanesulfonamide

Example 19 was obtained from the product obtained in Step 5; using procedures similar to those described for Compound 13 and Example 2. ¹ H NMR (500 MHz; CDCl ₃ ) 0.08-0.17 (2H, m), 0.38-0.47 (2H, m), 1.61(3H, s), 1.63(3H, s), 1.83(1H, s), 2.53(1H, d), 2.80(1H, d), 2.84-2 .93(4H, m), 3.16(1H, dd), 4.15(1H, d), 4.30(1H, t), 4.59(1H, d), 7.13-7, 19 (5H, m), 7.19-7.27 (4H, m), 7.75 (1H, dd), 8.00 (1H, d); MS ES+ 603.4, 605.3 [M+H] ⁺ .

Example 20: (3R)-3-(4-chlorophenyl)-2-[(4-ethynylphenyl)methyl]-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-6-(2-hydroxypropan-2-yl )-2,3-dihydro-1H-isoindol-1-one

Example 20 Step 1: 6-Acetyl-3-(4-chlorophenyl)-3-hydroxy-2-(4-((triisopropylsilyl)ethynyl)benzyl)isoindolin-1-one

Prepared in a manner similar to Compound 8 from: 5-acetyl-2-(4-chlorobenzoyl)benzoic acid (Compound 19) (1 g, 3.303 mmol), SOCl ₂ (0.48 ml, 6.607 mmol), ( 4-((triisopropylsilyl)ethynyl)phenyl)methanamine (Compound 42) (1.14 g, 3.964 mmol) and DIPEA (1.27 ml, 7.27 mmol) in THF (20 ml). Purify with Biotage using 0-30% EtOAc in gasoline as eluent to give the title compound as a pale yellow solid (1.283 g, 68%). MS: [M+H] ⁺ =456.4.

Example 20 Step 2: 6-Acetyl-3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-2-(4-((triisopropylsilyl)ethynyl)benzyl)isoindolin-1-one

Prepared in a manner similar to that described for Substance 22 from: 6-acetyl-3-(4-chlorophenyl)-3-hydroxy-2-(4-((triisopropylsilyl)ethynyl)benzyl)isoindolin-1-one (400 mg, 0 .70 mmol), SOCl ₂ (166 mg, 0.10 ml, 1.40 mmol), 1,1-bis (hydroxymethyl) cyclopropane (104 mg, 0.14 ml, 1.40 mmol) and K ₂ CO ₃ (194 mg, 1.40 mmol) in THF (1.5 ml). Purified with Biotage using 0-40% EtOAc in gasoline as eluent to give the title compound as a colorless oil (205 mg, 45%); 1H NMR (500 MHz, CDCl ₃ ) 0.13-0.17 (2H, m) 0.39-0.43 (2H, m), 1.11 (21H, s), 2.67-2.69 (4H, m), 2.77 (1H, d), 3.35 (1H, d), 3.50 (1H, d), 4.21 (1H, d), 4.59 (1H, d) , 7.12-7.13(2H, m), 7.17-7.26(5H, m), 7.28(2H, m), 8.14-8.15(1H, m), 8 .43-8.44 (1H, m).

Example 20 Step 3: 3-(4-Chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(2-hydroxypropan-2-yl)-2-(4-((triisopropylsilyl)ethynyl )benzyl)isoindoline-1-one

Prepared in a manner similar to that described in Example 1 from: 6-acetyl-3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-2-(4-((triisopropylsilyl)ethynyl)benzyl) isoindolin-1-one (180 mg, 0.27 mmol), Zn(II)Cl ₂ (7.5 mg, 0.055 mmol) and MeMgCl (0.23 ml, 3.0 M in THF, 0.17 mmol) in THF (1.94 ml). The title product was obtained as a white solid (148 mg, 82%); 1H NMR (500 MHz, CDCl ₃ ) 0.12-0.18 (2H, m), 0.36-0.43 (2H, m), 1.11 (21H, s), 1.61 (3H, s), 1.62(3H, s), 2.66(1H, d), 2.82(1H, d), 3.35(1H, d), 3.48(1H, d), 4, 19(1H, d), 4.57(1H, d), 7.09-7.13(3H, m), 7.17-7.21(4H, m), 7.26-7.28( 2H, m), 7.71 (1H, dd), 7.99 (1H, d).

Example 20 Step 4: (3R)-3-(4-chlorophenyl)-2-[(4-ethynylphenyl)methyl]-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-6-(2-hydroxypropane- 2-yl)-2,3-dihydro-1H-isoindol-1-one

Example 20 was prepared from 3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(2-hydroxypropan-2-yl)-2-(4-((triisopropylsilyl)ethynyl)benzyl )isoindolin-1-one by deprotection using a procedure similar to that described in Example 10. 1H NMR (500 MHz, CDCl ₃ ) 0.09-0.18 (2H, m), 0.37-0.42 (2H, m), 1.61 (3H, s), 1.62 (3H, s), 2.65(1H, d), 2.82(1H, d), 3.04(1H, s), 3.34(1H, d), 3.47(1H, d), 4, 17(1H, d), 4.60(1H, d), 7.11(1H, d), 7.16-7.22(6H, m), 7.31(2H, d), 7.72 (1H, dd), 7.99 (1H, d). MS: [M+H] ⁺ =516.4.

Example 21: (3R)-3-(4-chlorophenyl)-2-[(4-ethynylphenyl)methyl]-4-fluoro-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-6-(2-hydroxypropane -2-yl)-2,3-dihydro-1H-isoindol-1-one

Example 21 Step 1: 6-Bromo-3-(4-chlorophenyl)-4-fluoro-3-hydroxy-2-{4-[(triisopropylsilanyl)ethynyl]benzyl}-2,3-dihydroisoindole-1- He

The title compound was prepared from 5-bromo-2-(4-chloro-benzoyl)-3-fluorobenzoic acid (7.9 g, 22.2 mmol) and 4-[(triisopropylsilanyl)-ethynyl]-benzylamine (7.0 g , 24.4 mmol) in a manner similar to Compound 9. ¹ H NMR (400 MHz, DMSO-d6): 7.84-7.72 (2H, m), 7.59 (1H, s), 7 .33-7.20(6H, m), 7.12(2H,d), 4.46-4.37(1H, m), 4.29(1H, d), 1.13-1.05 (21H, m).

Example 21 Step 2: 6-Bromo-3-(4-chlorophenyl)-4-fluoro-3-(1-hydroxymethylcyclopropylmethoxy)-2-{4-[(triisopropylsilanyl)ethynyl]benzyl}-2,3- dihydroisoindol-1-one

The title compound was prepared from 6-bromo-3-(4-chlorophenyl)-4-fluoro-3-hydroxy-2-{4-[(triisopropylsilanyl)ethynyl]benzyl}-2,3-dihydroisoindol-1-one ( 5.0 g, 7.9 mmol) and (1-hydroxymethylcyclopropyl)-methanol (4.1 g, 39.9 mmol) in a manner similar to Compound 10. ¹ H NMR (400 MHz, DMSO-d6): 7.91(1H, d), 7.83(1H, dd), 7.35-7.12(6H, m), 7.03(2H, d), 4.51-4.27(3H, m), 3.44-3.33(2H, m), 2.86(2H, s), 1.09(21H, s), 0.41-0.26(2H, m), 0.26 -0.10 (2H, m).

Example 21 Step 3: 6-Acetyl-3-(4-chlorophenyl)-2-[4-(3,3-diisopropyl-4-methylpent-1-ynyl)-benzyl]-4-fluoro-3-(1 -hydroxymethylcyclopropylmethoxy)-2,3-dihydroisoindol-1-one

Pd(PPh ₃ ) ₄ (84 mg, 0.07 mmol) and LiCl (178 mg, 4.24 mmol) were added to a solution of 6-bromo-3-(4-chlorophenyl)-4-fluoro-3-(1- hydroxymethylcyclopropylmethoxy)-2-{4-[(triisopropylsilanyl)-ethynyl]-benzyl}-2,3-dihydroisoindol-1-one (1.0 g, 1.4 mmol) in dioxane/toluene (1:1, 20 ml ) under N ₂ and the resulting solution was degassed for 10 minutes. Tributyl(1-ethoxyvinyl)tin (475 µl, 1.41 mmol) was added and the reaction mixture was stirred at 110° C. for 1.5 hours. The reaction mixture was cooled to room temperature, quenched with NaHCO ₃ and extracted with EtOAc. The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated under vacuum. The crude material was loaded onto columns (gradient 0-50% EtOAc in gasoline) to give 900 mg of a pale yellow solid which was dissolved in dioxane (10 ml) and then in 2M HCl (6 ml). The solution was stirred at room temperature for 1 hour, quenched with NaHCO ₃ and extracted with DCM. The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the desired product as a yellow solid. 1H NMR (400 MHz, DMSO-d6): 8.21 (1H, d), 7.95 (1H, dd), 7.37-7.10 (6H, m), 7.06 (2H, d) , 4.51-4.28(3H, m), 3.43-3.33(2H, m), 2.94-2.77(2H, m), 2.69(3H, s), 1 0.08 (21H, s), 0.41-0.25 (2H, m), 0.23-0.10 (2H, m).

Example 21 Step 4: 3-(4-Chlorophenyl)-4-fluoro-3-(1-hydroxymethylcyclopropylmethoxy)-6-(1-hydroxy-1-methyl-ethyl)-2-{4-[(triisopropylsilanyl)- ethynyl]-benzyl}-2,3-dihydroisoindol-1-one

The title compound was obtained from 6-acetyl-3-(4-chlorophenyl)-2-[4-(3,3-diisopropyl-4-methyl-pent-1-ynyl)-benzyl]-4-fluoro-3-(1 -hydroxymethylcyclopropylmethoxy)-2,3-dihydroisoindol-1-one (871 mg, 1.29 mmol) in a manner similar to that described for Example 1. ¹ H NMR (400 MHz, DMSO-d6): 7.80 (1H, d ), 7.49(1H, d), 7.36-7.10(6H, m), 7.05(2H, d), 5.36(1H, s), 4.50-4.25( 3H, m), 3.42-3.32(2H, m), 2.91-2.75(2H, m), 1.48(6H, s), 1.09(21H, s), 0 .40-0.25 (2H, m), 0.15 (2H, s).

Example 21 Step 5: (3R)-3-(4-chlorophenyl)-2-[(4-ethynylphenyl)methyl]-4-fluoro-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-6-( 2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one

The title compound was obtained following procedures similar to those described for Example 11. Purification by preparative chiral HPLC afforded the title compound (173 mg). ¹ H NMR (400 MHz, DMSO-d ₆ ): 7.80 (1H, d), 7.50 (1H, d), 7.37-7.17 (6H, m), 7.09 (2H, d), 5.36(1H, s), 4.50-4.35(2H, m), 4.28(1H, d), 4.11(1H, s), 3.38(1H, dd ), 3.28(1H, dd), 2.89(1H, d), 2.77(1H, d), 1.48(6H, s), 0.39-0.24(2H, m) , 0.18-0.00 (2H, m). MS: [M+H] ⁺ =534.

Examples 22 and 23: (3R)-3-(4-chlorophenyl)-6-(1,2-dihydroxypropan-2-yl)-2-[(4-ethynylphenyl)methyl]-4-fluoro-3-{[ 1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one

(*Two isomers in position shown)

Example 22 and Example 23 Step 1: 3-(4-Chlorophenyl)-4-fluoro-3-(1-hydroxymethylcyclopropylmethoxy)-6-isopropenyl-2-{4-[(triisopropylsilanyl)ethynyl]benzyl}-2 ,3-dihydroisoindol-1-one

The title compound was prepared in a similar manner to Compound 13. ¹ H NMR (400 MHz, DMSO-d6): 7.79 (1H, d), 7.63-7.55 (1H, m), 7.34-7.09 (6H, m), 7.05 (2H, d), 5.68 (1H, s), 5.30 (1H, s), 4.49-4.28 (3H, m), 3.36 ( 2H, d), 2.87(2H, s), 2.17(3H, s), 1.16-1.03(21H, m), 0.42-0.26(2H, m), 0 .17 (2H, d).

Example 22 and Example 23 Step 2: 3-(4-Chlorophenyl)-6-(1,2-dihydroxy-1-methylethyl)-4-fluoro-3-(1-hydroxymethylcyclopropylmethoxy)-2-{4-[( triisopropylsilanyl)-ethynyl]-benzyl}-2,3-dihydroisoindol-1-one

The title compound was prepared using a procedure similar to that described in Example 27, Step 4. ¹ H NMR (400 MHz, DMSO-d6): 7.79 (1H, dd), 7.50-7.42 (1H, m) , 7.35-7.10(6H, m), 7.05(2H, d), 5.28(1H, s), 4.86-4.79(1H, m), 4.42(1H , t), 4.35(2H, s), 3.54-3.40(2H, m), 3.36(2H, dd), 2.93-2.78(2H, m), 2, 55-2.40(25H, m), 1.43(3H, s), 1.14-1.03(21H, m), 0.40-0.27(2H, m), 0.21- 0.09 (2H, m).

Example 22 and Example 23 Step 3: (3R)-3-(4-chlorophenyl)-6-(1,2-dihydroxypropan-2-yl)-2-[(4-ethynylphenyl)methyl]-4-fluoro- 3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one (Isomer A and B)

The title compounds were obtained from 3-(4-chlorophenyl)-6-(1,2-dihydroxy-1-methylethyl)-4-fluoro-3-(1-hydroxymethylcyclopropylmethoxy)-2-{4-[(triisopropylsilanyl)-ethynyl] -benzyl}-2,3-dihydroisoindol-1-one (1.0 g, 1.4 mmol) in a manner similar to that described in Example 10. Purification by preparative chiral HPLC gave:-

Example 22 (*isomer 1): 1H NMR (400 MHz, DMSO-d6): 7.78 (1H, s), 7.47 (1H, d), 7.36-7.16 (6H, m), 7.09(2H, d), 5.29(1H, s), 4.82(1H, t), 4.50-4.32(2H, m), 4.28(1H, d), 4 .12 (1H, s), 3.52-3.34 (3H, m), 3.29 (1H, dd), 2.89 (1H, d), 2.78 (1H, d), 1, 43 (3H, s), 0.38-0.25 (2H, m), 0.17-0.00 (2H, m). MS: [M-N] ^- =548.

Example 23 (*isomer 2): 1H NMR (400 MHz, DMSO-d6): 7.79 (1H, d), 7.46 (1H, d), 7.36-7.13 (6H, m), 7.09(2H, d), 5.42-5.12(1H, m), 4.98-4.60(1H, m), 4.41(1H, d), 4.29(1H, d), 4.12(1H, s), 3.50(1H, d), 3.44(1H, d), 3.38(2H, d), 3.29(1H, d), 2, 89 (1H, d), 2.79 (1H, d), 1.43 (3H, s), 0.39-0.29 (2H, m), 0.18-0.00 (2H, m)

Example 24 4-{[(1R)-1-(4-chlorophenyl)-7-fluoro-1-({1-[hydroxy( ² H ₂ )methyl] cyclopropyl}( ² H ₂ )methoxy)-5- (2-hydroxypropan-2-yl)-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzonitrile

Example 24 Step 1: 4-[5-Bromo-1-(4-chlorophenyl)-7-fluoro-1-hydroxy-3-oxo-1,3-dihydroisoindol-2-ylmethyl]-benzonitrile

The title compound was prepared from 5-bromo-2-(4-chloro-benzoyl)-3-fluorobenzoic acid (4.0 g, 11.2 mmol) and 4-aminomethylbenzonitrile hydrochloride (2.0 g, 11.2 mmol) as follows , similar to that described for Substance 9 MS: [M-H] ^- =470.

Example 24 Step 2: 4-{[5-Bromo-1-(4-chlorophenyl)-7-fluoro-1-({1-[hydroxy(2H2)methyl]cyclopropyl}(2H2)methoxy)-3-oxo -2,3-dihydro-1H-isoindol-2-yl]methyl}benzonitrile

The title compound was prepared from 4-[5-bromo-1-(4-chlorophenyl)-7-fluoro-1-hydroxy-3-oxo-1,3-dihydroisoindol-2-ylmethyl]-benzonitrile (1.0 g, 2 .1 mmol) and {1-[hydroxy( ² H ₂ )methyl]cyclopropyl}( ² H ₂ )methanol (890 mg, 8.4 mmol) in a manner similar to that described for Substance 10 MS: [M-H] ^- =558.

Example 24 Step 3: 4-{[1-(4-Chlorophenyl)-7-fluoro-1-({1-[hydroxy(2H2)methyl]cyclopropyl}(2H2)methoxy)-3-oxo-5-( prop-1-en-2-yl)-2,3-dihydro-1H-isoindol-2-yl]methyl}benzonitrile

The title compound was obtained from 4-{[5-bromo-1-(4-chlorophenyl)-7-fluoro-1-({1-[hydroxy( ² H ² )methyl] cyclopropyl}( ² H ² )methoxy)-3 -oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzonitrile (750 mg, 1.33 mmol) in a manner similar to that described for Compound 13. MS: [M-H] ^- =519.

Example 24 Step 4: 4-{[(1R)-1-(4-chlorophenyl)-7-fluoro-1-({1-[hydroxy( ² H ₂ )methyl] cyclopropyl}( ² H ₂ )methoxy) -5-(2-hydroxypropan-2-yl)-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzonitrile

The title compound was obtained from 4-{[1-(4-chlorophenyl)-7-fluoro-1-({1-[hydroxy(2H2)methyl]cyclopropyl}(2H2)methoxy)-3-oxo-5-(prop- 1-en-2-yl)-2,3-dihydro-1H-isoindol-2-yl]methyl}benzonitrile (660 mg, 1.27 mmol) in a manner similar to that described for Example 2. 1H NMR (400 MHz, DMSO-d6): 7.81 (1H, d), 7.61 (2H, d), 7.57-7.46 (1H, m), 7.34-7.15 (6H, m), 5 .37(1H, s), 4.44(2H, s), 4.40-4.30(1H, m), 1.48(6H, s), 0.39-0.26(2H, m ), 0.21-0.03 (2H, m). MS: [M-N] ^- =537.

Example 25 4-{[(1R)-1-(4-chlorophenyl)-1-{[1-(hydroxymethyl)cyclopropyl]methoxy}-5-(2-hydroxypropan-2-yl)-3-oxo-2 ,3-dihydro-1H-isoindol-2-yl]methyl}benzonitrile

Example 25 Step 1: 6-Acetyl-2-(4-bromobenzyl)-3-(4-chlorophenyl)-3-hydroxyisoindolin-1-one

Prepared in a manner similar to Compound 9 from: 5-acetyl-2-(4-chlorobenzoyl)benzoic acid. MS: [MH] ^- =470.2.

Example 25 Step 2: 6-Acetyl-2-(4-bromobenzyl)-3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)isoindolin-1-one

Prepared in a manner similar to Compound 22 from: 6-acetyl-2-(4-bromobenzyl)-3-(4-chlorophenyl)-3-hydroxyisoindolin-1-one. 1H NMR (500 MHz, CDCl ₃ ) 0.09-0.18 (2H, m), 0.40-0.44 (2H, m), 2.67-2.69 (4H, m), 2, 78 (1H, d), 3.36 (1H, d), 3.50 (1H, d), 4.19 (1H, d), 4.55 (1H, d), 7.07-7.08 (2H, m), 7.17-7.18 (2H, m), 7.21-7.26 (3H, m), 7.30-7.32 (2H, m), 8.14 (1H , dd), 8.43 (1H, d).

Example 25 Step 3: 2-(4-Bromobenzyl)-3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(2-hydroxypropan-2-yl)isoindoline-1 -He

Prepared in a manner similar to that described in Example 1 from: 6-acetyl-2-(4-bromobenzyl)-3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)isoindolin-1-one . 1H NMR (500 MHz, CDCl ₃ ) 0.12-0.20 (2H, m), 0.39-0.44 (2H, m), 1.61 (3H, s), 1.62 (3H, s), 2.66(1H, d), 2.83(1H, d), 3.37(1H, d), 3.48(1H, d), 4.17(1H, d), 4, 52 (1H, d), 7.07-7.11 (3H, m), 7.17-7.22 (4H, m), 7.29-2.31 (2H, m), 7.72 ( 1H, dd), 7.99 (1H, d).

Example 25 Step 4: 4-{[(1R)-1-(4-chlorophenyl)-1-{[1-(hydroxymethyl)cyclopropyl]methoxy}-5-(2-hydroxypropan-2-yl)-3- oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzonitrile

In a microwave vial, a mixture of 2-(4-bromobenzyl)-3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(2-hydroxypropan-2-yl)isoindoline-1 -one (140 mg, 0.25 mmol), zinc dust (3.3 mg, 0.05 mmol), Pd(OAc) ₂ (11.2 mg, 0.05 mmol), rac-2-(di- tert-butylphosphino)-1,1'-binaphthyl (39.8 mg, 0.10 mmol) and Zn(CN) ₂ (32.3 mg, 0.275 mmol) in MeCN (1.5 ml) were degassed under N ₂ for 20 min, then heated to 120°C for 1 h. The reaction mixture was cooled to RT, diluted with EtOAc (25 ml) and filtered through Celite. The organic layer was washed with water (100 ml), brine (100 ml), dried over Na ₂ SO ₄ and concentrated in vacuo. Purified with Biotage 0-50% EtOAc in gasoline as eluent, then using semi-preparative HPLC to give the racemic mixture as a white solid (55 mg, 43%). Purification by preparative chiral HPLC afforded the title compound as a white solid (24.4 mg). 1H NMR (500 MHz, CD ₃ OD-d ₄ ) 0.16-0.29 (2H, m), 0.41-0.46 (2H, m), 1.58 (6H, s), 2, 84-2.90(2H, m), 3.48-3.56(2H, m), 4.44(1H, d), 4.64(1H, d), 7.15-7.21( 5H, m), 7.26-7.28(2H, m), 7.47-7.49(2H, m), 7.78(1H, dd), 8.04(1H, d). MS: [M+H] ⁺ =517.4.

Example 26: (3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-6-(2-hydroxypropan-2-yl)-3-[(3-methyloxetan-3-yl) methoxy]-2,3-dihydro-1H-isoindol-1-one

Example 26 Step 1: 2-(Bromomethyl)-2-methylpropane-1,3-diol

At -10°C, to a solution of 3-methyl-3-oxetanemethanol (1.00 g, 9.8 mmol) in THF (12.3 ml) was added aqueous HBr (48% wt., 3.9 ml), and the resulting the yellow/brown solution was stirred for 4 h at -10° C., then at RT for 12 h. The mixture was diluted with brine (100 ml) and extracted with Et ₂ O (4×100 ml). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound as a white solid (1.36 g, 76%); 1 H NMR (500 MHz, CDCl ₃ ) 0.91 (3H, s), 2.73 (2H, s), 3.53 (2H, s), 3.65 (4H, s).

Example 26 Step 2: 6-Bromo-3-(3-bromo-2-(hydroxymethyl)-2-methylpropoxy)-2-(4-chlorobenzyl)-3-(4-chlorophenyl)isoindolin-1-one

Prepared in a manner similar to Compound 22 from: 6-bromo-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-hydroxyisoindolin-1-one (Compound 9) (635 mg, 1.37 mmol), SOCl ₂ (325 mg, 0.20 ml, 2.73 mmol), 2-(bromomethyl)-2-methylpropane-1,3-diol (500 mg, 2.73 mmol) and K ₂ CO ₃ ( 377 mg, 2.73 mmol) in THF (2.9 ml). Purify with Biotage using 0-20% EtOAc in gasoline as eluent to give the title compound as a white solid (302 mg, 35%). MS: [M+H] ⁺ =628.3.

Example 26 Step 3: 6-Bromo-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-((3-methyloxetan-3-yl)methoxy)isoindolin-1-one

To a solution of 6-bromo-3-(3-bromo-2-(hydroxymethyl)-2-methylpropoxy)-2-(4-chlorobenzyl)-3-(4-chlorophenyl)isoindolin-1-one (820 mg, 1, 31 mmol) in EtOH (28 ml) was added KOH (88 mg, 1.57 mmol) and the mixture was heated under reflux for 6 h, then cooled to RT. The reaction mixture was diluted with water (50 ml) and acidified to pH 6 with 1.0 M aqueous HCl. The reaction mixture was extracted with EtOAc (3×40 ml), washed with brine, dried over MgO ₄ and concentrated in vacuo. Purify with Biotage using 0-20% EtOAc in gasoline as eluent to give the title compound as a white solid (516 mg, 72%). 1H NMR (500 MHz, CDCl ₃ ) 1.13 (3H, s), 2.75-2.81 (2H, m), 4.16-4.22 (2H, m), 4.26-4, 27(1H, m), 4.32-4.34(2H, m), 4.51(1H, d), 6.97(1H, d), 7.07-7.09(2H, m) , 7.13-7.14(2H, m), 7.17-7.23(4H, m), 7.65(1H, dd), 8.06(1H, d).

Example 26 Step 4: 2-(4-Chlorobenzyl)-3-(4-chlorophenyl)-3-((3-methyloxetan-3-yl)methoxy)-6-(prop-1-en-2-yl) isoindoline-1-one

Prepared in a manner similar to Compound 13 from: 6-bromo-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-((3-methyloxetan-3-yl)methoxy)isoindoline-1- she. 1H NMR (500 MHz, CDCl ₃ ) 1.13 (3H, s), 2.20 (3H, s), 2.79 (2H, s), 4.16-4.27 (3H, m), 4 .32435(2H, m), 4.52-4.55(1H, m), 5.21(1H, s), 5.48(1H, s), 7.04(1H, d), 7, 09-7.14 (4H, m), 7.17-7.23 (4H, m), 7.63 (1H, dd), 8.00 (1H, d).

Example 26 Step 5: 6-Acetyl-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-((3-methyloxetan-3-yl)methoxy)isoindolin-1-one

Prepared in a manner similar to Compound 15 from: 2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-((3-methyloxetan-3-yl)methoxy)-6-(prop-1- en-2-yl)isoindoline-1-one. MS: [M+H] ⁺ =510.4.

Example 26 Step 6: (3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-6-(2-hydroxypropan-2-yl)-3-[(3-methyloxetane-3 -yl)methoxy]-2,3-dihydro-1H-isoindol-1-one

Prepared in a manner similar to that described in Example 1 from: 6-acetyl-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-((3-methyloxetan-3-yl)methoxy)isoindoline-1- she. 1H NMR (500 MHz, CDCl ₃ ) 1.13 (3H, s), 1.63 (3H, s), 1.64 (3H, s), 2.78 (2H, s), 4.16-4 .22(2H, m), 4.25-4.27(1H, m), 4.34-4.36(2H, m), 4.54(1H, d), 7.60(1H, d ), 7.10-7.14(4H, m), 7.19-7.22(4H, m), 7.73(1H, dd), 8.02(1H, d). MS: [M+H] ⁺ =526.4.

Examples 27 and 28: 4-{[(1R)-1-(4-chlorophenyl)-5-(1,2-dihydroxypropan-2-yl)-1-{[1-(hydroxymethyl)cyclopropyl]methoxy}-3 -oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzonitrile

(*both isomers in position shown)

Example 27 and Example 28 Step 1: 4-((5-Bromo-1-(4-chlorophenyl)-1-hydroxy-3-oxoisoindolin-2-yl)methyl)benzonitrile

Prepared in a manner similar to Compound 9 from: 5-bromo-2-(4-chlorobenzoyl)benzoic acid and 4-(aminomethyl)benzonitrile. MS: [MH] ^- =453.1.

Example 27 and Example 28 Step 2 and 3: 4-((1-(4-Chlorophenyl)-1-((1-(hydroxymethyl)cyclopropyl)methoxy)-3-oxo-5-(prop-1-en- 2-yl)isoindolin-2-yl)methyl)benzonitrile

The title compound was prepared from: 4-((5-bromo-1-(4-chlorophenyl)-1-hydroxy-3-oxoisoindolin-2-yl)methyl)benzonitrile in a manner similar to Compounds 12 and 13. 1H NMR ( 500 MHz, CD ₃ OD) 0.19-0.27 (2H, m), 0.41-0.46 (2H, m), 2.21 (3H, s), 2.85-2.91 ( 2H, m), 3.49-3.56(2H, m), 4.45(1H, d), 4.64(1H, d), 5.23(1H, s), 5.51(1H , s), 7.15-7.22(5H, m), 7.26-7.28(2H, m), 7.47-7.48(2H, m), 7.76(1H, dd ), 7.99 (1H, d).

Example 27 and Example 28 Step 4: 4-{[(1R)-1-(4-chlorophenyl)-5-(1,2-dihydroxypropan-2-yl)-1-{[1-(hydroxymethyl)cyclopropyl] methoxy}-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzonitrile

At 0°C, AD-mix-β (2.49 g) was added to a solution of tert-butanol/water (8.91 ml/8.91 ml) and then 4-((1-(4-chlorophenyl) -1-((1-(hydroxymethyl)cyclopropyl)methoxy)-3-oxo-5-(prop-1-en-2-yl)isoindolin-2-yl)methyl)benzonitrile (900 mg, 1.80 mmol) , and the resulting mixture was stirred at 0°C for 48 hours was Added Na ₂ SO ₃ (0.98 g, 7.78 mmol)and the reaction mixture was heated to KG and diluted with water (50 ml). The reaction mixture was extracted with EtOAc (2×50 ml), dried over MgO ₄ and concentrated under vacuum. Purified with Biotage using 0-100% EtOAc in gasoline as eluent to give a diastereomeric mixture of product (177 mg, 18%). Purification by chiral HPLC gave the title compounds:.

Example 27 (*isomer 1): 1H NMR (500 MHz, CDCl ₃ ) 0.13-0.21 (2H, m), 0.42-0.46 (2H, m), 1.58 (3H, s ), 2.64(1H, s), 2.72(1H, d), 2.88(1H, d), 3.40(1H, d), 3.51(1H, d), 3.71 (1H, d), 3.82 (1H, d), 4.41 (1H, d), 4.50 (1H, d), 7.14-7.18 (5H, m), 7.26- 7.28(2H, m), 7.44-7.46(2H, m), 7.72(1H, dd), 7.99(1H, d). MS: [M+H] ⁺ =533.4.

Example 28 (*isomer 2): 1H NMR (500 MHz, CDCl ₃ ) 0.13-0.21 (2H, m), 0.42-0.47 (2H, m), 1.59 (3H, s ), 2.64(1H, s), 2.73(1H, d), 2.86(1H, d), 3.41(1H, d), 3.51(1H, d), 3.70 (1H, d), 3.81 (1H, d), 4.41 (1H, d), 4.50 (1H, d), 7.14-7.18 (5H, m), 7.27- 7.28(2H, m), 7.44-7.46(2H, m), 7.72(1H, dd), 7.98(1H, d). MS: [M+H] ⁺ =533.4.

Example 29: (3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-3-[(1-hydroxycyclopropyl)methoxy]-6-(2-hydroxypropan-2-yl)-2 ,3-dihydro-1Н-isoindol-1-one

Example 29 Step 1: 6-Acetyl-3-((1-((tert-butyldiphenylsilyl)oxy)cyclopropyl)methoxy)-2-(4-chlorobenzyl)-3-(4-chlorophenyl)isoindolin-1-one

Prepared in a manner similar to that described for Compound 12 from: 6-acetyl-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-hydroxyisoindolin-1-one (Compound 20) and (1-((tert -butyldiphenylsilyl)oxy)cyclopropyl)methanol). 1H NMR (500 MHz, CDCl ₃ ) 0.07-0.12 (2H, m), 0.66-0.75 (2H, m), 0.99 (9H, s), 2.57 (1H, d), 2.67(3H, s), 2.76(1H, d), 4.24(2H, s), 6.83(1H, d), 6.97-6.98(2H, m ), 7.06-7.14(5H, m), 7.25-7.31(5H, m), 7.37-7.40(2H, m), 7.56-7.58(2H , m), 7.65-7.66(2H, m), 7.99(1H, dd), 8.34(1H, d).

Example 29 Step 2: 3-((1-((tert-butyldiphenylsilyl)oxy)cyclopropyl)methoxy)-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-6-(2-hydroxypropan-2- yl)isoindoline-1-one

Received in a manner similar to that described in Example 1. 1H NMR (500 MHz, CDCl ₃ ) 0.05-0.11 (2H, m), 0.62-0.72 (2H, m), 1.00 (9H , s), 1.61 (6H, s), 2.56 (1H, d), 2.84-2.86 (1H, m), 4.20-4.27 (2H, m), 6, 75-6.77(1H, m), 6.96-6.98(2H, m), 7.04-7.06(2H, m), 7.10-7.13(4H, m), 7.28-7.32(4H, m), 7.37-7.41(2H, m), 7.57-7.61(3H, m), 7.66-7.68(2H, m ), 7.91 (1H, d).

Example 29 Step 3: (3R-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-3-[(1-hydroxycyclopropyl)methoxy]-6-(2-hydroxypropan-2-yl) -2,3-dihydro-1H-isoindol-1-one

Deprotection _in a manner similar to that described for Example 10 allowed Example 29 to be obtained. ), 1.61-0.62(6H, m), 2.71(1H, d), 2.94(1H, d), 4.20(1H, d), 4.54(1H, d) , 7.10(1H, d), 7.13(4H, s), 7.20-7.24(4H, m), 7.71(1H, dd), 7.99(1H, d). MS: [M+H] ⁺ =512.4.

Example 30: 2-{[(1R)-1-(4-Chlorophenyl)-2-[(4-chlorophenyl)methyl]-5-(2-hydroxypropan-2-yl)-3-oxo-2,3- dihydro-1H-isoindol-1-yl]oxy}N,N-dimethylacetamide

Example 30 Step 1: Methyl 2-((5-bromo-2-(4-chlorobenzyl)-1-(4-chlorophenyl)-3-oxoisoindolin-1-yl)oxy)acetate

The title compound was prepared using methyl glycolate using a procedure similar to that described for Compound 10. MS: [M-C ₃ H ₅ O ₃ ] ⁺ 446.

Example 30 Step 2: 2-((5-Bromo-2-(4-chlorobenzyl)-1-(4-chlorophenyl)-3-oxoisoindolin-1-yl)oxy)-N,N-dimethylacetamide

Methyl 2-((5-bromo-2-(4-chlorobenzyl)-1-(4-chlorophenyl)-3-oxoisoindolin-1-yl)oxy)acetate (756 mg, 1.41 mmol) and 40% aqueous dimethylamine in water (7.6 ml) was mixed and stirred at room temperature for 6.5 h. The solvent was removed under vacuum and FCC [dichloromethane-methanol (100:0)→(94:6)] of the crude precipitate gave -((5-bromo-2-(4-chlorobenzyl)-1-(4-chlorophenyl)-3-oxoisoindolin-1-yl)oxy)-N,N-dimethylacetamide (524 mg, 68%) as white foam . MS: [MC ₄ H ₈ NO ₂ ] ⁺ 446.

Example 30 Step 3: (R)-2-((2-(4-chlorobenzyl)-1-(4-chlorophenyl)-5-(2-hydroxypropan-2-yl)-3-oxoisoindolin-1-yl) hydroxy)-N,N-dimethylacetamide

The title compound was prepared using procedures similar to those described for Compound 13 and Example 2. ¹ H NMR (500 MHz, CDCl ₃ ): 7.94 (1H, d, 7-H), 7.62 (1H, dd, ArH ), 7.35-7.30 (2H, m, 2×ArH), 7.24-7.18 (4H, m, 4×ArH), 7.12-7.07 (3H, m, 3× ArH), 4.74 (1H, d, NC-H'), 3.87 (1H, d, NC-H), 3.20 (1H, d, 4'-H'), 3.08 (1H , d, 4'-H), 2.76 (3H, s, NCH ₃ ), 2.37 (3H, s, NCH ₃ ) and 1.56-1.52 (6H, m, 2×CH ₃ ) . MS: [MC ₄ H ₈ NO ₂ ] ⁺ 424.

Example 31: (3R)-3-(4-Chlorophenyl)-2-[(4-chlorophenyl)methyl]-6-(2-hydroxypropan-2-yl)-3-{[1-(methoxymethyl)cyclopropyl]methoxy }-2,3-dihydro-1Н-isoindol-1-one

Example 31 Step 1: 2-(4-Chlorobenzyl)-3-(4-chlorophenyl)-3-((1-(methoxymethyl)cyclopropyl)methoxy)-6-(prop-1-en-2-yl)isoindoline -1-he

To a solution of 2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(prop-1-en-2-yl)isoindolin-1-one , Substances 13 (318 mg, 0.625 mmol), in anhydrous THF (3 ml) under nitrogen atmosphere was added ^t BuOK (140 mg, 1.25 mmol) at room temperature, and the mixture was stirred for 1 h before cooling to 0°C . Mel (0.08 ml, 1.25 mol) in anhydrous THF (1 ml) was added dropwise and stirred for 3.5 h. Dilute with EtOAc (10 ml) and washed with water (2×20 ml), brine ( 20 ml), dried over anhydrous Na ₂ SO ₄ , filtered, and the solvent was removed under vacuum. FCC [gasoline-ethyl acetate (100:0)→(80:20)] of the crude residue gave 2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-((1-(methoxymethyl)cyclopropyl)methoxy) -6-(prop-1-en-2-yl)isoindolin-1-one (278 mg, 85%) as a colorless gum. MS: [C ₆ H ₁₁ O ₂ ] ⁺ 406.

Example 31 Step 2: (R-2-(4-Chlorobenzyl)-3-(4-chlorophenyl)-6-(2-hydroxypropan-2-yl)-3-((1-(methoxymethyl)cyclopropyl)methoxy) isoindoline-1-one

Title compound using procedures similar to those described for Example 2. ¹ H NMR (500 MHz, CDCl ₃ ) 8.00 (1H, m, 7-H), 7.73 (1H, dd, ArH), 7.24 -7.17 (4H, m, 4 x ArH) 7.16-7.10 (4H, m, 4 x ArH), 7.08 (1H, d, ArH), 4.46 (1H, d, NC -H'), 4.30 (1H, d, NC-H), 3.43 (1H, d, 4'-H'), 3.31 (3H, s, OCH ₃ ), 3.16 (1H , d, 4'-H), 2.88 (1H, d, 2'-H'), 2.61 (1H, d, 2'-H), 1.67-1.62 (6H, m, 2×CH ₃ ), 0.45-0.38 (2H, m, Cy-Py-H ₂ ) and 0.25-0.15 (2H, m, Cy-Py-H). MS: [M-C ₆ H ₁₁ O ₂ ] ⁺ 424.

Example 32: (3R)-3-(4-Chlorophenyl)-2-[(4-chlorophenyl)methyl]-3-{[1-(hydroxymethyl)cyclobutyl]methoxy}-6-(2-hydroxypropan-2-yl )-2,3-dihydro-1H-isoindol-1-one

Example 32 Step 1: Cyclobutane-1,1-diyldimethanol

To a solution of diethyl 1,1-cyclobutanedicarboxylate (1.00 g, 4.99 mmol) in anhydrous THF (13 ml) at 0°C was added LiBH ₄ (239 mg, 11.0 mmol) in portions over 10 min and then stirred for another 10 min before heating to 60°C for 2 h. The reaction mixture was cooled to room temperature and then to 0°C. Water (2.5 ml) was added carefully and then 1 M HCl until gas evolution ceased, and then sat. NaOH solution. Extracted with EtOAc (3×10 ml) and then combined. Saline solution (5 ml) was added to the aqueous layer, which was then extracted with EtOAc (2×10 ml). The combined organic phases were washed with brine (15 ml), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give the title compound as a colorless thick oil (523 mg, 90%) which was used without purification. ¹ H NMR (500 MHz, CDCl ₃ ) 3.75 (4H, s, 2×HC ₂ OH), 2.32 (2H, br s, 2×OH), 1.96-1.90 (2H, m , H-3) and 1.80-1.77 (4H, m, H-2, H-4).

Example 32 Step 2: (R)-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclobutyl)methoxy)-6-(2-hydroxypropan-2-yl )isoindoline-1-one

The title compound was prepared from Compound 8 using procedures similar to those described for Compound 10, Compound 13, and Example 2. ¹ H NMR (500 MHz, CDCl ₃ ) 8.01 (1H, d, 7-H), 7.72 ( 1H, dd, ArH) 7.21-7.11 (8H, m, 8×ArH), 7.08 (1H, d, ArH), 4.52 (1H, d, NC-H'), 4, 23 (1H, d, NC-H), 3.53 (2H, d, OCH ₂ ), 2.88 (1H, d, CH ₂ OH), 2.79 (1H, d, CH ₂ OH) and 1 .86-1.51 (12H, m, 2×CH ₃ and 3×CH ₂ ). MS: [M-C ₆ H ₁₁ O ₂ ] ⁺ 424.

Example 33 5-chloro-2-{[(1R)-1-(4-chlorophenyl)-1-{[1-(hydroxymethyl)cyclopropyl]methoxy}-5-(2-hydroxypropan-2-yl)-3 -oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzoic acid

Example 33, Stage 1; (2-Bromo-4-chlorophenyl)methanamine

To a solution of 2-bromo-4-chlorobenzonitrile (500 mg, 2.3 mmol) in dry THF (50 ml) was slowly added the borohydride-THF complex (1 M, 12 ml, 11.5 mmol) at 0°C, after which heated under reflux for 1 h. After cooling, 1 M HCl in MeOH (20 ml) was slowly added under ice-cooling. The solvent was removed by concentration in vacuo, after which water (0.61 mmol/ml to benzonitrile) was added, then washed with Et ₂ O (0.61 mmol/ml to benzonitrile), after which it was basified with 2 M NaOH solution to pH 12. Added Et ₂ O (15 ml), and the mixture was washed with water (3×15 ml) and brine (1 ml). The organic phase was dried (MgO ₄ ) and concentrated in vacuo to give a yellow oil (345 mg, 68%). LCMS (ESI ⁺ ) m/z=220.1 [M+H] ⁺ .

Example 33, Stage 2; 6-Acetyl-2-(2-bromo-4-chlorobenzyl)-3-(4-chlorophenyl)-3-hydroxyisoindolin-1-one

The title compound was prepared using procedures similar to those described for Substance 9. LCMS (ESI ^- ) m/z=502.1 [M-H] ^-

Example 33, Stage 3; 6-Acetyl-2-(2-bromo-4-chlorobenzyl)-3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)isoindolin-1-one.

The title compound was prepared using procedures similar to those described for Compound 10. LCMS (ESI ⁺ ) m/z=588.3 [M+H] ⁺ .

Example 33, Stage 4; 6-Acetyl-2-(2-bromo-4-chlorobenzyl)-3-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-3-(4-chlorophenyl)isoindolin-1-one

The title compound was obtained using procedures similar to those described for Substance 29. LCMS (ESI ⁺ ) m/z=486.2 [M] ⁺ .

Example 33 Step 5 yl)methyl)-5-chlorobenzoic acid

To a solution of the previous compound (306 mg, 0.44 mmol) in dry DMF (4.0 ml) was added Xantphos (104 mg, 0.18 mmol), Pd(OAc) ₂ (20 mg, 0.09 mmol), HCOOLi ⋅H ₂ O (122 mg, 1.74 mmol) and Et ₃ N (0.25 ml, 1.74 mmol) before degassing for 15 min, and then Ac ₂ O (0.17 ml, 1.74 mmol) before being subjected to microwave irradiation for 30 min at 140°C. The mixture was passed through a pad of Celite, EtOAc (30 ml) was added, and the mixture was washed with water (3×30 ml) and brine (20 ml). The organic phase was dried (MgO ₄ ) and concentrated in vacuo. Chromatography (silica gel; EtOAc with 0.1% acetic acid, gasoline 20-80%) to give an oily solid (78 mg, 43%). LCMS (ESI ^- ) m/z=666.3 [M-H] ^- .

Example 33, Stage 6; 2-((1-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-1-(4-chlorophenyl)-5-(2-hydroxypropan-2-yl)-3-oxoisoindoline- 2-yl)methyl)-5-chlorobenzoic acid

The title compound was prepared using procedures similar to those described in Example 1:. LCMS (ESI ^- ) m/z=682.4 [M-H] ^- .

Example 33 Step 7: 5-chloro-2-{[(1R)-1-(4-chlorophenyl)-1-{[1-(hydroxymethyl)cyclopropyl]methoxy}-5-(2-hydroxypropan-2-yl )-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzoic acid

The product from Example 33, Step 6 was deprotected using techniques similar to those described in Example 10 to give Example 33. ¹ H-NMR (500 MHz, CDCl ₃ ) δ 0.26-0.30 (1H, m , cyclopropane CHHCH ₂ ), 0.36-0.40 (1H, m, cyclopropane CHHCH ₂ ), 0.50-0.59 (2H, m, cyclopropane CH ₂ CH ₂ ), 1.63 (6H, s, CH ₃ ), 2.50 (1H, d, C-O-CHH), 3.29 (1H, d, C-O-CHH), 3.45 (1H, d, CHOH), 3.86 (1H , d, CHHOH), 5.01 (1H, d, N-CHH), 5.19 (1H, d, N-CHH), 7.08 (2H, , d, H-Ar), 7.12 ( 1H, d, H-Ar), 7.16 (2H, d, H-Ar), 7.25-7.26 (2H, m, H-4 and H-Ar), 7.73-7.77 (2H, m, H-5 and H-Ar), 8.04 (1H, s, H-7). LCMS (ESI ^- ) m/z=568.3 [M-H] ^- .

Example 34: (3R)-2-{[4-chloro-2-(morpholine-4-sulfonyl)phenyl]methyl}-3-(4-chlorophenyl)-3-{[1-(hydroxymethyl)cyclopropyl]methoxy} -6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one

Example 34 Step 1 4-Chloro-2-mercaptobenzonitrile

4-Chloro-2-fluorobenzonitrile (200 mg, 1.29 mmol) and Na ₂ S (110 mg, 1.41 mmol) were added to the microwave vial, DMF (1 ml) was added to the mixture before stirring for 1 h at room temperature. 1 M NaOH was added until pH 12 was reached, then washed with Et ₂ O (3×10 ml, acidified with 1 M HCl to pH 1-2 and extracted with Et ₂ O (3×10 ml), the combined extracts were washed with water (30 ml) and brine (20 ml), dried over MgO ₄ , concentrated in vacuo to give a yellow solid (156 mg, 72%) ¹ H NMR (500 MHz, CDCl ₃ ) δ 4.14 (1H, s, SH ), 7.21 (1H, d, J=8.4 Hz, H-Ar), 7.42 (1H, s, H-Ar), 7.52 (1H, d, J=8.3 Hz, H-Ar).

Example 34 Step 2 4-Chloro-2-(morpholinosulfonyl)benzonitrile

To a stirred mixture of 4-chloro-2-mercaptobenzonitrile (50 mg, 0.30 mmol), t-BuNCl (333 mg, 1.20 mmol) and H ₂ O (0.02 ml) in MeCN (3 ml) was added NCS (120 mg, 0.90 mmol) at 0°C, after 30 min morpholine (0.03 ml, 0.30 mmol) was added to the reaction mixture before stirring overnight at room temperature, extracted with EtOAc (3×10 ml) , the combined organic extracts were washed with water (30 ml) and brine (20 ml), dried over MgO ₄ and concentrated in vacuo. Chromatography (silica gel; EtOAc, gasoline 20-50%) gave a white solid (59 mg, 70%). LCMS (ESI ⁺ ) m/z=287.2 [M+H] ⁺ .

Example 34 Step 3 (4-Chloro-2-(morpholinosulfonyl)phenyl)methanamine

Received using the same method as described in Example 33, Stage 1 (195 mg, 0.68 mmol), THF (4 ml), 1 mol/l borohydride-THF complex (3.4 ml, 3.40 mmol) and 1 M HCl in MeOH (4 ml). Concentration under vacuum gave a yellow oil (90 mg, 46%). LCMS (ESI ⁺ ) m/z=291.2 [M+H] ⁺ .

Example 34 Step 4 6-Acetyl-2-(4-chloro-2-(morpholinosulfonyl)benzyl)-3-(4-chlorophenyl)-3-hydroxyisoindolin-1-one

The title compound was prepared using procedures similar to those described for Substance 9. LCMS (ESI ^- ) m/z=573.3 [M-H] ^- .

Example 34 Step 5 6-Acetyl-2-(4-chloro-2-(morpholinosulfonyl)benzyl)-3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)isoindoline-1- He

The title compound was prepared using procedures similar to those described for Compound 22. LCMS (ESI ⁺ ) m/z=681.4 [M+Na] ⁺ .

Example 34 Step 6 (3R)-2-{[4-chloro-2-(morpholine-4-sulfonyl)phenyl]methyl}-3-(4-chlorophenyl)-3-{[1-(hydroxymethyl)cyclopropyl ]methoxy}-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one

The title compound was prepared using procedures similar to those described in Example 1. ¹ H-NMR (500 MHz, CDCl ₃ ) δ 0.21-0.23 (1H, m, cyclopropane CHHCH ₂ ), 0.30-0.32 (1H, m, cyclopropane CHHCH ₂ ), 0.44-0.49 (2H, m, cyclopropane CH ₂ CH ₂ ), 1.65 (6H, s, CH ₃ ), 1.85 (2H, bs, 2H ), 2.66 (1H, d, C-O-CHH), 2.96-3.01 (2H, m, H-morpholine), 3.07-3.11 (2H, m, H-morpholine) , 3.18 (1H, d, C-O-CHH), 3.33 (1H, d, CHHOH), 3.64-3.71 (4H, m, H-morpholine), 3.82 (1H, d, CHHOH), 4.92 (1H, d, N-CHH), 5.01 (1H, d, N-CHH), 7.11 (2H, d, H-Ar), 7.18-7, 24 (5H, m, H-Ar), 7.72 (1H, s, H-Ar), 7.79 (1H, d, H-5), 8.04 (1H, s, H-7). LCMS (ESI ^- ) m/z=673.4 [M-H] ^- .

Example 35: 1-({[(1R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-1-(4-chlorophenyl)-7-fluoro-5-(2-hydroxypropan-2-yl) -3-oxo-2,3-dihydro-1H-isoindol-1-yl]oxy}methyl)cyclopropan-1-carboxamide

Example 35 Step 1: Methyl 1-carbamoylcyclopropanecarboxylate

A solution of dimethylcyclopropane-1,1-dicarboxylate (57.8 g, 0.365 mol) in 7 M ammonia in methanol was stirred at room temperature for 90 h, then evaporated under reduced pressure to give the title compound as a colorless solid (52.2 g , 99%). ¹ H NMR (400 MHz; DMSO-d ₆ ): 7.82 (1H, s), 7.35 (1H, s), 3.63 (3H, s), 1.34 (4H, s).

Example 35 Step 2: 1-(Hydroxymethyl)cyclopropanecarboxamide

Lithium aluminum hydride (27.2 g, 0.719 mol) was added portionwise over 0.75 h to a stirred suspension of methyl 1-carbamoylcyclopropanecarboxylate (51.2 g, 0.358 mol) in THF (1.5 L) at 0°C in nitrogen atmosphere. After the addition was completed, the mixture was stirred at 0°C for another 1.25 h, after which water (27 ml), 15% NaOH (27 ml) and water (82 ml) were added dropwise successively. The mixture was allowed to warm to room temperature, stirred for 0.5 h and filtered through Celite. Celite was washed with EtOAc and the combined filtrate and washings were evaporated to give the title compound as a colorless solid (33.4 g, 71%). ¹ H NMR (400 MHz; DMSO-d ₆ ): 7.10-6.85 (2H, m), 4.97 (1H, t), 3.48 (2H, d), 0.90-0, 85 (2H, m), 0.61-0.58 (2H, m).

Example 35 Step 3: (4-Chloro-2-(methylsulfonyl)phenyl)methanamine

Hexamethylenetetramine (40.8 g, 0.291 mol) was added in one portion to a stirred solution of 1-(bromomethyl)-4-chloro-2-(methylsulfonyl)benzene (75 g, 0.264 mol) in EtOAc (1 L) at room temperature. After 1.5 h the mixture was cooled in ice and the precipitate was filtered, washed with cold EtOAc and air dried. This material was suspended in MeOH (375 ml), concentrated HCl (150 ml) was added dropwise over 0.33 h, and the mixture was heated at 40° C. for 2 h. The mixture was cooled, concentrated under reduced pressure, and the precipitate was made basic at with 5M NaOH, with cooling, and extracted with dichloromethane (3×500 ml). The combined extracts were dried (MgO ₄ ) and evaporated and the residue was chromatographed on silica gel eluting with a gradient of 20-100% EtOAc in isohexane followed by a gradient of 0-10% MeOH containing 7N. NH ₃ in EtOAc to give the title compound as a pale brown solid (27.8 g, 48%). 1 H NMR (400 MHz, CDCl ₃ ): 8.02 (1H, d), 7.58 (1H, dd), 7.51 (1H, d), 4.19 (2H, s), 3.23 ( 3H, s), 1.64 (2H, s).

Example 35 Step 4: (4-Chloro-2-(methylsulfonyl)phenyl)methanamine6-bromo-2-(4-chloro-2-(methylsulfonyl)benzyl)-3-(4-chlorophenyl)-4-fluoro-3 -hydroxyisoindolin-1-one

HATU (45.6 g, 0.12 mol) was added to a stirred solution of 5-bromo-2-(4-chlorobenzoyl)-3-fluorobenzoic acid (35.79 g, 0.1 mol) and (4-chloro-2 -(methylsulfonyl)phenyl)methanamine (21.95 g, 0.1 mol) in anhydrous DMF (100 ml) at room temperature. The mixture was stirred at room temperature for 18 hours, at 60°C for 18 hours, then cooled and concentrated under reduced pressure. The residual oil was poured into water (1.5 L), extracted with dichloromethane (4×500 ml) and the combined extracts washed with water (2×1 L), dried (MgO ₄ ) and evaporated, and the residue was chromatographed on silica gel, eluting with a gradient of 20 -100% EtOAc in isohexane to give the title compound as a pale yellow solid (42.7 r, 76%). 1 H NMR (400 MHz, CDCl ₃ ): 7.88 (1H, d), 7.70 (1H, d), 7.57 (1H, d), 7.49-7.45 (1H, m), 7.36-7.33(1H, m), 7.25(4H, s), 5.13(1H, d), 4.73(1H, d), 5.00-4.20(1H, br s), 3.07 (3H, s).

Example 35 Step 5: 1-(((5-Bromo-2-(4-chloro-2(methylsulfonyl)benzyl)-1-(4-chlorophenyl)-7-fluoro-3-oxoisoindolin-1-yl)oxy )methyl)cyclopropanecarboxamide

The title compound was prepared using procedures similar to those described for Compound 12. 1H NMR (400 MHz, CDCl ₃ ): 7.99 (1H, d), 7.93 (1H, dd), 7.75 (1H, d) , 7.51-7.47(1H, m), 7.30-7.19(5H, m), 6.98(1H, s), 6.76(1H, s), 4.99-4 .88(2H, m), 3.36-3.20(5H, m), 1.05-0.90(2H, m), 0.63-0.53(2H, m).

Example 35 Step 6: 1-(((2-(4-Chloro-2-(methylsulfonyl)benzyl)-1-(4-chlorophenyl)-7-fluoro-3-oxo-5-(prop-1-ene -2-yl)isoindolin-1-yl)oxy)methyl)cyclopropanecarboxamide

The title compound was prepared using procedures similar to those described for Compound 13., H NMR (400 MHz; DMSO-d ₆ ): 7.87 (1H, d), 7.76 (1H, d), 7.70 (1H , dd), 7.50(1H, dd), 7.30-7.20(5H, m), 6.98(1H, s), 6.70(1H, s), 5.73(1H, s), 5.33(1H, s), 5.00-4.85(2H, m), 3.36-3.23(5H, m), 2.20(3H, s), 0.97 -0.85(2H, m, 0.65-0.45(2H, m).

Example 35 Step 7 yl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]oxy}methyl)cyclopropan-1-carboxamide

The title compound was prepared using procedures similar to those described in Example 2. Chiral separation using supercritical fluid chromatography afforded the title compound as the slower moving isomer (0.245 g). 1 H NMR (400 MHz, CDCl ₃ ): 7.91-7.87 (2H, m 7.53 (1H, d), 7.37-7.30 (1H, m, 7.78-7.15 ( 5H, m, 6.53(1H, s), 5.45(1H, s), 5.05-4.95(2H, m, 3.36(1H, d), 3.00(3, s ), 2.96(1H, d), 1.96(1H, s), 1.65(6H, s), 1.32-1.15(2H, m, 0.60-0.30(2H , m) MS(ES+) m/z 633.3\635.3 [M+H] ⁺ .

Example 36: (3R)-2-[(4-chloro-2-methanesulfonylphenyl ₎ methyl]-3-(4-chlorophenyl)-3-({1-[hydroxy( ^2H2 )methyl]cyclopropyl}( ^2H ₂ )methoxy)-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one

Example 36 Step 1, 6-Bromo-2-(4-chloro-2-(methylsulfonyl)benzyl)-3-(4-chlorophenyl)-3-hydroxyisoindolin-1-one

The title compound was obtained using procedures similar to those described for Substance 9: LCMS (ESI ^- ) m/z=538.0 [M-H] ^- .

Example 36 Step 2 6-Bromo-2-(4-chloro-2-(methylsulfonyl)benzyl)-3-(4-chlorophenyl)-3-((1-(deuterated hydroxymethyl)cyclopropyl)deuterated methoxy)isoindoline-1 -He

The title compound was prepared using procedures similar to those described for Compound 22, but using 1,1-bis(deuterated hydroxymethyl)cyclopropane LCMS (ESI ⁺ ) m/z=650.2 [M+Na] ⁺ .

Example 36 Step 3: (3R)-2-[(4-chloro-2-methanesulfonylphenyl ₎ methyl]-3-(4-chlorophenyl)-3-({1-[hydroxy( ^2H2 )methyl]cyclopropyl}( ² H ₂ )methoxy)-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one

The title compound was prepared from Example 36 Step 2 using procedures similar to those described for Compound 13 and Example 2. ¹ H-NMR (500 MHz, CDCl ₃ ) δ 0.22-0.26 (1H, m, cyclopropane CHHCH ₂ ), 0.32-0.36 (1H, m, cyclopropane CHHCH ₂ ), 0.45-0.51 (2H, m, cyclopropane CH ₂ CH ₂ ), 1.65 (6H, s, CH ₃ ) , 1.83 (2H, bs, 2H), 3.06 (3H, s, SO ₂ CH ₃ ), 5.02 (2H, s, N-CH ₃ ), 7.13-7.20 (4H, m, H-Ar), 7.24-7.26 (2H, m, H-Ar), 7.30 (1H, d, H-Ar), 7.79 (1H, d, H-5), 7.89 (1H, s, H-Ar), 8.02 (1H, s, H-Ar). LCMS (ESI ⁺ ) m/z=608.4 [M+H] ⁺

Example 37 and 38: (3R)-3-(4-Chlorophenyl)-2-[(4-chlorophenyl)methyl]-6-(2-hydroxypropan-2-yl)-3-(oxolan-3-yloxy)- 2,3-dihydro-1H-isoindol-1-one

(*both isomers in positions shown)

The title compounds were prepared using procedures similar to those described for Compounds 10 and 13 and Example 2. The two diastereoisomers were isolated by preparative chiral HPLC.

Example 37 (isomer 1): ¹ H-NMR spectrum: δH (500 MHz, CDCl3): 8.01 (1H, d), 7.79 (1H, dd), 7.25-7.13 (9H, m ), 4.52(1H, d), 4.31(1H, d), 3.88-3.83(2H, m), 3.59-3.55(1H, m), 3.27- 3.19(2H, m), 1.79-1.74(1H, m), 1.59(6H, s), 1.53-1.46(1H, m).

Example 38: (isomer 2): ¹ H-NMR spectrum: δH (500 MHz, CDCl ₃ ): 8.01 (1H, d), 7.79 (1H, dd), 7.21-7.13 (9H , m), 4.49(1H, d), 4.43(1H, d), 3.88-3.82(2H, m), 3.63-3.59(1H, m), 3, 49 (1H, dd), 3.14 (1H, dd), 1.65-1.61 (2H, m), 1.59 (6H, s).

Example 39 and 40: (3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-6-(2-hydroxypropan-2-yl)-3-[(oxolan-3-yl) methoxy]-2,3-dihydro-1H-isoindol-1-one

(*both isomers in position shown)

Stage 1: 3-(Hydroxymethyl)tetrahydrofuran,

To a solution of tetrahydrofuran-3-carboxylic acid (0.247 ml, 2.58 mmol) in THF (13 ml) at 0°C was slowly added lithium aluminum hydride (1.0 M in THF, 5.2 ml, 5.16 mmol), stirred for 10 minutes, then left to reach room temperature and stirred for another 3 hours. The reaction mixture was cooled to 0°C and diluted with diethyl ether (15 ml), then treated successively with water (0.2 ml), NaOH (15% solution, 0.2 ml) and water (0.6 ml), and stirred in within 30 minutes. The white suspension was then treated with sodium sulfate, stirred for another 20 minutes, filtered through Celite, washed with diethyl ether (2×20 ml) and concentrated under vacuum to give 224 mg (85%) of the title compound as a colorless oil which was transferred to next step without further purification. ¹ H-NMR Spectrum: δ _H (500 MHz, CDCl ₃ ): 3.90-3.84 (2H, m), 3.78-3.73 (1H, m), 3.66-3.63 ( 2H, m), 3.61-3.57 (1H, m), 2.51-2.46 (1H, m), 2.08-2.01 (1H, m), 1.69-1, 62 (1H, m)

Step 2: (3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-6-(2-hydroxypropan-2-yl)-3-[(oxolan-3-yl)methoxy] -2,3-dihydro-1H-isoindol-1-one

(*both isomers in position shown)

The title compounds were prepared from 3-(hydroxymethyl)tetrahydrofuran and Compound 8 using procedures similar to those described for Compounds 10 and 13 and Example 2. The two diastereoisomers were isolated by preparative chiral HPLC.

Example 39 (*isomer 1): ¹ H-NMR spectrum: δH (500 MHz, (CD ₃ OD): 8.06 (1H, d), 7.79 (1H, dd), 7.31-7.22 (8H, m), 7.16 (1H, d), 4.67 (1H, d), 4.15 (1H, d), 3.77-3.75 (1H, m), 3.68- 3.59 (2H, m), 3.49-3.47 (1H, m), 2.79-2.77 (1H, m), 2.69-2.66 (1H, m), 2. 10-2.02(1H, m), 1.83-1.76(1H, m), 1.59(6H, s), 1.30-1.24(1H, m).

Example 40 (*isomer 2): ¹ H-NMR spectrum: δ _H (500 MHz, (CD ₃ OD): 7.94 (1H, d), 7.68-7.66 (1H, m), 7, 17-7.14(4H, m), 7.07-7.04(5H, m), 4.46(1H, d), 4.13(1H, d), 3.59-3.55( 3H, m), 3.18-3.15(1H, m), 2.68-2.60(2H, m), 2.12-2.04(1H, m), 1.86-1, 79 (1H, m), 1.47 (6H, s), 1.44-1.39 (1H, m).

Examples 41 and 42: (3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[1-hydroxy-1-(oxan-4- yl)ethyl]-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one

(*both isomers in positions shown)

Step 1: 6-Bromo-2-(4-chloro-2-(methylsulfonyl)benzyl)-3-(4-chlorophenyl)-4-fluoro-3-((1-(hydroxymethyl)cyclopropyl)methoxy)isoindole in- 1-he

Thionyl chloride (3 ml, 42.2 mmol) was added dropwise to a solution of 6-bromo-2-(4-chloro-2-(methylsulfonyl)benzyl)-3-(4-chlorophenyl)-4-fluoro-3-hydroxyisoindoline- 1-one (Example 35, Step 4) (4.72 g, 8.44 mmol) in THF (50 ml) at 0° C. under nitrogen. DMF (20 drops) was added and the orange solution was allowed to warm to rt. for 1 day. The reaction mixture was concentrated in vacuo and dissolved in THF (40 ml). Cyclopropane-1,1-diyldimethanol (1.72 g, 16.9 mmol) was added followed by K ₂ CO ₃ (2.33 g, 16.9 mmol) and the orange mixture was stirred at RT under nitrogen for 1 day . DCM and water were added and the layers were separated. The aqueous layer was extracted with DCM and the combined organic layers were dried (phase separator) and concentrated in vacuo. The precipitate was purified with Biotage (30-35% EtOAc in isohexanes) to give the title compound (3.33 g, 61%) as a pale yellow solid.

¹ H NMR (400 MHz, DMSO) 8.01 (1H, d), 7.95 (1H, dd), 7.79 (1H, d), 7.56 (1H, dd), 7.36 (2H , d), 7.30-7.26(3H, m), 5.01-4.90(2H, m), 4.45(1H, t), 3.48-3.31(2H, m ), 3.29 (3H, s), 3.05-2.96 (2H, m), 0.42-0.40 (2H, m), 0.27 (1H, d), 0.19 ( 1H, dd).

Step 2: 6-Acetyl-2-(4-chloro-2-(methylsulfonyl)benzyl)-3-(4-chlorophenyl)-4-fluoro-3-((1-(hydroxymethyl)cyclopropyl)methoxy)isoindoline-1 -He

The title compound was prepared in a manner similar to that described in Example 21, Step 3 using 6-bromo-2-(4-chloro-2-(methylsulfonyl)benzyl)-3-(4-chlorophenyl)-4-fluoro-3- ((1-(hydroxymethyl)cyclopropyl)methoxy)isoindolin-1-one.

¹ H NMR (400 MHz, DMSO) 8.30 (1H, d), 8.06 (1H, d), 7.80 (1H, d), 7.58 (1H, dd), 7.38-7 .28 (5H, m), 5.04-4.94 (2H, m), 3.48-3.30 (2H, m), 3.30 (3H, s), 3.06-2.98 (2H, m), 2.75 (3H, s), 0.41 (2H, dd), 0.28-0.25 (1H, m), 0.16 (1H, d).

Step 3: (3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[1-hydroxy-1-(oxan-4-yl) ethyl]-3-{[1-(hydroxymethyl)cyclopropyl]methoxy)-2,3-dihydro-1H-isoindol-1-one

LaCl ₃ .2LiCl (0.6 M in THF, 1.93 ml, 1.16 mmol) was added to a solution of 6-acetyl-2-(4-chloro-2-(methylsulfonyl)benzyl)-3-(4-chlorophenyl )-4-fluoro-3-((1-(hydroxymethyl)cyclopropyl)methoxy)isoindolin-1-one (703 mg, 1.16 mmol) in THF (7 mL) under nitrogen atmosphere and the yellow solution was stirred at RT at for 50 min and cooled to 0°C. (Tetrahydro-2H-pyran-4-yl) magnesium chloride (Novel Compound Solutions, 0.5 M in 2-Me-THF, 23.2 ml, 11.6 mmol) was added slowly and the cool bath was removed. The red solution was left to heat up to rt. for 30 min and quenched with saturated aqueous NH ₄ Cl. DCM and water were added and the layers were separated. The aqueous layer was extracted with DCM and the combined organic layers were washed with brine, dried (phase separator) and concentrated in vacuo. The precipitate was purified with Biotage (65-100% EtOAc in isohexanes) and subjected to chiral purification by SLC.

Example 41, Diastereoisomer 1:

¹ H NMR (400 MHz, CDCl3) 7.91 (1H, d), 7.76 (1H, d), 7.40-7.33 (2H, m), 7.30-7.27 (2H, m), 7.24-7.17(3H, m), 5.06-4.96(2H, m), 4.07-3.93(2H, m), 3.80(1H, dd) , 3.42-3.23(4H, m), 3.04(3H, s), 2.80(1H, d), 2.00(1H, dd), 1.91-1.82(1H , m), 1.79 (1H, s), 1.61 (3H, s), 1.53-1.40 (2H, m), 1.29-1.22 (2H, m), 0. 51 (2H, s), 0.49-0.39 (1H, m), 0.22 (1H, d). MS(ES+) m/z 692 [M+H] ⁺

Example 42, Diastereoisomer 2:

¹ H NMR (400 MHz, CDCl3) 7.91 (1H, d), 7.72 (1H, s), 7.43 (1H, d), 7.36 (1H, dd), 7.31-7 .17(5H, m), 5.07-4.96(2H, m), 4.07-3.93(2H, m), 3.81(1H, dd), 3.40-3.22 (4H, m), 3.03 (3H, s), 2.77 (1H, d), 2.01 (1H, s), 1.86-1.80 (2H, m), 1.62 ( 3H, s), 1.52-1.39 (2H, m), 1.31-1.25 (2H, m), 0.51 (2H, s), 0.49-0.40 (1H, m), 0.22 (1H, d). MS(ES+) m/z 692 [M+H] ⁺

Examples 43 and 44: (3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[2-hydroxy-1-(piperazine-1- yl)propan-2-yl]-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one

(*both isomers in position shown)

Stage 1

The product from Example 41, Step 1 was purified by preparative chiral HPLC to give

(3R)-6-bromo-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2 ,3-dihydro-1H-isoindol-1-one as a single enantiomer. Protection using TBDMS (according to a procedure similar to Compound 11) gave (R)-6-acetyl-3-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-2-(4- chloro-2-(methylsulfonyl)benzyl)-3-(4-chlorophenyl)-4-fluoroisoindolin-1-one.

Stage 2:

60% Sodium hydride dissolved in mineral oil (0.132 g; 3.44 mmol) was added portionwise over 10 minutes to a stirred solution of (R)-6-acetyl-3-((1-(((tert-butyldimethylsilyl) hydroxy)methyl)cyclopropyl)methoxy)-2-(4-chloro-2-(methylsulfonyl)benzyl)-3-(4-chlorophenyl)-4-fluoroisoindolin-1-one (1.56 g; 2.17 mmol) and trimethylsulfoxonium iodide (0.533 g; 2.42 mmol) in anhydrous DMSO (9 ml) and anhydrous THF (9 ml), at room temperature, under nitrogen atmosphere. After 20 hours, water (400 ml) was added, the mixture was extracted with EtOAc (2×250 ml) and the combined organic layers were dried (MgO ₄ ) and evaporated under reduced pressure. The residue was purified by chromatography on silica gel (100 g) eluting with a gradient of 0-50% EtOAc in isohexane to give 3-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-2-(4 -chloro-2-(methylsulfonyl)benzyl)-3-(4-chlorophenyl)-4-fluoro-6-(2-methyloxiran-2-yl)isoindolin-1-one as a pale yellow foam (0.736 g, 46 %). 1 H NMR (400 MHz, CDCl ₃ ): 7.90 (1H, d), 7.77 (1H, d), 7.40-7.27 (2H, m), 7.25-7.20 (2H , m), 7.22-7.10 (3H, m), 5.10-4.85 (2H, m), 3.85-3.70 (1H, m), 3.35-3.20 (2H, m), 3.10-3.00 (1H, m), 2.97 (3H, s), 2.80-2.60 (2H, m), 1.55 (3H, s), 0.82(9H, s), 0.50-0.35(2H, m), 0.25-0.05(2H, m), 0.01(6H, s).

Stage 3 and 4:

Step 3 was carried out following procedures similar to those described for Compound 34 (but using piperazine instead of dimethylamine). Step 4 was carried out following procedures similar to those described for Example 10. Chiral separation using supercritical liquid chromatography gave

Example 43 (faster moving isomer) (74 mg, 30%). 1 H NMR (400 MHz, CDCl ₃ ): 7.90 (1H, d), 7.77 (1H, d), 7.46 (1H, dd), 7.40-7.30 (1H, m), 7.30-7.10(5H, m), 5.10-4.98(2H, m), 3.82(1H, d), 3.40-3.30(1H, m), 3, 30-3.20(1H, m), 3.03(3H, s), 2.85-2.65(7H, m), 2.55-2.45(2H, m), 2.38-2, 25(2H, m), 2.20-1.65(3H, m), 1.51(3H, s), 0.55-0.45(2H, m), 0.45-0.35( 1H, m), 0.30-0.15 (1H, m). MS(ES+) m/z 706 [M+H] ⁺ .

Example 44 (slower moving isomer) (76 mg, 31%). 1 H NMR (400 MHz, CDCl ₃ ): 7.90 (1H, d), 7.75 (1H, d), 7.48 (1H, dd), 7.40-7.30 (1H, m), 7.30-7.10(5H, m), 5.10-4.90(2H, m), 3.82(1H, d), 3.40-3.30(1H, m), 3, 30-3.20(1H, m), 3.03(3H, s), 2.85-2.65(7H, m), 2.55-2.45(2H, m), 2.38- 2.25(2H, m), 2.20-1.65(3H, m), 1.51(3H, s), 0.55-0.45(2H, m), 0.45-0, 35 (1H, m), 0.30-0.15 (1H, m). MS(ES+) m/z 706 [M+H] ⁺ .

Examples 45 and 46: (3R)-3-(4-Chlorophenyl)-2-[(1S)-1-(4-chlorophenyl)ethyl]-3-{[(3S,4R)-4-hydroxyoxolane-3- yl]oxy}-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one and (3R)-3-(4-chlorophenyl)-2-[(1S)- 1-(4-chlorophenyl)ethyl]-3-{[(3R,4S)-4-hydroxyoxolan-3-yl]oxy}-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1Н -isoindole-1-one

Examples 45 and 46, Stage 1:

3-(4-Chlorophenyl)-2-[(1S)-1-(4-chlorophenyl)ethyl]-3-[(4-hydroxyoxolan-3-yl)oxy]-6-(prop-1-en-2 -yl)-2,3-dihydro-1H-isoindol-1-one

The title compound (as a mixture of 4 isomers) was prepared using a procedure similar to that described for Compound 10 using 1,4-anhydroerythritol and Compound 13. The crude material was purified by silica gel chromatography (Pet:EtOAc 1:0 to 1 :2) to obtain the desired products in the form of a foamy colorless oil. | The product (a mixture of 4 isomers) was used directly in the next step.

Example 45 and Example 46, Stage 2

Example 45 and Example 46 were prepared using a procedure similar to that described for Example 2. The desired products were isolated using silica gel chromatography (Pet:EtOAc 2:1 to 0:1).

Example 45 (isomer 1): R _f =0.25 (Pet:EtOAc/1:2). ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm) 1.61 (s, 3H, C(CH ₃ ) ₂ ), 1.62 (s, 3H, C(CH ₃ ) ₂ ), 1.85 ( s, 1H, C(CH ₃ ) ₂ OH), 1.91 (d, 3H, J=7.3 Hz, NCHCH ₃ ), 2.49 (d, 1H, J=3.6 Hz, CHOH), 3.27-3.37 (M, 1H, H-b), 3.67 (dd, 1H, J=10.4, 4.0 Hz, H-a), 3.83 (dd, 1H, J =10.3, 1.2 Hz, H'-a), 3.87-4.01 (m, 3H, Hd, H'-d, H-c), 4.28 (q, 1H, J= 7.3 Hz, NCH), 6.94 (d, 2H, J=8.5 Hz, Ar-H), 6.97-7.09 (m, 6H, Ar-H); 7.20 (d, 1H, J=8.0 Hz, isoindolinone-H), 7.73 (d, 1H, J=7.9, 1.5 Hz, isoindolinone-H), 7.98 (d, 1H, J=1.3 Hz, isoindolinone-H); MS(ES+) m/z 484.3 [M+H] ⁺ ;

Example 46 (isomer 2): R _f =0.57 (Pet:EtOAc/1:2); ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm) 1.61 (s, 6H, C(CH ₃ ) ₂ ), 1.74 (d, 3H, J=7.2 Hz, NCHCH ₃ ), 1 .82 (s, 1H, C(CH ₃ ) ₂ OH), 2.06 (s, 1H, CHOH), 2.63-2.68 (m, 1H, Hb), 2.71 (dd, 1H, J=8.5, 7.3 Hz, Hd), 3.28 (dd, 1H, J=8.5, 8.4 Hz, H'-d), 3.42 (dd, 1H, J=10 .3, 4.1 Hz, Ha), 3.44-3.49 (m, 1H, Hc), 3.53 (dd, 1H, J=10.4, 1.5 Hz, H'-a) , 4.19 (q, 1H, J=7.3 Hz, NCH), 6.97 (d, 1H, J=8.0 Hz, isoindolinone-H), 7.28 (d, 2H, J=8 .4 Hz, Ar-H), 7.31-7.44 (m, 4H, Ar-H), 7.57 (d, 2H, J=8.4 Hz, Ar-H), 7.68 ( dd, 1H, J=7.9, 1.6 Hz, isoindolinone-H), 7.98 (d, 1H, J=1.3 Hz, isoindolinone-H); MS(ES+) m/z 484.3 [M+H] ⁺ ;

Example 47: (3R)-3-(4-Chlorophenyl)-2-[(4-chlorophenyl)methyl]-6-(2-hydroxypropan-2-yl)-3-methoxy-2,3-dihydro-1H- isoindole-1-one

The title compound was prepared from Compound 8 using (successively) procedures similar to those described for Compound 12;

Example 21 Step 3 and Example 1 ¹ H-NMR Spectrum: (in CDCl ₃ ) δ (ppm) 1.61 (s, 6H, C(CH ₃ ) ₂ ), 2.12 (s, 1H, OH ), 2.62 (s, 3H, OCH ₃ ), 4.07 (d, 1H, J=14.8 Hz, NCHH), 4.58 (d, 1H, J=14.8 Hz, NCHH), 7.06 (d, 1H, J=8.0 Hz, Ar-H), 7.12-7.17 (m, 2H, Ar-H), 7.15-7.25 (m, 6H, Ar -H), 7.69 (dd, 1H, J=8.0, 1.7 Hz, Ar-H), 8.00 (d, 1H, J=1.6 Hz, Ar-H. ms (M -H ⁺ ) m/z=456.4.

Example 48: (3R)-3-(4-Chlorophenyl)-2-[(4-chlorophenyl)methyl]-3-({1-[hydroxy( ^2H ₂ )methyl]cyclopropyl}(2H ₂ )methoxy)- 6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one

The title compound was prepared using procedures similar to those described for Example 1. ¹ H NMR (500 MHz; CDCl ₃ ) L _H 0.10-0.18 (2H, m, 2×H-cyclopropyl), 0.38-0 .44 (2H, m, 2×H-cyclopropyl), 1.52 (1H, br s, OH), 1.61 (3H, s, CH ₃ ), 1.63 (3H, s, CH ₃ ), 1.75 (1H, br s, OH), 4.18 (1H, d, J=15.0 Hz, CH _a H _b Ph), 4.55 (1 H, d, J=15.0 Hz, CH _a H _b Ph), 7.10 (1H, d, J=8.0 Hz, H-4), 7.12-7.23 (8H, m, H-Ar), 7.72 (1H, dd , J=1.7 and 8.0 Hz, H-5), 7.99 (1H, d, J=1.7 Hz, H-7). LCMS (ES+) m/z 424.3, 426.3 [(M-c3 side chain)+H] ⁺

Example 49: (3R)-3-(4-Chlorophenyl)-2-[(4-chlorophenyl)methyl]-6-(2-hydroxypropan-2-yl)-3-(3-hydroxypropoxy)-2,3- dihydro-1H-isoindol-1-one

The title compound was prepared using procedures similar to those described for Example 1. 1H-NMR spectrum: δH (500 MHz, CDCl3) 1.40-1.55 (2H, m, CH2CH2CH2OH), 1.60-1.64 (6H , m, 2×CH3), 2.79-2.85 (1H, m, CH2CH2CH2OH), 2.85-2.93 (1H, m, CH2CH2CH2OH), 3.57 (2H, t, J=6, 1 Hz, CH2CH2CH2OH), 4.05 (1H, d, J=14.8 Hz, NC-H), 4.65 (1H, d, J=14.9 Hz, NC-H'), 7.08 (1H, d, J=7.9 Hz, ArH), 7.14-7.25 (8H, m, 8×ArH), 7.70 (1H, dd, J=1.7 and 7.9 Hz , ArH) and 7.99 (1H, d, J=1.2 Hz, 7-H).; (ES+) m/z 424.3 [M-O(CH-2)3OH]+

Example 50: (3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-6- (2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one

The title compound was prepared using procedures similar to those described for Example 36. 1H-NMR spectrum: δH (500 MHz, CDCl3) 0.17-0.25 (1H, m, Cy-Py-H), 0.38-0 .42 (1H, m, Cy-Py-H), 0.46-0.53 (2H, m, Cy-Py-H2), 1.60-1.64 (6H, 2xs, 2xCH3 ), 2.77 (1H, d, J=9.1 Hz, 2'-H), 3.03 (3H, s, SO2CH3), 3.25 (1H, J=9.1 Hz, 2'- H'), 3.36 (1H, d, J=11.2 Hz, 4'-H'), 3.81 (1H, d, J=11.1 Hz, 4'-H'), 4.94 -5.04 (2H, m, NC-H, NC-H'), 7.14-7.21 (3H, m, 3×ArH), 7.25-7.29 (2H, m, 2× ArH), 7.32 (1H, dd, J=2.3 and 8.4 Hz, ArH), 7.45 (1H, dd, J=1.3 and 10.8 Hz, ArH), 7.81 (1H, d, J=1.4 Hz, ArH) and 7.89 (1H, d, J=2.3, 7-H). (ES+) m/z 520.3 [M-C5H9O2]+

Example 51: (3R)-3-(4-Chlorophenyl)-2-[(4-chlorophenyl)methyl]-3-(2,2-difluoro-3-hydroxypropoxy)-6-(2-hydroxypropan-2-yl )-2,3-dihydro-1H-isoindol-1-one

The title compound was prepared from Compound 20 and difluoropropanediol following procedures similar to those described for Compound 12 and Example 1. 1H-NMR spectrum: δH (500 MHz, CDCl3) 1.55 (3H, s, CH3), 1.56 (3H , s, CH3), 2.93-3.02 (2H, m, CH2), 3.63-3.78 (2H, m, CH2), 4.19 (1H, d, J=15.0 Hz , NCHH'), 4.45 (1H, d, J=15.0 Hz, NCHH'), 7.04-7.11 (7H, m, 7×ArH), 7.13-7.15 (2H , m, 2×ArH), 7.67 (1H, dd, J=1.7 and 8.0 Hz, ArH), 7.94 (1H, d, J=1.7 Hz, ArH). m/z 536.4 [M+H]+

Examples 52 and 53: (3R)-3-(4-Chlorophenyl)-2-[(4-chlorophenyl)methyl]-3-{[2-(hydroxymethyl)cyclobutyl]methoxy}-6-(2-hydroxypropane-2 -yl)-2,3-dihydro-1H-isoindol-1-one

(both isomers as shown)

Example 52 and 53 Step 1: (2-Hydroxymethylcyclobutyl)-methanol

A suspension of cyclobutanedicarboxylic acid (649mg, 4.50mmol) in tetrahydrofuran (45mL) was cooled to 0°C and treated with lithium aluminum hydride (1M in THF, 18.0mL, 18.01mmol) and stirred for 3 hours. After completion of the reaction according to TLC (SiO2; 30% MeOH in DCM), the reaction mixture was diluted with diethyl ether (45 ml) and treated successively with water (0.68 ml), sodium hydroxide (15% aq., 0.68 ml) and water (2.1 ml), then stirred for 30 minutes. Added sodium sulfate, and the mixture of solutions was stirred for another 30 minutes. After filtration, the organic layer was concentrated in vacuo to give the title compound (305 mg, 58%) as a colorless oil which was used without the need for further purification.

Example 52 and 53, Stage 2:

Examples 52 and 53 were prepared from (2-hydroxymethylcyclobutyl)-methanol in a similar manner to Example 1. The two desired isomers were isolated by preparative chiral HPLC.

Example 52 (isomer 1): δ _H (500 MHz, (CD ₃ OD): 8.05 (1H, d), 7.79 (1H, dd), 7.25-7.21 (4H, m), 7.19-7.14(5H, m), 4.52(1H, d), 4.33(1H, d), 3.54-3.49(1H, m), 3.44-3, 40 (1H, m), 3.06-3.03 (1H, m), 2.91-2.87 (1H, m), 2.53-2.49 (1H, m), 2.37- 2.35(1H, m), 2.04-1.96(2H, m), 1.73-1.63(2H, m), 1.59(6H, s).

Example 53 (isomer 2): δ _H (500 MHz, (CD ₃ OD): 8.06 (1H, d), 7.79 (1H, dd), 7.25-7.21 (4H, m), 7.19-7.14(5H, m), 4.52(1H, d), 4.33(1H, d), 3.54-3.49(1H, m), 3.44-3, 40 (1H, m), 3.06-3.03 (1H, m), 2.91-2.87 (1H, m), 2.53-2.48 (1H, m), 2.39- 2.35(1H, m), 2.04-1.96(2H, m), 1.72-1.63(2H, m), 1.59(6H, s).

Examples 54 and 55: (3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-6-[2-hydroxy-1-oxo-1-(pyrrole-idin-1-yl)propane -2-yl]-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one

(*both isomers in positions shown)

Example 54 and Example 55 Step 1: (R)-3-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-2-(4-chlorobenzyl)-3-(4-chlorophenyl) -6-(prop-1-en-2-yl)isoindole in-1-one

TBSCI (2.62 g, 17.4 mmol, 1.5 eq.), imidazole (1.19 g, 1.5 eq.) and 2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3 -((1-(hydroxymethyl) cyclopropyl)methoxy)-6-(prop-1-en-2-yl)isoindolin-1-one (R-isomer) (5.9 g, 11.6 mmol, 1 eq. ) was dissolved in THF (100 ml) and heated to 50°C for 6 h. Left to cool to rt, and divided between EtOAc (2×70 ml) and H ₂ O (70 ml). The organic extracts were combined, dried over MgO ₄ and the solvent was removed under vacuum. The precipitate was purified with HPLC (1-5% EtOAc/petrol) to give a clear oil (6.045 g, 84%); ¹ H NMR (500 MHz; CDCl ₃ ) δ -0.02 (3H, s, CH ₃ Si), 0.00 (3H, s, CH ₃ Si), 0.07-0.12 (2H, m, cPr), 0.33-0.38 (2H, m, cPr), 0.83 (9H, s, tBu), 1.27 (3H, s, Me), 2.16-2.19 (2H, br s,), 2.62 (1H, d, CH _a H _b O), 2.89 (1H, d, CH _a H _b O), 3.36 (1H, d, CH _a H _b O), 3.65 (1H, d, CH _a H _b O), 4.32 (1H, d, CH _a H _b N), 4.39 (1H, d, CH _a H _b N)), 5.18 ( 1H, m, H-alkene), 5.44 (1H, m, H-alkene), 7.01-7.22 (9H, m, H-Ar), 7.58 (1H, dd, H-5 ), 7.96 (1H, d, H-7).

Example 54 and Example 55, Stage 2:

(3R)-3-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-6-(1,2-dihydroxypropane -2-yl)isoindoline-1-one

The title compound was prepared using procedures similar to those described for Example 27 to give the product as a mixture of two stereoisomers. ¹ H NMR (500 MHz; CDCl ₃ ) δ -0.02 (3H, s, CH ₃ Si), 0.00 (3H, s, CH ₃ Si), 0.07-0.13 (2H, m, cPr), 0.33-0.39 (2H, m, cPr), 0.83 (9H, s, tBu), 1.56 (3H, s, Me), 1.82 (1H, br s, OH ), 2.60 (1H, d, CH _a H _b O), 2.64 (1H, br s, OH), 2.88 (1H, d, CH _a H _b O), 3.36 (1H, d, CH _a H _b O), 3.62-3.74 (2H, m, CH _a H _b O and CH _a H _b OH), 3.81 (1H, d, CH _a H _b OH), 4 .31 (1H, d, CH _a H _b N), 4.40 (1H, d, CH _a H _b N)), 7.03-7.13 (5H, m, H-Ar), 7.13 -7.20 (4H, m, H-Ar), 7.67 (1H, dd, H-5), 7.94 (1H, d, J=1.5 Hz, H-7); MS ES+440.3, 442.3 [M-side chain] ⁺ .

Example 54 and Example 55, Stage 3:

2-((R)-1-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-2-(4-chlorobenzyl)-1-(4-chlorophenyl)-3-oxoisoindoline-5 -yl)-2-hydroxypropanoic acid

TEMPO (161 mg, 1.03 mmol, 0.25 eq.), NaClO ₂ (744 mg, 8.22 mmol, 2 eq.) and NaOCl (30 μl, 0.08 mmol, 0.02 eq.) were added to (3R)-3-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-6-(1,2- dihydroxypropan-2-yl)isoindolin-1-one (2.7 g, 4.11 mmol, 1 eq.) in a mixture of MeCN (20 ml) and sodium phosphate buffer (pH 6.5, 16 ml), and a mixture stirred at rt. within 5 days. Water was added and the pH was adjusted to pH 8 with NaOH (1 M aq.). Na ₂ SO ₃ (aq.) was added and the pH was adjusted to pH 2 with HCl (1 M aq.). The mixture was extracted with EtOAc (2×50 ml), dried over MgO ₄ and the solvent was removed under vacuum. Purification with HPLC on silica gel with a gradient of 0-10% MeOH/DCM afforded a white foam (2.27 g, 83%, diastereomeric mixture approx. 3:1); Dominant diastereoisomer: ¹ H NMR (500 MHz; CDCl ₃ ) δ 0.00 (3H, s, CH ₃ Si), 0.02 (3H, s, CH ₃ Si), 0.10-0.17 (2H, m, cPr), 0.35-0.42 (2H, m, cPr), 0.85 (9H, s, tBu), 1.94 (3H, s, Me), 2.65 (1H, d, CH _a H _b O), 2.90 (1H, d, CH _a H _b O), 3.39 (1H, d, CH _a H _b O), 3.65 (1H, m, CH _a H _b O ), 3.81 (1H, d, CH _a H _b OH), 4.35 (1H, d, CH _a H _b N), 4.41 (1H, d, CH _a H _b N)), 7, 00-7.20 (9H, m, H-Ar), 7.96 (1H, dd, H-5), 8.29 (1H, d, H-7); MS ES - 668.3, 670.3 [MH] ^-

Example 54 and Example 55, Step 4:

The title compound was prepared from 2-((R)-1-((1-((((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-2-(4-chlorobenzyl)-1-(4-chlorophenyl)-3 -oxoisoindolin-5-yl)-2-hydroxypropanoic acid using PyBrop and pyrrolidine. Deprotection using procedures similar to those described for Example 10 followed by preparative HPLC yielded two isomers.

Example 54 (*isomer 1). ¹ H-NMR spectrum: (500 MHz, CDCl ₃ ) δ 0.12-0.18 (2H, m, cyclopropane CH ₂ CH ₂ ), 0.40-0.44 (2H, m, cyclopropane CH ₂ CH ₂ ), 1.55-1.59 (2H, m, H-pyrrolidine), 1.72-1.77 (3H, m, H-pyrrolidine and OH), 1.85 (3H, s, CH ₃ ), 2.56-2.61 (1H, m, H-pyrrolidine), 2.72 (1H, d, J=9.4 Hz, C-O-CHH), 2.76 (1H, d, J=9 .4 Hz, C-O-CHH), 3.09-3.14 (1H, m, H-pyrrolidine), 3.39 (1H, d, J=11.4 Hz, CHHOH), 3.47 ( 1H, d, J=11.4 Hz, CHHOH), 3.51-3.56 (2H, m, H-pyrrolidine), 4.24 (1H, d, J=14.9 Hz, N-CHH) , 4.51 (1H, d, J=14.9 Hz, N-CHH), 5.44 (1H, s, OH), 7.11-7.21 (9H, m, H-Ar), 7 .51 (1H, d, J=8.0 Hz, H-5), 8.0 (1H, s, H-7). MS (ESI ⁺ ) m/z=507.4 [M+H] ⁺

Example 55 (*isomer 2): ¹ H-NMR Spectrum: (500 MHz, CDCl ₃ ) δ 0.09-0.13 (2H, m, cyclopropane CH ₂ CH ₂ ), 0.38-0.43 (2H , m, cyclopropane CH ₂ CH ₂ ), 1.51-1.59 (2H, m, H-pyrrolidine), 1.70-1.78 (3H, m, H-pyrrolidine and OH), 1.85 ( 3H, s, CH ₃ ), 2.59-2.66 (2H, m, H-pyrrolidine and C-O-CHH), 2.74 (1H, d, J=9.3 Hz, C-O- CHH), 3.05-3.10 (1H, m, H-pyrrolidine), 3.33 (1H, d, J=11.3 Hz, CHHOH), 3.48 (1H, d, J=11, 3 Hz, CHHOH), 3.55-3.58 (2H, m, H-pyrrolidine), 4.17 (1H, d, J=14.8 Hz, N-CHH), 4.54 (1H, d , J=14.8 Hz, N-CHH), 5.38 (1H, s, OH), 7.11-7.22 (9H, m, H-Ar), 7.53 (1H, d, J = 8.1 Hz, H-5), 8.0 (1H, s, H-7). MS (ESI ⁺ ) m/z=507.4 [M+H] ⁺

Examples 56 and 57: 2-[(1R)-1-(4-Chlorophenyl)-2-[(4-chlorophenyl)methyl]-1-{[1-(hydroxymethyl)cyclopropyl]methoxy}-3-oxo-2 ,3-dihydro-1H-isoindol-5-yl]-2-hydroxy-N,N-dimethylpropanamide (*both isomers in position shown)

Example 56 and 57, Stage 1:

2-((R)-1-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-2-(4-chlorobenzyl)-1-(4-chlorophenyl)-3-oxoisoindoline-5 -yl)-2-hydroxy-N,N-dimethylpropanamide

To a solution of 2-((R)-1-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-2-(4-chlorobenzyl)-1-(4-chlorophenyl)-3-oxoisoindoline -5-yl)-2-hydroxypropanoic acid (Example 54 and Example 55, step 3) (400 mg, 0.60 mmol), PyBroP (420 mg, 0.90 mmol) and pyridine (0.05 ml, 0. 60 mmol) in MeCN (4 ml) was added a solution of dimethylamine (2M in MeCN, 0.75 ml, 1.5 mmol) before stirring at room temperature overnight. The reaction mixture was extracted with EtOAc (3×10 ml), the combined organic extracts were washed with water (30 ml) and brine (20 ml), dried over MgO ₄ and concentrated under vacuum. Chromatography (silica gel; EtOAc, gasoline 20-90%) gave a white solid (250 mg, 71%). LCMS (ESI ⁺ ) m/z=719.5 [M+Na] ⁺ .

Example 56 and 57, Stage 2

2-((1R)-2-(4-Chlorobenzyl)-1-(4-chlorophenyl)-1-((1-(hydroxymethyl)cyclopropyl)methoxy)-3-oxo-2,3-dihydro-1H-isoindole -5-yl)-2-hydroxy-N,N-dimethylpropanamide (*both isomers in position shown)

The title compound was prepared using procedures similar to those described for Example 10. Purification by chiral HPLC gave the title compound:

¹ H-NMR (500 MHz, CDCl ₃ ) δ 0.11-0.15 (2H, m, cyclopropane CH ₂ CH ₂ ), 0.39-0.43 (2H, m, cyclopropane CH ₂ CH ₂ ), 1.63 (1H, brs, OH), 1.86 (3H, s, CH ₃ ), 2.59-2.64 (4H, m, C-O-CHH and N-CH ₃ ), 2.80 (1H, d, C-O-CHH), 3.02 (3H, brs, N-CH ₃ ), 3.34 (1H, d, CHOH), 3.50 (1H, d, CHOH), 4, 18 (1H, d, N-CHH), 4.54 (1H, d, N-CHH), 5.39 (1H, s, OH), 7.11-7.18 (7H, m, H-Ar ), 7.21 (2H, d, H-Ar), 7.50 (1H, d, H-5), 8.0 (1H, s, H-7). LCMS (MER ^- ) m/z=627.4 [M+Formate] ^- .

Example 56 (*isomer 1): ¹ H-NMR spectrum: (500 MHz, CDCl ₃ ) δ 0.12-0.18 (2H, m, cyclopropane CH ₂ CH ₂ ), 0.40-0.44 (2H , m, cyclopropane CH ₂ CH ₂ ), 1.59 (1H, brs, OH), 1.87 (3H, s, CH ₃ ), 2.59 (3H, brs, N-CH ₃ ), 2.70 (1H, d, J=9.4Hz, C-O-CHH), 2.79 (1H, d, J=9.4Hz, C-O-CHH), 3.00 (3H, brs, N -CH ₃ ), 3.38 (1H, d, J=11.4 Hz, CHOH), 3.48 (1H, d, J=11.4 Hz, CHOH), 4.24 (1H, d, J =14.8 Hz, N-CHH), 4.51 (1H, d, J=14.8 Hz, N-CHH), 5.44 (1H, s, OH), 7.11-7.17 ( 7H, m, H-Ar), 7.20 (2H, d, J=8.9 Hz, H-Ar), 7.47 (1H, d, J=8.0 Hz, H-5), 8 .0 (1H, s, H-7). MS (ESI ⁺ ) m/z=481.3 [M+H] ⁺

Example 57 (*isomer 2): ¹ H-NMR spectrum: (500 MHz, CDCl ₃ ) δ 0.11-0.15 (2H, m, cyclopropane CH ₂ CH ₂ ), 0.39-0.43 (2H , m, cyclopropane CH ₂ CH ₂ ), 1.63 (1H, brs, OH), 1.86 (3H, s, CH ₃ ), 2.59-2.64 (4H, m, C-O-CHH and N-CH ₃ ), 2.80 (1H, d, J=9.5 Hz, C-O-CHH), 3.02 (3H, brs, N-CH ₃ ), 3.34 (1H, d , J=11.3 Hz, CHOH), 3.50 (1H, d, J=11.3 Hz, CHOH), 4.18 (1H, d, J=14.8 Hz, N-CHH), 4 .54 (1H, d, J=14.8 Hz, N-CHH), 5.39 (1H, s, OH), 7.11-7.18 (7H, m, H-Ar), 7.21 (2H, d, J=8.9Hz, H-Ar), 7.50 (1H, d, J=8.0Hz, H-5), 8.0 (1H, s, H-7). MS (ESI ⁺ ) m/z=481.3 [M+H] ⁺

Examples 58 and 59: 2-[(1R)-1-(4-Chlorophenyl)-2-[(4-chlorophenyl)methyl]-1-{[1-(hydroxymethyl)cyclopropyl]methoxy}-3-oxo-2 ,3-dihydro-1H-isoindol-5-yl]-2-hydroxy-N-methylpropanamide

(*both isomers in positions shown)

The title compound was prepared from 2-((R)-1-((1-((((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-2-(4-chlorobenzyl)-1-(4-chlorophenyl)-3 -oxoisoindolin-5-yl)-2-hydroxypropanoic acid using PyBrop and methylamine. Deprotection using procedures similar to those described for Example 10 followed by preparative HPLC yielded two isomers.

Example 58 (*isomer 1): ¹ H-NMR: (500 MHz, CDCl ₃ ) δ 0.13-0.19 (2H, m), 0.39-0.44 (2H, m), 1.67 (1H, brs), 1.84(3H, s), 2.66(1H, d), 2.79(3H, d), 2.83(1H, d), 3.36(1H , d), 3.48 (1H, d), 4.05 (1H, s), 4.21 (1H, d), 4.50 (1H, d), 6.88 (1H, q, ), 7.08-7.18 (9H, m), 7.82 (1H, d), 8.23 (1H, s). LCMS (ESI) m/z=567.3 [M-H] ^-

Example 59 (*isomer 2): ¹ H-NMR: (500 MHz, CDCl ₃ ) δ 0.12-0.18 (2H, m), 0.38-0.43 (2H, m), 1.85 (3H, s), 2.63 (1H, d,), 2.79 (3H, d,), 2.85 (1H, d,), 3.34 (1H, d, J = 11.4 Hz , CHHOH), 3.50 (1H, d, J=11.4 Hz, CHHOH), 4.19 (1H, d,), 4.52 (1H, d), 6.90 (1H, q,) , 7.09-7.20(9H, m,), 7.81(1H, d), 8.23(1H). LCMS (ESI) m/z=567.3 [M-H] ^-

Examples 60: (3R)-2-{[4-Chloro-2-(methylsulfanyl)phenyl]methyl}-3-(4-chlorophenyl)-4-fluoro-3-{[1-(hydroxymethyl)cyclopropyl]methoxy} -6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one

The title compound was prepared from 5-bromo-2-(4-chlorobenzoyl)-3-fluorobenzoic acid and Compound 43 (4-chloro-2-(methylthio)phenyl)methanamine) following procedures similar to those described for Compound 9, Compound 10 , Example 21, Stage 3, and Example 1; in the given sequence.

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.81 (1H, s, H-7), 7.39 (1H, d5), 7.23 (2H, d, 7.16-7.19 (3H , m), 7.01 (1H, s), 6.96 (1H, d), 4.68 (1H, d), 4.43 (1H, d), 3.49 (1H, q), 3 .41 (1H, q), 2.95 (1H, d), 2.89 (1H, d), 2.38 (3H, s), 1.90 (1H, s), 1.71 (1H, t), 1.61 (6H, d), 0.41-0.48 (2H, m), 0.28-0.31 (1H, m), 0.14-0.17 (1H, m) LCMS (ESI ^- ) m / z \u003d 634.3 [M + Formate] ^-

Examples 61 and 62: (3R)-2-[(4-Chloro-2-methanesulfinylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}- 6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one

(*both isomers in position shown)

To a solution of (3R)-2-{[4-chloro-2-(methylsulfanyl)phenyl]methyl}-3-(4-chlorophenyl)-4-fluoro-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}- 6-(2-Hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one (Example 60) (140 mg, 0.24 mmol) in MeOH (3 ml) was added portionwise sodium periodate ( 56 mg, 0.26 mmol) for 3 min at 0°C. The mixture was stirred overnight, H ₂ O was added and extracted with EtOAc. The combined organic extracts were washed with brine, dried (MgO ₄ ) and concentrated in vacuo. Chromatography (SP4, silica gel; MeOH/EtOAc 0-30%) gave products as white solids (70 mg, 48% and 70 mg, 48%).

Example 61: *fast moving isomer: ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.85 (1H, d'), 7.81 (1H, d), 7.48 (1H, d), 7.40 (1H, dd), 7.30-7.34 (3H, m), 7.25-7.26 (2H, m), 4.71 (1H, d), 4.28 (1H, d), 3.62 (1H, d), 3.33 (1H, d), 2.82 (1H, d), 2.72 (1H, d), 2.62 (3H, s, CH ₃ ), 2, 27 (1H, br s), 1.99 (1H, s), 1.62 (3H, s), 1.61 (3H, s), 0.39-0.44 (2H, m), 0. 19-0.21 (1H, m), 0.01-0.03 (1H, m). LCMS (ESI ⁺ ) m/z=682.3 [M+Na] ⁺ ;

Example 62: *slow moving isomer: ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.82 (1H, d), 7.78 (1H, d), 7.42 (1H, dd), 7.24 ( 1H, dd), 7.15-7.19(4H, m), 7.13(1H, d), 4.60(1H, d), 4.46(1H, d), 3.59(1H , dd, J=6.1 and 11.5 Hz, CHOH), 3.49 (1H, dd, J=6.1 and 11.5 Hz, CHOH), 3.04 (1H, d,), 2 .91 (1H, d), 1.90 (1H, s), 2.72 (3H, s), 1.67 (1H, t), 1.63 (3H, s), 1.62 (3H, s), 0.41-0.49(2H, m), 0.30-0.33(1H, m), 0.05-0.09(1H, m). LCMS (ESI ⁺ ) m/z=628.3 [M+Na] ⁺

Examples 63 and 64: (3R)-2-[(4-Chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-(2-hydroxy-1-methoxypropan-2-yl )-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one

(*both isomers in position shown)

Title compounds were obtained using methods similar to those described in Example 43; but using sodium methoxide instead of piperazine.

Example 63 (faster moving isomer) (31 mg, 14%). 1H NMR (400 MHz, DMSO-d6): 7.85 (1H, d), 7.77 (1H, d), 7.58-7.50 (2H, m), 7.34-7.23 ( 5H, m), 5.49(1H, S), 5.02-4.66(2H, m), 4.39(1H, t), 3.53-3.44(2H, m), 3 .28 (3H, s), 3.24 (3H, s), 3.02 (1H, d), 2.89 (1H, d), 1.47 (3H, s), 0.41-0, 32 (2H, m), 0.26-0.17 (1H, m), 0.06 (1H, d). MS(ES+) m/z 652 [M+H] ⁺ .

Example 64 (slower moving isomer) (11 mg, 5%). 1H NMR (400 MHz, DMSO-d6): 7.85 (1H, d), 7.77 (1H, d), 7.57-7.50 (2H, m), 7.33-7.22 ( 5H, m), 5.49(1H, s), 5.01-4.81(2H, m), 4.39(1H, t), 3.54-3.44(2H, m), 3 .28 (3H, s), 3.24 (3H, s), 3.02 (1H, d), 2.90 (1H, d), 1.47 (3H, s), 0.37 (2H, d), 0.27-0.18 (1H, m), 0.11-0.03 (1H, m). MS(ES+) m/z 652 [M+H] ⁺ .

Examples 65 and 66: (3R)-2-[(4-Chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-6-(1,2-dihydroxypropan-2-yl)-4-fluoro- 3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one

(*both isomers in position shown)

Title compounds were obtained using methods similar to those described in Example 41, Step 1, and Example 27; in the given sequence.

Example 65 (faster moving, dominant isomer, 174 mg, 26%): 1H NMR (400 MHz, DMSO-d6): 7.84 (1H, d), 7.77 (1H, d), 7.58- 7.50(2H, m), 7.32-7.21(5H, m), 5.30(1H, s), 4.98-4.80(3H, m), 4.39(1H, t), 3.57-3.40(3H, m), 3.25(3H, s), 3.03(1H, d), 2.90(1H, d), 1.46(3H, s ), 0.37(2H, s), 0.27-0.18(1H, m), 0.07(1H, d). MS(ES+) m/z 638 [M+H] ⁺ .

Example 66 (slower moving, smaller isomer, 74 mg, 11%): 1H NMR (400 MHz, DMSO-d6): 7.85 (1H, dd), 7.77 (1H, d), 7.57- 7.48(2H, m), 7.32-7.23(5H, m), 5.30(1H, s), 4.99-4.79(3H, m), 4.39(1H, t), 3.57-3.39(3H, m), 3.25(3H, s), 3.02(1H, d), 2.94-2.87(1H, m), 1.46 (3H, s), 0.37 (2H, s), 0.28-0.17 (1H, m), 0.08 (1H, d). MS(ES+) m/z 638 [M+H] ⁺ .

Examples 67 and 68: (3R)-2-[(4-Chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[2-hydroxy-1-(4-methylpiperazine- 1-yl)propan-2-yl]-3-[(3R)-oxolan-3-yloxy]-2,3-dihydro-1H-isoindol-1-one (*both isomers in position shown)

The title compounds were prepared from Compound 44 using methods similar to those described in Example 43 steps 2 and 3 (but using N-methylpiperazine instead of piperazine).

Example 67 (faster moving isomer, 132 mg, 28%): 1H NMR (400 MHz, DMSO-d6): 7.92 (1H, d), 7.80 (1H, d), 7.60-7, 49(2H, m), 7.36-7.19(5H, m), 5.26(1H, s), 5.09-4.67(2H, m), 4.02-3.94( 1H, m), 3.78 (1H, q), 3.57-3.48 (1H, m), 3.27-3.15 (4H, m), 2.61 (1H, d), 2 .34 (4H, s), 2.16 (4H, s), 2.08 (3H, s), 1.74-1.62 (1H, m), 1.59-1.38 (4H, m ). MS(ES+) m/z 706 [M+H] ⁺ .

Example 68 (slower moving isomer, 131 mg, 28%): 1H NMR (400 MHz, DMSO-d6): 7.85 (1H, d), 7.78 (1H, d), 7.62-7, 51(2H, m), 7.32-7.20(5H, m), 5.23(1H, s), 4.92(2H, s), 3.99-3.92(1H, m) , 3.78(1H, q), 3.58-3.49(1H, m), 3.43-3.36(1H, m), 3.24(3H, s), 2.59(1H , d), 2.35(5H, d), 2.16(4H, s), 2.08(3H, s), 1.74-1.63(1H, m), 1.57-1, 40 (4H, m). MS(ES+) m/z 706 [M+H] ⁺ .

Examples 69 and 70: (3R)-2-[(4-Chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[2-hydroxy-1-(4-methylpiperazine- 1-yl)propan-2-yl]-3-[(3S)-oxolan-3-yloxy]-2,3-dihydro-1H-isoindol-1-one (*both isomers in position shown)

The title compounds were prepared using procedures similar to those described for Examples 67 and 68, but using (3S)-hydroxytetrahydrofuran.

Example 69 (faster moving isomer, 96 mg, 39%): 1H NMR (400 MHz, DMSO-d6): 7.92 (1H, d), 7.78 (1H, d), 7.59-7, 50(2H, m), 7.34-7.19(5H, m), 5.27(1H, s), 5.06-4.71(2H, m), 4.01-3.93( 1H, m), 3.75 (1H, q), 3.60-3.51 (1H, m), 3.45-3.40 (1H, m), 3.24 (3H, s), 3 .15 (1H, dd), 2.61 (1H, d), 2.41-2.26 (5H, m), 2.16 (4H, s), 2.07 (3H, s), 1, 81-1.64 (1H, m), 1.59 (1H, d), 1.50 (3H, s). MS(ES+) m/z 706 [M+H] ⁺ .

Example 70 (slower moving isomer, 97 mg, 39%): 1H NMR (400 MHz, DMSO-d6): 7.84 (1H, d), 7.77 (1H, d), 7.63-7, 50(2H, m), 7.30-7.19(5H, m), 5.23(1H, s), 4.98(2H, s), 3.99-3.92(1H, m) , 3.77(1H, q), 3.62-3.54(1H, m), 3.46-3.40(1H, m), 3.25(3H, s), 3.17(1H , dd), 2.59 (1H, d), 2.34 (5H, s), 2.16 (4H, s), 2.08 (3H, s), 1.86-1.73 (1H, m), 1.73-1.61 (1H, m), 1.53 (3H, s). MS(ES+) m/z 706 [M+H] ⁺ .

Example 71: (3S)-3-(4-Chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-(2-hydroxypropan-2-yl)-3-oxo- 1-[(3S)-oxolan-3-yloxy]-2,3-dihydro-1H-isoindol-2-yl]propanoic acid

Step 1: (3S)-3-[(1R)-5-Acetyl-1-(4-chlorophenyl)-7-fluoro-3-oxo-1-[(3S)-oxolan-3-yloxy]-2, 3-dihydro-1H-isoindol-2-yl]-3-(4-chlorophenyl)propanoic acid

The title compound was prepared from ethyl-(3S)-3-[(1R)-5-acetyl-1-(4-chlorophenyl)-7-fluoro-3-oxo-1-[(3S)-oxolan-3-yloxy] -2,3-dihydro-1H-isoindol-2-yl]-3-(4-chlorophenyl)propanoate (Substance 45) in a manner similar to that described for Substance 40. MS(ES+) m/z 570 [M-H] ^-

Step 2: (3S)-3-(4-Chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-(2-hydroxypropan-2-yl)-3-oxo- 1-[(3S)-oxolan-3-yloxy]-2,3-dihydro-1H-isoindol-2-yl]propanoic acid

The title compound was prepared using the product from Step 1 in a similar manner to Example 1.

1H NMR (400 MHz, DMSO-d6): 12.42 (1H, s), 7.79 (1H, s), 7.51 (1H, d), 7.10 (4H, dd), 6.99 (4H, d), 5.36 (1H, s), 4.62 (1H, dd), 4.21-4.13 (1H, m), 3.92 (1H, q), 3.77- 3.63(2H, m), 3.50(1H, d), 3.23(1H, dd), 3.12(1H, dd), 2.25-2.09(1H, m), 2 .09-1.94 (1H, m), 1.47 (6H, s); MS(ES+) m/z 570 [M-H] ^-

Example 72: 1-({[(1R)-2-{[4-Chloro-2-(hydroxymethyl)phenyl]methyl}-1-(4-chlorophenyl)-7-fluoro-5-(2-hydroxypropane-2 -yl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]oxy}methyl)cyclopropan-1-carbonitrile

To a solution of 5-chloro-2-{[(1R)-1-(4-chlorophenyl)-1-[(1-cyanocyclopropyl)methoxy]-7-fluoro-5-(2-hydroxypropan-2-yl)-3 -oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzoic acid (Example 79) (233 mg, 0.4 mmol) in THF (10 ml) was added triethylamine (0.17 ml, 1, 2 mmol) and isobutyl chloroformate (0.08 ml, 0.6 mmol) and the reaction mixture was stirred for 1 h. Water (0.1 ml) was added followed by NaBH ₄ (0.045 g, 1.2 mmol) in small portions. Stirred for 1 h, added water (10 ml) and the product was extracted with EtOAc. The crude product was purified on silica gel eluting with petrol-EtOAc 0-80% to give the title compound (150 mg, 66%).

1H NMR (400 MHz, DMSO-d6): 7.82 (1H, d), 7.53 (1H, dd), 7.37-7.22 (5H, m), 7.14-7.03 ( 2H, m), 5.37(1H, s), 5.21(1H, t), 4.54-4.36(3H, m), 4.33(1H, d), 3.02(1H , d), 2.80 (1H, d), 1.48 (6H, s), 1.23-1.13 (2H, m), 0.78-0.68 (1H, m), 0. 61-0.52 (1H, m). MS(ES+) m/z 472 [3[M-CN(c-Pr)CH ₂ O)] ⁺ .

Examples 73 and 74: 1-({[(1R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1- (1-methyl-1H-pyrazol-4-yl)ethyl]-3-oxo-2,3-dihydro-1H-isoindol-1-yl]oxy}methyl)cyclopropan-1-carboxamide

(*both isomers in position shown)

Step 1: 2-(4-Chlorobenzoyl)-3-fluoro-5-(hydroxy(1-methyl-1H-pyrazol-4-yl)methyl)benzoic acid

In a 5 L round bottom flask equipped with an overhead stirrer were placed 5-bromo-2-(4-chlorobenzoyl)-3-fluorobenzoic acid (100 g, 0.28 mol) and anhydrous THF (1.5 L). The solution was cooled to -3°C and methylmagnesium chloride (2.15M in THF, 130 ml, 0.279 mol) was added dropwise at such a rate that the internal temperature remained below -1°C (25 min). After completion of the addition, the mixture was stirred at 0°C for 15 min, then cooled to -78°C. A solution of n-butyllithium (2.2M in hexanes, 152 ml; 0.33 mol) was added dropwise over 30 minutes at such a rate that the internal temperature remained below -70°C. After completion of the addition, the mixture was stirred at -78°C for 30 minutes. A solution of 1-methyl-1H-pyrazole-4-carboxaldehyde (39.7 g, 0.36 mol) in anhydrous THF (500 ml) was added dropwise over 20 min at such a rate that the internal temperature remained below -70°C . After completion of the addition, the mixture was stirred at -78°C for 15 min, the cooling bath was removed and the mixture was left to reach RT. The mixture was quenched with 1 M HCl, the pH was adjusted to 1-2 and extracted with EtOAc (2×500 ml). The combined organic layers were dried (MgO ₄ ) and the solvent was evaporated. The precipitate was divided into four equal portions and each portion was chromatographed on silica gel (300 g) eluting with a gradient of 0-20% MeOH in DCM to give the title compound as a colorless solid (48.33 g, 44.5%). The crude fractions were combined, evaporated and chromatographed to give additional title compound (11.05 g, 10.2%). MS:[M+H] ⁺ =389

Stage 2: 2-(4-Chlorobenzoyl)-3-fluoro-5-(1-methyl-1H-pyrazole-4-carbonyl)benzoic acid

To a stirred mixture of 2-(4-chlorobenzoyl)-3-fluoro-5-(hydroxy(1-methyl-1H-pyrazol-4-yl)methyl)benzoic acid (20 g, 51.48 mmol) in EtOAc (86 ml ) at 0°C was added 10% aqueous KBr (29.83 ml, 25 mmol) and then TEMPO (0.82 g, 5.23 mmol). To this stirred mixture was added a solution of sodium bicarbonate (5.40 g, 64.25 mmol) and sodium hypochlorite (89 ml, 5-20% aqueous solution from Fisher, catalog number S/5040/PB17) in water (47 ml) at such a rate that the reaction temperature remains below 5°C. The addition was stopped after the completion of the oxidation according to LCMS (about half of the solution was required). The reaction mixture was quenched with dilute aqueous sodium sulfite solution and the mixture was extracted with EtOAc (4×500 ml). The combined organic layers were dried (MgO ₄ ) and the solvent was removed under reduced pressure to give the title compound as a pale orange solid (15.27 g, 76%). The aqueous layer was acidified with 2M HCl and extracted with EtOAc (500 ml). The organics were dried (MgO ₄ ) and the solvent removed under reduced pressure to give more of the title compound (3.44 g, 17%). MS: [M+H] ⁺ =387.

Step 3: 2-(4-Chloro-2-(methylsulfonyl)benzyl)-3-(4-chlorophenyl)-4-fluoro-3-hydroxy-6-(1-methyl-1H-pyrazole-4-carbonyl)isoindoline -1-he

2-(4-Chlorobenzoyl)-3-fluoro-5-(1-methyl-1H-pyrazole-4-carbonyl)benzoic acid (18.20 g, 46.55 mmol) and (4-chloro-2-(methylsulfonyl )phenyl)methanamine (Example 35, step 3) (19.4 g, 88.30 mmol) was stirred in DMF (90 ml) at RT under nitrogen atmosphere. HATU (26.80 g, 70.53 mmol) was added and the reaction mixture was stirred at RT for 1.25 h. The reaction mixture was diluted with water, sat. water. NaHCO ₃ solution and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with 4% aq. LiCl solution, dried (MgO ₄ ), filtered and concentrated in vacuo. The precipitate was purified using a 340 g SNAP column eluting with EtOAc in isohexanes (0 to 100%) to give 8.8 g of the title compound, 32% yield. MS:[M+H] ⁺ =587.

Step 4: (R)-1-(((2-(4-Chloro-2-(methylsulfonyl)benzyl)-1-(4-chlorophenyl)-7-fluoro-5-(1-methyl-1H-pyrazole- 4-carbonyl)-3-oxoisoindolin-1-yl)oxy)methyl)cyclopropanecarboxamide

The title compound was prepared from 2-(4-chloro-2-(methylsulfonyl)benzyl)-3-(4-chlorophenyl)-4-fluoro-3-hydroxy-6-(1-methyl-1H-pyrazole-4-carbonyl) isoindolin-1-one (2.0 g, 3.40 mmol) in a manner similar to Compound 10. The product was separated using chiral SLC. Slowest eluting isomer. MS: [M+H] ⁺ =685.

Step 5: 1-({[(1R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(1 -methyl-1H-pyrazol-4-yl)ethyl]-3-oxo-2,3-dihydro-1H-isoindol-1-yl]oxy}methyl)cyclopropan-1-carboxamide

(R)-1-(((1-(4-Chlorophenyl)-2-((5-chloropyridin-2-yl)methyl)-7-fluoro-5-(1-methyl-1H-pyrazole-4-carbonyl )-3-oxoisoindolin-1-yl)oxy)methyl) cyclopropanecarbonitrile (620 mg, 0.90 mmol) was stirred in THF (5 ml) at -15° C. under nitrogen. MeMgCl (2.15M in THF, 0.91 ml, 1.96 mmol) was added dropwise to form an orange solution and then stirred for 10 minutes at this temperature. The reaction mixture was quenched with sat. water. NH ₄ Cl solution, then water was added and the reaction mixture was heated to RT. The aqueous phase was extracted with DCM (2×50 ml) and the combined organics were dried (phase separator) and concentrated in vacuo. The precipitate was purified using a 25 g SNAP column eluting with MeOH in DCM (0 to 5%). Fractions containing the title compound were concentrated in vacuo and the compound separated using chiral SLC.

Example 73: *faster eluting isomer. ¹ H NMR (400 MHz, CDCl ₃ ) 7.90 (1H, d), 7.82 (1H, d), 7.53-7.49 (1H, m), 7.42 (1H, s), 7.37-7.33(2H, m), 7.25-7.18(5H, m), 6.52-6.52(1H, m), 5.42-5.42(1H, m ), 5.04-4.92(2H, m), 3.90(3H, s), 3.36(1H, d), 2.99(3H, s), 2.91(1H, d) , 2.32(1H, s), 1.94(3H, s), 1.32-1.20(2H, m), 0.53-0.46(1H, m), 0.39-0 .33 (1H, m); MS: [M+H] ⁺ = 701.

Example 74: *slower eluting isomer. ¹ H NMR (400 MHz, CDCl ₃ ) 7.89 (1H, d), 7.82 (1H, s), 7.55-7.50 (1H, m), 7.41 (1H, s), 7.37-7.32(2H, m), 7.25-7.17(5H, m), 6.52-6.52(1H, m), 5.42-5.42(1H, m), 5.04-4.94(2H, m), 3.91(3H, s), 3.36(1H, d), 3.00(3H, s), 2.93(1H, d ), 2.34 (1H, s), 1.94 (3H, s), 1.32-1.21 (2H, m), 0.54-0.47 (1H, m), 0.42- 0.36 (1 H, m); MS: [M+H] ⁺ =701.

Example 75 and 76: (3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[1-hydroxy-1-(1-methyl- 1H-pyrazol-4-yl)ethyl]-3-[(1-hydroxycyclopropyl)methoxy]-2,3-dihydro-1H-isoindol-1-one

(*both isomers in position shown)

Step 1: (R)-2-(4-Chloro-2-(methylsulfonyl)benzyl)-3-(4-chlorophenyl)-4-fluoro-3-((1-hydroxycyclopropyl)methoxy)-6-(1- methyl-1H-pyrazole-4-carbonyl)isoindolin-1-one

The title compound was prepared from 2-(4-chloro-2-(methylsulfonyl)benzyl)-3-(4-chlorophenyl)-4-fluoro-3-hydroxy-6-(1-methyl-1H-pyrazole-4-carbonyl) isoindolin-1-one (2.0 g, 3.4 mmol) in a manner similar to Compound 12. The product was separated using chiral SLC. The slowest eluting isomer. MS: [M+H] ⁺ =658.

Step 2: (3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[1-hydroxy-1-(1-methyl-1H- pyrazol-4-yl)ethyl]-3-[(1-hydroxycyclopropyl)methoxy]-2,3-dihydro-1H-isoindol-1-one

The title compound was prepared from (R)-2-(4-chloro-2-(methylsulfonyl)benzyl)-3-(4-chlorophenyl)-4-fluoro-3-((1-hydroxycyclopropyl)methoxy)-6-(1 -methyl-1H-pyrazole-4-carbonyl)isoindolin-1-one (255 mg, 0.39 mmol) in a manner similar to that described in Examples 73 and 74, step 5. The product was separated using chiral SLC.

Example 75: *slower eluting isomer. ¹ H NMR (400 MHz, CDCl ₃ ) 7.84 (1H, d), 7.80 (1H, d), 7.45 (1H, dd), 7.40 (1H, s), 7.34- 7.20(5H, m), 7.08(2H, d), 5.22(1H, d), 5.02(1H, d), 3.90(3H, s), 3.34(1H , d), 3.24 (1H, s), 3.03 (3H, s), 2.90 (1H, d), 2.27 (1H, s), 1.93 (3H, s), 0 .93-0.80 (2H, m), 0.63-0.56 (1H, m), 0.43-0.37 (1H, m); MS: [M+H] ⁺ =674.

Example 76: *faster eluting isomer. ¹ H NMR (400 MHz, CDCl ₃ ) 7.84 (1H, d), 7.81 (1H, d), 7.45 (1H, dd), 7.40 (1H, d), 7.33- 7.21(5H, m), 7.08(2H, d), 5.21(1H, d), 5.01(1H, d), 3.90(3H, s), 3.32(1H , d), 3.21 (1H, s), 3.02 (3H, s), 2.91 (1H, d), 2.28 (1H, s), 1.93 (3H, s), 0 .93-0.80 (2H, m), 0.62-0.55 (1H, m), 0.43-0.36 (1H, m); MS: [M+H] ⁺ =674.

Examples 77 and 78: (3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[2-hydroxy-1-(4-methylpiperazine- 1-yl)propan-2-yl]-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one

Title compounds were prepared using methods similar to those described in Example 43.

Example 77: *fast moving isomer: ¹ H NMR (400 MHz, CDCl ₃ ) 7.91 (1H, d), 7.77 (1H, d), 7.46 (1H, dd), 7.35 (1H , dd), 7.29 - 7.28 (2H, m), 7.22 (1H, d), 7.17 (2H, d), 5.00 (2H, d), 4.40 (1H, s) 3.83(1H, d), 3.35(1H, d), 3.27(1H, d), 3.04(3H, s), 2.80(1H, d), 2.71 (2H, dd), 2.53-2.37 (8H, m), 2.25 (3H, s), 2.01-2.01 (1H, m), 1.51 (3H, s), 0.50 (2H, dd), 0.49-0.37 (1H, m), 0.21 (1H, d). MS [M+H] ⁺ =720.

Example 78: *slow moving isomer: ¹ H NMR (400 MHz, CDCl ₃ ) 7.91 (1H, d), 7.76 (1H, d), 7.48 (1H, dd), 7.34 (1H , dd), 7.28(2H, d), 7.21-7.16(3H, m), 5.00(2H, s), 4.47(1H, d), 3.82(1H, d), 3.37(1H, d), 3.26(1H, d), 3.04(3H, s), 2.81(1H, d), 2.73-2.67(2H, m ), 2.52 (2H, s), 2.37 (6H, s), 2.25 (3H, s), 2.00-2.00 (1H, m), 1.51 (3H, s) , 0.52-0.37 (3H, m), 0.21-0.17 (1H, m). MS [M+H] ⁺ = 720.

Example 79: 5-chloro-2-{[(1R)-1-(4-chlorophenyl)-1-[(1-cyanocyclopropyl)methoxy]-7-fluoro-5-(2-hydroxypropan-2-yl)- 3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzoic acid

Step 1: 2-(2-Bromo-4-chlorobenzyl)-3-(4-chlorophenyl)-4-fluoro-3-hydroxy-6-(2-hydroxypropan-2-yl)isoindolin-1-one

The title compound was prepared from Compound 46 and (2-bromo-4-chlorophenyl)methanamine (Example 33, Step 1) (1.3 g, 6.24 mmol) using methods similar to Example 35, Step 4 to give 2-(2-bromo-4-chlorobenzyl)-3-(4-chlorophenyl)-4-fluoro-3-hydroxy-6-(2-hydroxypropan-2-yl)isoindolin-1-one as a colorless solid ( 2.15 g, 64%). MS [M+H] ⁺ =538.

Step 2: 1-(((2-(2-Bromo-4-chlorobenzyl)-1-(4-chlorophenyl)-7-fluoro-3-oxo-5-(prop-1-en-2-yl)isoindoline -1-yl)oxy)methyl)cyclopropanecarbonitrile

The title compound was obtained from 2-(2-bromo-4-chlorobenzyl)-3-(4-chlorophenyl)-4-fluoro-3-hydroxy-6-(2-hydroxypropan-2-yl)isoindolin-1-one (2 .1 g, 3.9 mmol) and 1-(hydroxymethyl)cyclopropanecarbonitrile (3.42 g, 9.6 mmol) using the method of Compound 10 to give (1.7 g, 71%). MS [M+H] ⁺ =599.

Step 3: (R)-1-(((2-(2-Bromo-4-chlorobenzyl)-1-(4-chlorophenyl)-7-fluoro-5-(2-hydroxypropan-2-yl)-3- oxoisoindolin-1-yl)oxy)methyl)cyclopropanecarbonitrile

Step 3 was carried out in a similar manner to Example 2 to give the title compound as a racemate (1.6 g). Purification by SLC gave the title compound as a fast moving isomer. MS [M+H] ⁺ =617.

Stage 4: 5-chloro-2-{[(1R)-1-(4-chlorophenyl)-1-[(1-cyanocyclopropyl)methoxy]-7-fluoro-5-(2-hydroxypropan-2-yl)- 3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzoic acid

Step 4 was carried out in a similar manner to Example 33, Step 5. Purification by preparative HPLC gave (R)-5-chloro-2-((1-(4-chlorophenyl)-7-fluoro-1-((1-( hydroxymethyl)cyclopropyl)methoxy)-5-(2-hydroxypropan-2-yl)-3-oxoisoindolin-2-yl)methyl)benzoic acid (305 mg, 62%). ¹ H NMR (400 MHz, DMSO) 7.84 (1H, s), 7.67 (1H, d), 7.58 (1H, s), 7.56 (1H, s), 7.41 (1H , dd), 7.32-7.22(5H, m), 4.90(1H, d), 4.79(1H, d), 3.16(1H, d), 2.84(1H, d), 1.48(6H, s), 1.27-1.15(2H, m), 0.86-0.79(1H, m), 0.69-0.62(1H, m) , HE did not observe. MS [M+H] ⁺ =583.

Examples 80 and 81: (3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[1-hydroxy-1-(1-methylpiperidine- 4-yl)ethyl]-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one

(*both isomers in position shown)

Steps 1 and 2 were performed using procedures similar to those described for Examples 73 and 74; but using tert-butyl-4-formylpiperidine-1-carboxylate instead of 1-methyl-1H-pyrazole-4-carboxaldehyde. Bu ₂ Mg was also used instead of methylmagnesium chloride.

Step 3: 5-(1-(1-(tert-Butoxycarbonyl)piperidin-4-yl)-1-hydroxyethyl)-2-(4-chlorobenzoyl)-3-fluorobenzoic acid

To an RB flask containing 5-(1-(tert-butoxycarbonyl)piperidine-4-carbonyl)-2-(4-chlorobenzoyl)-3-fluorobenzoic acid (15.57 g, 31.7 mmol) under N ₂ added THF (300 ml) and cooled to -10°C. MeMgCl (34.5 ml, 79.4 mmol, 2.3M in THF) was added over 5 minutes. Immediately after completion of the addition, LCMS analysis showed complete conversion of the starting material. The reaction mixture was quenched with 1 M HCl (200 ml). The reaction mixture was extracted with EtOAc (2×200 ml), dried with MgO ₄ , filtered and concentrated under vacuum. The crude material was purified by column chromatography, Biotage Isolera, 340 g cartridge, 0%-60% EtOAc (0.1% formic acid) in DCM (0.1% formic acid) to give 5-(1-(1-( tert-butoxycarbonyl)piperidin-4-yl)-1-hydroxyethyl)-2-(4-chlorobenzoyl)-3-fluorobenzoic acid as an off-white foam (15.1 g, 93%). Purification by chiral preparative LCMS.

* Fast moving isomer (Isomer A): MS: [MH] ^- =504, [α] _D ²⁰ = +28.7 (s 1.9, MeOH)

* Slow moving isomer (Isomer B): MS: [M-H] ^- =504, [α] _D ²⁰ = -27.8 (s 1.8, MeOH)

Step 4: 2-(4-Chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-(piperidin-4-yl)ethyl)benzoic acid hydrochloride

(-)-5-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1-hydroxyethyl)-2-(4-chlorobenzoyl)-3-fluorobenzoic acid (Isomer B) (6.09 g , 12.0 mmol) was stirred in 4N. HCl in dioxane (70 ml) at RT for 10 min. The orange solution was concentrated in vacuo to give 2-(4-chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-(piperidin-4-yl)ethyl)benzoic acid hydrochloride (Isomer B) as an orange solid ( 6.88 g) which was used in the next step without further purification. MS: [M+H] ⁺ =406.

Similarly, from (+)-5-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1-hydroxyethyl)-2-(4-chlorobenzoyl)-3-fluorobenzoic acid (Isomer A) ( 7.50 g, 14.8 mmol) gave 2-(4-chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-(piperidin-4-yl)ethyl)benzoic acid hydrochloride (Isomer A), which used in the next step without further purification. MS: [M+H] ⁺ =406.

Step 5: 2-(4-Chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-(1-methylpiperidin-4-yl)ethyl)benzoic acid

(-)-2-(4-Chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-(piperidin-4-yl)ethyl)benzoic acid hydrochloride (Isomer B) (6.88 g, ca. 12 .0 mmol) was stirred in MeOH (100 ml) at RT under nitrogen atmosphere and a solution of formaldehyde (37% wt. in water, 24 mmol, 1.95 ml) was added. The orange solution was stirred at RT for 5 min and NaBH ₃ CN (14.4 mmol, 905 mg) was added. The yellow solution was stirred at RT for 1 day, after which a colorless solid precipitated. The mixture was concentrated in vacuo to give 2-(4-chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-(1-methylpiperidin-4-yl)ethyl)benzoic acid (Isomer B) as a yellow solid ( 6 g), which was used in the next step without further purification.

Similarly, from (+)-2-(4-chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-(piperidin-4-yl)ethyl)benzoic acid hydrochloride (Isomer A) (6.00 g , ca 14.8 mmol) gave 2-(4-chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-(1-methylpiperidin-4-yl)ethyl)benzoic acid (Isomer A), which was used in the next step without further purification. MS: [M+H] ⁺ =419.9.

Step 6: 2-(4-Chloro-2-(methylsulfonyl)benzyl)-3-(4-chlorophenyl)-4-fluoro-3-hydroxy-6-(1-hydroxy-1-(1-methylpiperidine-4- yl)ethyl)isoindolin-1-one

(-)-2-(4-chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-(1-methylpiperidin-4-yl)ethyl)benzoic acid (Isomer B) (2 g, 4 mmol) 2 -(4-chloro-2-(methylsulfonyl)benzyl)-3-(4-chlorophenyl)-4-fluoro-3-hydroxy-6-(1-hydroxy-1-(1-methylpiperidin-4-yl)ethyl) isoindolin-1-one (Isomer B), 939 mg, 38% as a pale orange solid. MS: [M+H] ⁺ =621

Similarly, from (+)-2-(4-Chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-(1-methylpiperidin-4-yl)ethyl)benzoic acid (Isomer A) (1.55 g, about 3.70 mmol) gave 2-(4-chloro-2-(methylsulfonyl)benzyl)-3-(4-chlorophenyl)-4-fluoro-3-hydroxy-6-(1-hydroxy-1- (1-methylpiperidin-4-yl)ethyl)isoindolin-1-one (Isomer A), 1.05 g, 46%. MS: [M+H] ⁺ =621.

Step 7: (3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[1-hydroxy-1-(1-methylpiperidine-4- yl)ethyl]-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one

Stage 7 was carried out in a manner similar to Example 41, Stage 1, obtaining from (-)-2-(4-chloro-2-(methylsulfonyl)benzyl)-3-(4-chlorophenyl)-4-fluoro-3-hydroxy- 6-(1-hydroxy-1-(1-methylpiperidin-4-yl)ethyl)isoindolin-1-one (Isomer B) (847mg, 1.36mmol) 366mg 2-(4-chloro-2-( methylsulfonyl)benzyl)-3-(4-chlorophenyl)-4-fluoro-6-(1-hydroxy-1-(1-methylpiperidin-4-yl)ethyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy )isoindolin-1-one (Isomer B) as a pale yellow solid which was further purified by preparative HPLC and separated by chiral SLC to give Example 80 (55 mg, slower moving isomer)

Example 80 ¹ H NMR (400 MHz, CDCl3) 7.91 (1H, d), 7.72 (1H, d), 7.46-7.42 (1H, m), 7.36 (1H, dd) , 7.30(2H, d), 7.24-7.17(3H, m), 5.06-4.96(2H, m), 3.80(1H, d), 3.38(1H , d), 3.24 (1H, d), 3.03 (3H, s), 2.92 (2H, dd), 2.78 (1H, d), 2.35-2.35 (3H, m), 2.25(3H, s), 1.96-1.83(2H, m), 1.74(1H, d), 1.61(3H, s), 1.49-1.35 (3H, m), 0.50 (2H, s), 0.49-0.38 (1H, m), 0.23 (1H, d); MS: [M+H] ⁺ =705.4.

Similarly, from (+)-2-(4-chloro-2-(methylsulfonyl)benzyl)-3-(4-chlorophenyl)-4-fluoro-3-hydroxy-6-(1-hydroxy-1-(1 -methylpiperidin-4-yl)ethyl)isoindolin-1-one (Isomer A) (787 mg, 1.27 mmol) gave 138 mg of 2-(4-chloro-2-(methylsulfonyl)benzyl)-3-(4- chlorophenyl)-4-fluoro-6-(1-hydroxy-1-(1-methylpiperidin-4-yl)ethyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)isoindolin-1-one (Isomer A) , which was further purified by preparative HPLC and separated by chiral SLC to give Example 81 (8 mg, slower moving isomer).

Example 81 ¹ H NMR (400 MHz, CDCl3) 8.40 (1H, s), 7.91 (1H, d), 7.70 (1H, d), 7.45 (1H, dd), 7.35 (1H, dd), 7.30(2H, d), 7.23(1H, d), 7.19(2H, d), 5.00(2H, s), 3.73-3.67( 1H, m), 3.44(1H, d), 3.35-3.23(2H, m), 3.14(1H, d), 3.03(3H, s), 2.88(1H , d), 2.51 (3H, s), 2.28-2.24 (3H, m), 1.94-1.77 (4H, m), 1.62 (3H, s), 1, 40-1.31 (1H, m), 0.50 (2H, dd), 0.48-0.38 (1H, m), 0.26 (1H, d); MS: [M+H] ⁺ =705.

Example 82: (3R)-2-{[4-Chloro-2-(dimethylphosphoryl)phenyl]methyl}-3-(4-chlorophenyl)-4-fluoro-3-{[1-(hydroxymethyl)cyclopropyl]methoxy} -6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one

The title compound was prepared from 5-bromo-2-(4-chlorobenzoyl)-3-fluorobenzoic acid and Compound 47: (2-(aminomethyl)-5-chlorophenyl)dimethylphosphine oxide using procedures similar to those described for Compound 9, Compound 10 ., Example 21, Step 3, and Example 41, Step 3; in the given sequence.

*fast moving isomer: ¹ H NMR (400 MHz, CDCl ₃ ) 7.81 (1H, d), 7.45 (1H, dd), 7.31 (2H, d), 7.19-7.13 ( 2H, m), 7.10-7.06(3H, m), 5.36(1H, d), 5.09(2H, d), 4.37(1H, dd), 3.84(1H , d), 2.97 (1H, d), 2.18 (1H, d), 1.89 (1H, s), 1.77 (3H, d), 1.74 (3H, d), 1 .65 (3H, s), 1.64 (3H, s), 0.58-0.42 (3H, m), 0.27-0.22 (1H, m). [M+H]+=620.

Examples 83 and 84: (3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[hydroxy(oxan-4-yl)methyl]- 3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one

(*both isomers in position shown)

Step 1 and 2: From Substance 48, Steps 1 and 2 were performed using procedures similar to those described for Examples 73 and 74, Step 3 and Step 4, but using 1,1-bis(hydroxymethyl)cyclopropane instead of 1-( hydroxymethyl)cyclopropane-1-carboxamide. MS: [M-1-(cyclopropane-1,1-diyldimethanol]+=574

Step 3: (3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[hydroxy(oxan-4-yl)methyl]-3- {[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one

The product from Step 2 (300 mg, 0.44 mmol) was dissolved in methanol (1 ml) under nitrogen at RT with stirring. Sodium borohydride (25 mg, 0.66 mmol) was added to the reaction mixture and the reaction mixture was left to stir at room temperature for 10 minutes, then quenched and diluted with water. The reaction mixture was extracted with DCM. The combined organic layers were dried (MgO ₄ ) and concentrated under reduced pressure. The crude precipitate was purified on a 10 g SNAP silica gel cartridge eluting with ethyl acetate in isohexane (10 to 100%). Fractions containing pure product were concentrated under reduced pressure to give a white solid (247 mg) which was separated using chiral SLC.

Example 83 *slower eluting isomer. ¹ H NMR (400 MHz, CDCl3) 7.91 (1H, a), 7.72 (1H, s), 7.35 (1H, dd), 7.28-7.26 (2H, m), 7 .24-7.16(4H, m), 5.06-4.96(2H, m), 4.55(1H, dd), 4.05-3.93(2H, m), 3.80 (1H, dd), 3.42-3.23(4H, m), 3.04(3H, s), 2.78(1H, d), 2.11(1H, d), 2.01- 1.96 (1H, m), 1.94-1.84 (1H, m), 1.78 (1H, d), 1.54-1.37 (2H, m), 1.29-1, 21 (1H, m), 0.54-0.48 (2H, m), 0.46-0.38 (1H, m), 0.22 (1H, d); MS: [M+H]+=678.

Example 84 *faster eluting isomer. ¹ H NMR (400 MHz, CDCl3) 7.91 (1H, d), 7.67 (1H, s), 7.35 (1H, dd), 7.30-7.26 (3H, m), 7 .24-7.17(3H, m), 5.06-4.96(2H, m), 4.56(1H, dd), 4.06-3.94(2H, m), 3.82 (1H, dd), 3.40-3.25(4H, m), 3.03(3H, s), 2.75(1H, d), 2.16(1H, d), 2.03- 1.99 (1H, m), 1.93-1.83 (1H, m), 1.78 (1H, d), 1.55-1.37 (2H, m), 1.28 (1H, d), 0.54-0.47 (2H, m), 0.46-0.40 (1H, m), 0.23 (1H, d); MS: [M+H]+=678.

Example 85 and 86: 1-({[(1R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1- (oxan-4-yl)ethyl]-3-oxo-2,3-dihydro-1H-isoindol-1-yl]oxy}methyl)cyclopropan-1-carboxamide

(*both isomers in position shown)

The title compound was prepared using 2-(4-chloro-2-(methylsulfonyl)benzyl)-3-(4-chlorophenyl)-4-fluoro-3-hydroxy-6-(tetrahydro-2H-pyran-4-carbonyl)isoindoline -1-one (Examples 83 and 84; Step 1) using methods similar to those described for Compound 12 (using 1-(hydroxymethyl)cyclopropanecarboxamide instead of 1,1-bis(hydroxymethyl)cyclopropane) and Examples 73 and 74, Step 5.

Example 85 *slower eluting isomer. ¹ H NMR (400 MHz, CDCl3) 7.90 (1H, d), 7.77 (1H, d), 7.50-7.46 (1H, m), 7.36 (1H, dd), 7 .28-7.18(5H, m), 6.52-6.52(1H, m), 5.42-5.42(1H, m), 5.06-4.95(2H, m) , 4.07-3.94(2H, m), 3.41-3.28(3H, m), 3.00(3H, s), 2.93(1H, d), 1.91-1 .84 (1H, m), 1.82 (1H, s), 1.63 (3H, s), 1.56 (1H, s), 1.53-1.40 (2H, m), 1, 33-1.22(3H, m), 0.53-0.47(1H, m), 0.42-0.35(1H, m); MS: [M+H]+=705.

Example 86 *faster eluting isomer. ¹ H NMR (400 MHz, CDCl3) 7.91 (1H, s), 7.81 (1H, s), 7.44 (1H, d), 7.36 (1H, d), 7.26-7 .19 (5H, m), 6.52-6.52 (1H, m), 5.42 (1H, s), 5.05-4.95 (2H, m), 4.06-3.96 (2H, m), 3.39-3.35 (3H, m), 3.00 (3H, s), 2.92 (1H, d), 1.91-1.84 (2H, m), 1.67-1.56(4H, m), 1.47(2H, s), 1.26-1.24(3H, m), 0.51(1H, s), 0.37-0, 37 (1H, m);; MS: [M+H]+=705

Example 87: 5-chloro-2-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(1methylpiperidin-4-yl)ethyl]-1-methoxy- 3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzoic acid

(Example highlighted as single isomer at position shown)

Stage 1: tert-butyl-4-[1-[2-[(2-bromo-4-chlorophenyl)methyl]-1-(4-chlorophenyl)-7-fluoro-1-hydroxy-3-oxoisoindoline-5- yl]-1-hydroxyethyl]piperidine-1-carboxylate

Prepared in a manner similar to that described in Example 35, step 4, from (-)-5-[1-(1-tert-butoxycarbonyl-4-piperidyl)-1-hydroxyethyl]-2-(4-chlorobenzoyl)-3- fluorobenzoic acid; and (2-bromo-4-chlorophenyl)methanamine. MS: [MH ₂ O] ⁺ =691.

Step 2: 2-[(2-Bromo-4-chlorophenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[1-hydroxy-1-(4-piperidyl)ethyl]-3-methoxyisoindoline -1-he

Prepared in a manner similar to Compound 10 from tert-butyl-4-[1-[2-[(2-bromo-4-chlorophenyl)methyl]-1-(4-chlorophenyl)-7-fluoro-1- hydroxy-3-oxoisoindolin-5-yl]-1-hydroxyethyl]piperidine-1-carboxylate and methanol. MS: [M+H] ⁺ =623.

Step 3: 2-[(2-Bromo-4-chlorophenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[1-hydroxy-1-(1-methyl-4-piperidyl)ethyl] -3-methoxyisoindolin-1-one

The title compound was prepared from 2-[(2-bromo-4-chlorophenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[1-hydroxy-1-(4-piperidyl)ethyl]-3- methoxyisoindolin-1-one in a manner analogous to Example 81, step 5. MS: [M+H] ⁺ =637.

Stage 4: 5-Chloro-2-[[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(1-methyl-4-piperidyl)ethyl]-1- methoxy-3-oxoisoindolin-2-yl]methyl]benzoic acid

Prepared in a manner similar to that described for Example 33, step 5, from 2-[(2-bromo-4-chlorophenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[1-hydroxy-1- (1-methyl-4-piperidyl)ethyl]-3-methoxyisoindolin-1-one. ¹ H NMR (400 MHz, CDCl3) 7.87 (1H, s), 7.53 (1H, d), 7.49 (1H, d), 7.31 (2H, d), 7.24 (2H , d), 7.19 (1H, d), 7.11 (1H, dd), 4.96 (1H, d), 4.81 (1H, d), 3.47 (1H, d), 3 .36-3.32(1H, m), 2.87(3H, s), 2.87-2.71(2H, m), 2.73(3H, s), 2.11-2.02 (1H, m), 1.99-1.90 (1H, m), 1.80-1.63 (2H, m), 1.62 (3H, s), 1.51 (1H, m). MS: [M+H] ⁺ =601.

Examples 88 and 89: (3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(oxane-4- yl)ethyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoic acid

(*both isomers were separated and isolated)

Step 1: (3S)-Ethyl-3-(4-chlorophenyl)-3-(1-(4-chlorophenyl)-7-fluoro-1-hydroxy-3-oxo-5-(tetrahydro-2H-pyran-4 -carbonyl)isoindolin-2-yl)propanoate

A reaction was carried out between 2-(4-chlorobenzoyl)-3-fluoro-5-(tetrahydro-2H-pyran-4-carbonyl)benzoic acid (Compound 48) (3.99 g, 10.2 mmol) and hydrochloride (S) -ethyl-3-amino-3-(4-chlorophenyl)propanoate (3.5 g, 13.25 mmol) in a manner analogous to that described in Example 35, step 4 to give the title compound (3.4 g, 50%) as a yellow solid. MS: [M-N] ^- =598.

Step 2: (S)-Ethyl-3-(4-chlorophenyl)-3-((R)-1-(4-chlorophenyl)-7-fluoro-1-methoxy-3-oxo-5-(tetrahydro-2H -pyran-4-carbonyl)isoindolin-2-yl)propanoate

The title compound was obtained from (3S)-ethyl-3-(4-chlorophenyl)-3-(1-(4-chlorophenyl)-7-fluoro-1-hydroxy-3-oxo-5-(tetrahydro-2H-pyran- 4-carbonyl)isoindolin-2-yl)propanoate and methanol in a manner similar to that described for Compound 12. The diastereoisomers were separated by chiral SLC. [M+H]+=614.

Step 3: (S)-3-(4-Chlorophenyl)-3-((R)-1-(4-chlorophenyl)-7-fluoro-1-methoxy-3-oxo-5-(tetrahydro-2H-pyran -4-carbonyl)isoindolin-2-yl)propanoic acid

The title compound was obtained from (S)-ethyl-3-(4-chlorophenyl)-3-((R)-1-(4-chlorophenyl)-7-fluoro-1-methoxy-3-oxo-5-(tetrahydro- 2H-pyran-4-carbonyl)isoindolin-2-yl)propanoate in a manner analogous to that described for Compound 40. [M+H] ⁺ =586.

Stage 4: (3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(oxan-4-yl) ethyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoic acid

The title compound was prepared from (S)-3-(4-chlorophenyl)-3-((R)-1-(4-chlorophenyl)-7-fluoro-1-methoxy-3-oxo-5-(tetrahydro-2H- pyran-4-carbonyl)isoindolin-2-yl)propanoic acid in a manner similar to that described in Example 1 to give a racemate which was separated by chiral SLC.

Example 88: *Fast moving isomer ¹ H NMR (400 MHz, CDCl3) 7.67 (1H, d), 7.34-7.29 (1H, m), 7.03 (4H, s), 7.00 (4H, s), 4.68 (1H, dd), 4.04-3.90 (2H, m), 3.68 (1H, dd), 3.36-3.24 (3H, m), 3.08 (3H, s), 1.86-1.77 (1H, m), 1.61-1.55 (4H, m), 1.47-1.36 (2H, m), 1, 26-1.17 (1H, m), (OH and CO ₂ H not visible). [M+H] ⁺ =602.

Example 89: *slow moving isomer ¹ H NMR (400 MHz, CDCl3) 7.68 (1H, s), 7.29 (1H, d), 7.03 (4H, s), 7.00 (4H, s ), 4.69 (1H, dd), 4.05-3.90 (2H, m), 3.69-3.61 (1H, m), 3.37-3.24 (3H, m), 3.09 (3H, s), 1.87-1.77 (1H, m), 1.63-1.56 (4H, m), 1.50-1.37 (2H, m), 1, 20 (1H, d), (OH and CO ₂ H are not visible). [M+H] ⁺ =602.

Examples 90 and 91: 4-[(1R)-1-[(1R)-1-(4-Chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(1-methyl-1H-imidazole-4 -yl)propyl]-3-oxo-1-[(3S)-oxolan-3-yloxy]-2,3-dihydro-1H-isoindol-2-yl]-2-hydroxyethyl]benzonitrile

(*both isomers were separated and isolated)

Step 1, 2, and 3: From Compounds 49 and 50, Steps 1, 2, and 3 were performed using procedures similar to those described for Example 73, Step 3, Step 4, and Step 5, but using and (3S)-hydroxytetrahydrofuran instead of 1-(hydroxymethyl)cyclopropane-1-carboxamide in step 2 and EtMgCl instead of MeMgCl in step 3.

Step 4: 4-[(1R)-1-[(1R)-1-(4-Chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(1-methyl-1H-imidazol-4-yl )propyl]-3-oxo-1-[(3S)-oxolan-3-yloxy]-2,3-dihydro-1H-isoindol-2-yl]-2-hydroxyethyl]benzonitrile

Pd(PPh ₃ ) ₄ (56 mg, 0.05 mmol) and K ₂ CO ₃ (252 mg, 1.88 mmol) were added to a solution of 4-[(1R)-1-[(1R)-1-(4 -chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(1-methyl-1H-imidazol-4-yl)propyl]-3-oxo-1-[(3S)-oxolan-3-yloxy] -2,3-dihydro-1H-isoindol-2-yl]-2-(prop-2-en-1-yloxy)ethyl]benzonitrile (630 mg, 0.94 mmol) in MeOH (10 ml), and the resulting the mixture was stirred at 80° C. for 2 hours. The solvent was then removed in vacuo and the residue was purified by silica gel flash chromatography (gradient (0-100% EtOAc in gasoline). The two diastereoisomers were then separated by chiral HPLC.

Example 90 Isomer 1 (73 mg, 12% yield): 1H NMR (400 MHz, DMSO-d6): 7.90 (1H, s), 7.58-7.50 (2H, m), 7.47 (2H, d), 7.18(2H, d), 7.07-6.82(5H, m), 5.56(1H, s), 5.13(1H, dd), 4.49- 4.40(1H, m), 4.35-4.24(2H, m), 4.10-3.96(1H, m), 3.87(1H, q), 3.69-3, 62 (1H, m), 3.61 (3H, s), 3.48-3.42 (1H, m), 3.20-3.08 (1H, m), 2.26-2.05 ( 4H, m), 0.70 (3H, t); LCMS: [M+H] ⁺ =631.

Example 91 Isomer 2 (97 mg, 16% yield): 1H NMR (400 MHz, DMSO-d6): 7.85 (1H, s), 7.61-7.51 (2H, m), 7.46 (2H, d), 7.18(2H, d), 7.10-6.83(5H, m), 5.56(1H, s), 5.13(1H, t), 4.49- 4.39(1H, m), 4.36-4.24(2H, m), 4.09-3.97(1H, m), 3.87(1H, q), 3.70-3, 58 (4H, m), 3.43-3.37 (1H, m), 3.11 (1H, dd), 2.25-2.02 (4H, m), 0.70 (3H, t) ; LCMS: [M+H] ⁺ = 631.

Examples 92 and 93: 4-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(1-methyl-1H-imidazol-4-yl)propyl]- 3-oxo-1-[(3S)-oxolan-3-yloxy]-2,3-dihydro-1H-isoindol-2-yl]methyl}-3-(hydroxymethyl)benzonitrile

(*both isomers were separated and isolated)

Title compounds were prepared in a manner similar to that described in Example 90, but using Compound 51 instead of 49 in step 1.

Example 92: *fast moving isomer ¹ H NMR (400 MHz, CDCl3) 7.81 (1H, d), 7.57 (1H, d), 7.45-7.38 (2H, m), 7.36 (1H, d), 7.28 (1H, d), 7.20 (4H, s), 6.83 (1H, d), 4.74-4.65 (2H, m), 4.58 ( 1H, dd), 4.42(1H, d), 3.85-3.70(2H, m), 3.69(3H, s), 3.62-3.53(3H, m), 3 .23 (1H, dd), 2.75-2.66 (1H, m), 2.23-2.06 (2H, m), 1.48-1.37 (2H, m), 0.84 (3H, dd). [M+H] ⁺ =631.

Example 93: *slow moving isomer ¹ H NMR (400 MHz, CDCl3) 7.69 (1H, d), 7.58-7.51 (2H, m), 7.41-7.36 (2H, m) , 7.25-7.23(1H, m), 7.19(4H, s), 6.85(1H, d), 4.73-4.66(2H, m), 4.58(1H , d), 4.42(1H, d), 3.86-3.72(2H, m), 3.70(3H, s), 3.62-3.54(3H, m), 3, 22 (1H, dd), 2.23-2.06 (2H, m), 1.50-1.40 (2H, m), 1.27-1.08 (1H, m), 0.84 ( 3H, dd). [M+H] ⁺ =631.

Examples 94 and 95: 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

(*both isomers were separated and isolated)

Step 1 and 2: From Compound 50, Steps 1 and 2 were performed using procedures similar to those described for Example 73, Step 3 and Step 4, but using 4-(aminomethyl)benzonitrile in Step 1 and [1-(hydroxymethyl) cyclopropyl]methanol in step 2.

Stage 3: 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

(R)-4-((1-(4-chlorophenyl)-7-fluoro-1-((1-(hydroxymethyl)cyclopropyl)methoxy)-5-(1-methyl-1H-imidazole-4-carbonyl) solution -3-oxoisoindolin-2-yl)methyl)benzonitrile) (190 mg, 0.325 mmol) in anhydrous CH ₂ Cl ₂ (10 ml) was stirred at 0°C under nitrogen atmosphere. AlEt ₃ (2.5 ml, 1M in hexanes, 2.5 mmol) was added dropwise and the mixture was stirred at 0° C. for 1 h. The reaction mixture was quenched with sat. water. NH ₄ Cl and diluted with CH ₂ Cl ₂ (10 ml) and water (7 ml). Solids were removed by filtration and the filtrate was extracted with CH ₂ Cl ₂ (2×15 ml). The combined organic layers were dried (MgO ₄ ) and the solvent was evaporated. The crude residue was purified by column chromatography, Interchim, 12 g KP-sil cartridge, 0-5% MeOH in EtOAc, to give the racemate (98 mg, 49%). Chiral preparative HPLC yielded the title compounds:

Example 94 (faster moving isomer) ¹ H NMR (400 MHz, CDCl3) 7.71 (1H, s), 7.47 (3H, dd), 7.36 (1H, s), 7.27-7, 26 (2H, m), 7.18 (4H, s), 6.84 (1H, s), 4.49 (1H, d), 4.32 (1H, d), 3.69 (3H, s ), 3.53(1H, d), 3.41(1H, d), 2.97(1H, d), 2.79(1H, d), 2.24-2.07(2H, m) , 1.25 (1 H, s), 0.86 (3H, dd), 0.45 (2H, dd), 0.28-0.23 (1 H, m), 0.15-0.09 (1H, m). MS: [M+H ⁺ =615

Example 95: (slower moving isomer) ¹ H NMR (400 MHz, CDCl3) 7.71 (1H, s), 7.49 (3H, dd), 7.36 (1H, s), 7.28-7 .27(2H, m), 7.19(4H, s), 6.85(1H, s), 4.51(1H, d), 4.31(1H, d), 3.69(3H, s), 3.55(1H, s), 3.52-3.47(1H, m), 3.41(1H, dd), 2.96(1H, d), 2.78(1H, d ), 2.22-2.06 (2H, m), 0.85 (3H, dd), 0.44 (2H, dd), 0.29-0.23 (1H, m), 0.15- 0.08 (1H, m). MS: [M+H] ⁺ =615

Examples 96 and 97: 4-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(1-methyl-1H-imidazol-4-yl)propyl]- 3-oxo-1-[(3S)-oxolan-3-yloxy]-2,3-dihydro-1H-isoindol-2-yl]methyl}benzonitrile

(*both isomers were separated and isolated)

The title compounds were prepared in a manner similar to those described in Example 94 and Example 95, but using (3S)-hydroxytetrahydrofuran in Step 2. Chiral preparative HPLC allowed the title compounds to be obtained.

Example 96: ¹ H NMR (400 MHz, CDCl3) 7.70 (1H, d), 7.55-7.52 (1H, m), 7.46 (2H, d), 7.36 (1H, s ), 7.27-7.24(2H, m), 7.16(4H, s), 6.85(1H, d), 4.50(1H, d), 4.32(1H, d) , 3.84-3.76(2H, m), 3.70(3H, s), 3.63-3.52(3H, m), 3.23(1H, dd), 2.24-2 .07 (2H, m), 1.51-1.44 (2H, m), 0.84 (3H, t). MS: [M+H] ⁺ =601

Example 97: ¹ H NMR (400 MHz, CDCl3) 7.81 (1H, d), 7.48-7.42 (3H, m), 7.36 (1H, s), 7.28-7.25 (2H, m), 7.17 (4H, s), 6.83 (1H, d), 4.51 (1H, d), 4.32 (1H, d), 3.82-3.75 ( 2H, m), 3.69 (3H, s), 3.62-3.54 (3H, m), 3.25 (1H, dd), 2.23-2.07 (2H, m), 1 .49-1.42 (2H, m), 0.84 (3H, t). MS: [M+H] ⁺ =601.

Examples 98 and 99: (3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-(4-fluoroxan-4-yl) -1-hydroxyethyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoic acid

(*both isomers were separated and isolated)

Step 1 and 2: Ethyl-(3S)-3-(4-chlorophenyl)-3-(1-(4-chlorophenyl)-7-fluoro-5-(4-fluorotetrahydro-2H-pyran-4-carbonyl)- 1-hydroxy-3-oxoisoindolin-2-yl)propanoate

From 2-(4-chlorobenzoyl)-3-fluoro-5-(4-fluorotetrahydro-2H-pyran-4-carbonyl)benzoic acid (Compound 53), (S)-ethyl-3-amino-3-(4) hydrochloride -chlorophenyl)propanoate (Substance 35) and MeOH, Steps 1-2 were carried out following procedures similar to those described for Example 35, Step 4, and Substance 10, respectively. The diastereoisomers were separated using chiral SLC to give ethyl-(S)-3-(4-chlorophenyl)-3-((R)-1-(4-chlorophenyl)-7-fluoro-5-(4-fluorotetrahydro-2H- pyran-4-carbonyl)-1-methoxy-3-oxoisoindolin-2-yl)propanoate. MS: [M-MeOH] ⁺ =600.

Step 3: (S)-3-(4-Chlorophenyl)-3-((R)-1-(4-chlorophenyl)-7-fluoro-5-(4-fluorotetrahydro-2H-pyran-4-carbonyl)- 1-methoxy-3-oxoisoindolin-2-yl)propanoic acid

Step 3 was performed using procedures similar to those described for Compound 52, Step 3. MS: [M-H] ^- = 602.

Step 4: (3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-(4-fluoroxan-4-yl)-1 -hydroxyethyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoic acid

Step 4 was performed using procedures similar to those described for Example 73, Step 5.

Example 98: *fast moving isomer: ¹ H NMR (400 MHz, CDCl ₃ ) 7.78 (1H, s), 7.39 (1H, d), 7.04 (4H, s), 7.00 (4H , s), 4.68 (1H, dd), 3.89-3.56 (5H, m), 3.31 (1H, dd), 3.10 (3H, s), 1.98-1, 60 (7H, m), 1.44 (1H, dd); COOH absent. MS: [M+H] ⁺ =620.

Example 99: * Slow moving isomer: ¹ H NMR (400 MHz, CDCl ₃ ) 7.79 (1H, s), 7.39 (1H, d), 7.03 (4H, s), 7.00 (4H , s), 4.69 (1H, dd); 3.90-3.56(5H, m), 3.30(1H, dd), 3.11(3H, s), 1.97-1.73(3H, m), 1.73-1, 63 (4H, m), 1.47-1.39 (1H, m); COOH absent. MS: [M+H] ⁺ =620.

Example 100: (4S)-4-(4-chlorophenyl)-4-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(1-methyl-1H- pyrazol-3-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]butanoic acid

(*obtained as a mixture of epimers at positions shown)

The title compound was prepared from Compound 65 and methyl-(4S)-4-amino-4-(4-chlorophenyl)butanoate using procedures similar to those described in Example 99; but using EtMgCl/ZnCl ₂ instead of MeMgCl in the final step. 1 H NMR (400 MHz, CDCl ₃ ): 7.74 (1H, d), 7.49-7.44 (1H, m), 7.34 (1H, d), 7.04-7.00 (8H , m), 6.21(1H, t), 4.23-4.15(1H, m), 3.88(3H, s), 3.19(3H, d), 3.11-3, 02 (1H, m), 2.55-2.44 (2H, m), 2.32-2.11 (6H, m), 0.90-0.85 (4H, m). MS: [M+H] ⁺ =626.

Example 101 and 102: (3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-(4-fluoroxan-4-yl) -1-hydroxypropyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoic acid

(*both isomers were separated and isolated)

The title compounds were prepared from (S)-3-(4-chlorophenyl)-3-((R)-1-(4-chlorophenyl)-7-fluoro-5-(4-fluorotetrahydro-2H-pyran-4-carbonyl) -1-Methoxy-3-oxoisoindolin-2-yl)propanoic acid (Example 99 Step 3) using procedures similar to those described for Compound 52, Step 1.

The title compounds, obtained as a mixture, were sequentially separated using chiral SLC.

Example 101: *fast moving isomer: ¹ H NMR (400 MHz, CDCl ₃ ) 7.74 (1H, s), 7.39 (1H, d), 7.04 (4H, s), 7.01 (4H , d), 4.68 (1H, dd), 3.86-3.57 (5H, m), 3.30 (1H, dd), 3.10 (3H, s), 2.25-2, 15(2H, m), 2.05-1.81(3H, m), 1.66-1.42(2H, m), 0.69(3H, t); COOH absent. MS: [M+H] ⁺ =634.

Example 102: * Slow moving isomer: ¹ H NMR (400 MHz, CDCl ₃ ) 7.75 (1H, s), 7.37 (1H, d), 7.04 (4H, s), 7.01 (4H , s), 4.70 (1H, dd), 3.87-3.58 (5H, m), 3.29 (1H, dd), 3.11 (3H, s), 2.25-2, 15(2H, m), 2.02-1.80(3H, m), 1.71-1.51(1H, m), 1.43(1H, dd), 0.69(3H, t) ; COOH absent. MS: [M+H] ⁺ =634.

Example 103 and 104: (3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-5-(1-cyclobutyl-1-hydroxyethyl)-7-fluoro-1- methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoic acid

(*both isomers were separated and isolated)

The title compound was prepared from 2-(4-chlorobenzoyl)-5-(cyclobutanecarbonyl)-3-fluorobenzoic acid (Compound 55) using methods similar to those described for Example 98. Except for using 2M aqueous HCl instead of LiOH in step 3.

Example 103: *fast moving isomer: ¹ H NMR (400 MHz, CDCl ₃ ) 7.70 (1H, s), 7.31 (1H, d), 7.04-6.99 (4H, m), 6 .98 (4H, s), 4.67 (1H, dd), 3.61-3.60 (1H, m), 3.33-3.25 (1H, m), 3.06 (3H, s ), 2.74-2.65(1H, m), 2.05-1.93(2H, m), 1.87-1.73(2H, m), 1.66(1H, d), 1.56-1.54 (1H, m), 1.44 (3H, s); OH and COOH are absent; MS: [M+H] ⁺ =572.

Example 104: *Slow moving isomer: ¹ H NMR (400 MHz, CDCl ₃ ) 7.71 (1H, s), 7.29 (1H, d), 7.05-6.93 (8H, m), 4 .70 (1H, dd), 3.59 (1H, s), 3.22-3.17 (1H, m), 3.06 (3H, s), 2.74-2.65 (1H, m ), 2.07-1.66(5H, m), 1.61-1.54(1H, m), 1.44(3H, s); OH and COOH are absent; MS: [M+H] ⁺ =572.

Example 105: (3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxane- 4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoic acid

Step 1: Ethyl-(3S)-3-(4-chlorophenyl)-3-(1-(4-chlorophenyl)-7-fluoro-1-hydroxy-5-((S)-1-hydroxy-1-( tetrahydro-2H-pyran-4-yl)propyl)-3-oxoisoindolin-2-yl)propanoate

(S)-2-(4-Chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-(tetrahydro-2H-pyran-4-yl)propyl)benzoic acid was reacted (Compound 52, 1.43 g, 3.39 mmol) and (S)-ethyl 3-amino-3-(4-chlorophenyl)propanoate hydrochloride (Compound 35, 1.16 g, 4.41 mmol) in a manner analogous to that described in Example 35, step 4 , to give the title compound (1.37 g, 64%) as a colorless foam. MS: [M-H] ⁺ =628.

Step 2: Ethyl-(S)-3-(4-chlorophenyl)-3-((R)-1-(4-chlorophenyl)-7-fluoro-5-((S)-1-hydroxy-1-( tetrahydro-2H-pyran-4-yl)propyl)-1-methoxy-3-oxoisoindolin-2-yl)propanoate

The title compound was prepared from ethyl-(3S)-3-(4-chlorophenyl)-3-(1-(4-chlorophenyl)-7-fluoro-1-hydroxy-5-((S)-1-hydroxy-1- (tetrahydro-2H-pyran-4-yl)propyl)-3-oxoisoindolin-2-yl)propanoate (1.3 g, 2.06 mmol) and methanol (0.83 ml, 20 mmol) in a manner similar to that described for Substance 10. The diastereoisomers were separated using chiral SLC to give the title compound (0.39 g) as a pale yellow foam. MS: [M-MeOH] ⁺ =612.

Step 3: (3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxane- 4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoic acid

The title compound was prepared from ethyl-(S)-3-(4-chlorophenyl)-3-((R)-1-(4-chlorophenyl)-7-fluoro-5-((S)-1-hydroxy-1- (tetrahydro-2H-pyran-4-yl)propyl)-1-methoxy-3-oxoisoindolin-2-yl)propanoate (0.391 g, 0.6 mmol) using procedures similar to those described for Compound 52, Step 3. The crude product was purified by preparative HPLC to give the pure title compound (80 mg) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) 7.62 (1H, d), 7.29 (1H, dd), 7.04 (4H, s), 7.00 (4H, s), 4.68 ( 1H, dd), 4.03(1H, dd), 3.90(1H, dd), 3.74(1H, dd), 3.40-3.25(3H, m), 3.09(3H , s), 1.97-1.86(3H, m), 1.73(1H, d), 1.49-1.35(2H, m), 1.07(1H, d), 0. 68 (3H, t); OH and COOH are absent. MS: [M+H] ⁺ =616.

The following Examples were prepared from a suitable chiral acid intermediate (eg Substance 52, Substance 52b or Substance 54) using procedures similar to those described for Example 105, steps 1-3. A suitably protected α- or β-amino acid was used in Step 1 [e.g. methyl-(S)-4-amino-4-(4-chlorophenyl)butanoate or (S)-ethyl-3-amino-3-(4 -chlorophenyl)propanoate (Compound 35)], and a suitable alcohol (eg MeOH, EtOH, CD ₃ OH) was used in step 2.

In some cases, the product was isolated in the form of tris(hydroxymethyl)aminomethane (TRIS) salt (by dissolution in MeOH, exposure to tris(hydroxymethyl)aminomethane and evaporation).

Example 106: (3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1R)-1-hydroxy-1-(oxane- 4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoic acid

¹ H NMR (400 MHz, CDCl ₃ ) 7.62 (1H, d), 7.28 (2H, d), 7.04 (4H, s), 7.01 (4H, s), 4.68 ( 1H, dd), 4.03(1H, dd), 3.89(1H, dd), 3.73(1H, dd), 3.42-3.25(3H, m), 3.10(3H , s), 1.96-1.85(3H, m), 1.74(1H, d), 1.49-1.36(2H, m), 1.06(1H, d), 0. 68 (3H, t); COOH is absent. MS: [M+H] ⁺ =616.

Example 107: (4S)-4-(4-chlorophenyl)-4-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxane- 4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]butanoic acid

¹ H NMR (400 MHz, CDCl ₃ ) 7.61 (s, 1H), 7.06-7.01 (m, 4H), 6.99 (d, 2H), 4.19 (dd, 1H), 4.02 (dd, 1H), 3.90 (dd, 1H), 3.40-3.24 (m, 2H), 3.19 (s, 3H), 3.13-3.03 (m, 1H), 2.54-2.44 (m, 1H), 2.32-2.11 (m, 2H), 2.07-1.96 (m, 1H), 1.96-1.84 ( m, 3H), 1.73(d, 3H), 1.47-1.36(m, 3H), 1.27-1.16(m, 1H), 1.07(d, 1H), 0 .69 (dd, 2H). MS: [M+H] ⁺ =630.

Example 108: (4S)-4-(4-chlorophenyl)-4-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1R)-1-hydroxy-1-(oxane- 4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]butanoic acid

¹ H NMR (400 MHz, CDCl ₃ ) 7.62-7.59 (3H, m), 7.41 (2H, d), 7.35 (2H, d), 7.31-7.26 (3H , m), 4.09-4.00(2H, m), 3.91(1H, dd), 3.41-3.27(2H, m), 2.88-2.77(1H, m ), 2.51-2.42(4H, m), 2.03-1.97(2H, m), 1.97-1.85(3H, m), 1.73(1H, d), 1.48-1.38(2H, m), 1.08(1H, d), 0.70-0.64(3H, m); OH and COOH are absent. MS: [M+H] ⁺ =630.

Example 109: (4S)-4-(4-Chlorophenyl)-4-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1R)-1-(4-fluoroxane-4- yl)-1-hydroxypropyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]butanoic acid (tris(hydroxymethyl)aminomethane salt)

¹ H NMR (400 MHz, DMSO) 7.76 (1H, s), 7.48 (1H, d), 7.18-7.12 (4H, m), 7.10-7.02 (4H, m), 4.25(1H, dd), 3.88(1H, dd), 3.72(1H, dd), 3.56-3.50(1H, m), 3.47-3.39 (1H, m), 3.37 (6H, s), 3.18 (3H, s), 2.84-2.73 (1H, m), 2.48-2.38 (1H, m), 2.26-2.17(1H, m), 2.05-1.88(6H, m), 1.07-0.99(1H, m), 0.63(3H, t); 7 protons are missing (OH×4, NH2 and COOH). MS: [M+H] ⁺ =648.

Example 110: (3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1R)-1-(4-fluoroxane-4- yl)-1-hydroxypropyl]-1-trideuteromethoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoic acid

¹ H NMR (400 MHz, CDCl ₃ ) 7.61 (1H, s), 7.26 (1H, d), 7.07-6.99 (8H, m), 4.19 (1H, dd), 3.51-3.43(1H, m), 3.19(3H, s), 3.14-3.04(1H, m), 2.53-2.44(1H, m), 2, 30-1.85(7H, m), 1.67-1.60(1H, m), 1.31-1.07(5H, m), 0.66(3H, dd). MS: [M+H] ⁺ =637.

Example 111: (3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-1-ethoxy-7-fluoro-5-[(1R)-1-(4- fluoroxan-4-yl)-1-hydroxypropyl]-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoic acid

¹ H NMR (400 MHz, CDCl ₃ ) 7.73 (1H, s), 7.36 (1H, d), 7.06-7.00 (8H, m), 4.69 (1H, dd), 3.86-3.75(3H, m), 3.66-3.57(2H, m), 3.30-3.12(3H, m), 2.26-2.13(2H, m ), 2.02-1.82(3H, m), 1.67-1.40(3H, m), 1.28(3H, dd), 0.68(3H, dd). MS: [M+H] ⁺ =637.

Example 113: (4S)-4-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1R)-1-(4-fluoroxan-4-yl)-1-hydroxypropyl]- 1-Methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]-4-(4-methoxyphenyl)butanoic acid

¹ H NMR (400 MHz, CDCl ₃ ) 7.73 (1H, s), 7.35 (1H, d), 7.05-6.93 (6H, m), 6.58 (2H, d), 4.16(1H, dd), 3.81(2H, d), 3.73(3H, s), 3.66-3.58(2H, m), 3.17(3H, s), 3 .11-3.10 (1H, m), 2.51-2.42 (1H, m), 2.31-2.28 (4H, m), 2.27-2.13 (3H, m) , 1.69-1.44 (2H, m), 0.69 (3H, dd); COOH was not observed. MS: [M+H] ⁺ =644.

Example 114: (4S)-4-(4-chlorophenyl)-4-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-{1-hydroxy-1-[trans-4-hydroxycyclohexyl] propyl}-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]butanoic acid (*Example prepared and isolated as single isomer at position shown*)

The title compound was prepared from a single isomer of 2-(4-chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-trans-4-hydroxycyclohexyl)propyl)benzoic acid (Compound 64, Step 3) following procedures similar to described for Example 105. ¹ H NMR (400 MHz, CDCl ₃ ) 7.61 (1H, s), 7.26 (1H, d), 7.07-6.99 (8H, m), 4.19 ( 1H, dd), 3.51-3.43(1H, m), 3.19(3H, s), 3.14-3.04(1H, m), 2.53-2.44(1H, m), 2.30-1.85(7H, m), 1.67-1.60(1H, m), 1.31-1.07(5H, m), 0.66(3H, dd) capable of exchange were not observed. MS: [M+H] ⁺ =644.

Example 115: 2-(5-chloro-2-{[1-(4-chlorophenyl)-7-fluoro-5-[(1R)-1-(4-fluoroxan-4-yl)-1-hydroxypropyl]- 1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}phenoxy)acetic acid (tris(hydroxymethyl)aminomethane salt)

The title compound was prepared from (R)-2-(4-chlorobenzoyl)-3-fluoro-5-(1-(4-fluorotetrahydro-2H-pyran-4-yl)-1-hydroxypropyl)benzoic acid (Compound 54) and ethyl 2-[2-(aminomethyl)-5-chlorophenoxy]acetate hydrochloride (Compound 63) following procedures similar to those described for Example 105. ¹ H NMR (400 MHz, DMSO-d ₆ -D ₂ O): 7 .71 (1H, s), 7.40 (1H, d), 7.26-7.17 (4H, m), 6.91 (1H, d), 6.67 (1H, dd), 6, 50(1H, d), 4.38(2H, s), 4.19-4.00(2H, m), 3.84-3.74(1H, m), 3.66(1H, dd) , 3.46(7H, s), 2.84(3H, s), 2.19-2.03(1H, m), 1.99-1.74(4H, m), 1.14(1H , d), 1.04-0.95 (1H, m), 0.56 (3H, t). MS: [M+H] ⁺ =650.

Example 116: 5-chloro-2-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl]- 1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzoic acid

Step 1 and Step 2: From (-)-(S)-2-(4-chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-(tetrahydro-2H-pyran-4-yl)propyl)benzoic acid (Substance 52), (2-bromo-4-chlorophenyl)methanamine (Example 33, Step 1) and MeOH, Step 1 and Step 2 were carried out following procedures similar to those described for Example 35, Step 4, and Substance 10, respectively. . Chiral separation using supercritical liquid chromatography gave (R)-2-(2-bromo-4-chlorobenzyl)-3-(4-chlorophenyl)-4-fluoro-6-((S)-1-hydroxy-1- (tetrahydro-2H-pyran-4-yl)propyl)-3-methoxyisoindolin-1-one. MS: [M+H] ⁺ =638

Stage 3: 5-chloro-2-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl]- 1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzoic acid

The title compound was obtained in a manner similar to that described for Example 33, step 5. ¹ H NMR (400 MHz, DMSO) 7.78 (1H, s), 7.69 (1H, s), 7.50 (1H, d) , 7.37-7.31(5H, m), 7.24(1H, s), 4.98(1H, s), 4.94-4.81(2H, m), 3.98-3 .93 (1H, m), 3.82 (1H, dd), 3.40-3.30 (1H, m), 3.28-3.21 (1H, m), 2.88 (3H, s ), 2.05-1.90(3H, m), 1.73(1H, d), 1.48-1.30(2H, m), 1.02(1H, d), 0.65( 3H, t), no COOH. MS: [M+H] ⁺ =602.

The following Examples were prepared from a suitable chiral acid intermediate (eg Compound 52, Compound 54) using procedures similar to those described for Example 116, steps 1-3. An appropriate benzylamine [e.g. (2-bromo-4-chlorophenyl)methanamine, Compound 58 or Compound 59] was used in Step 1 and an appropriate alcohol was used in Step 2. In some cases, the product was isolated as tris(hydroxymethyl)aminomethane (TRIS) salt (by dissolution in MeOH, exposure to tris(hydroxymethyl)aminomethane and evaporation). Purification by preparative HPLC gave products as single isomers with the configuration shown.

Example 117: 5-chloro-2-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1R)-1-hydroxy-1-(oxan-4-yl)propyl]- 1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzoic acid

Prepared from (+)-(R)-2-(4-chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-(tetrahydro-2H-pyran-4-yl)propyl)benzoic acid (Compound 52b) . ¹ H NMR (400 MHz, CDCl ₃ ) 7.73 (2H, d), 7.30-7.18 (6H, m, overlap with CHCl3), 7.14 (1H, d), 5.12 ( 1H, d), 4.64(1H, d), 4.01(1H, dd), 3.84(1H, dd), 3.37-3.19(2H, m), 2.81(3H , s), 1.98-1.71(4H, m), 1.71(1H, d), 1.45-1.33(2H, m), 1.05-0.99(1H, m ), 0.64 (3H, t). COOH absent MS: [M+H] ⁺ =602.

Example 118: 5-chloro-2-{[(1R)-1-(4-chlorophenyl)-1-ethoxy-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl )propyl]-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzoic acid - (tris(hydroxymethyl)aminomethane salt)

¹ H NMR (400 MHz, CDCl ₃ ) 7.79 (1H, s), 7.50 (1H, s), 7.21 (2H, d), 7.08-7.00 (2H, m), 6.82(1H, d), 5.02(2H, s), 4.59-4.59(3H, m), 3.97-3.94(1H, m), 3.85-3, 81 (1H, m), 3.73 (6H, s), 3.33-3.17 (2H, m), 3.06-2.94 (2H, m), 1.84-1.59 ( 4H, m), 1.43-1.34 (2H, m), 1.00 (4H, dd), 0.55 (3H, t), no exchangeable proton was observed. MS: [M+H] ⁺ =616.

Example 119 2-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1R)-1-(4-fluoroxan-4-yl)-1-hydroxypropyl]-1-methoxy -3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}-5-methylbenzoic acid

¹ H NMR (400 MHz, CDCl3) 7.78 (1H, s), 7.69 (1H, s), 7.40-7.31 (4H, m), 7.26-7.19 (3H, m), 4.99 (1H, d, J=15.4 Hz), 4.83 (1H, d, J=15.4 Hz), 3.86-3.77 (2H, m), 3, 68-3.57(2H, m), 2.80(3H, s), 2.34(3H, s), 2.25-2.14(1H, m), 2.00-1.80( 2H, m), 1.70-1.42(3H, m), 1.26(1H, s), 0.69(3H, dd); COOH was not observed. [M+H]+=601

Example 120 2-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1R)-1-(4-fluoroxan-4-yl)-1-hydroxypropyl]-1-methoxy -3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}-5-methoxybenzoic acid -tris(hydroxymethyl)aminomethane salt

¹ H NMR (400 MHz, CDCl3) 7.83 (1H, s), 7.32-7.18 (5H, m), 7.13-7.13 (1H, m), 6.95 (1H, d), 6.68(1H, d), 4.92(2H, d), 4.65(1H, d), 3.82-3.78(1H, m), 3.72(6H, s ), 3.61-3.48(4H, m), 2.87(3H, s), 2.62(1H, s), 2.08-2.00(1H, m), 1.94- 1.60 (6H, m), 1.26-1.16 (1H, m), 0.55 (3H, s). [M+H]+=616

Example 121: 2-(5-chloro-2-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl) propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}phenyl)-2-methylpropanoic acid (tris(hydroxymethyl)aminomethane salt)

Stage 1: Methyl-2-(5-chloro-2-(((R)-1-(4-chlorophenyl)-7-fluoro-5-((S)-1-hydroxy-1-(tetrahydro-2H- pyran-4-yl)propyl)-1-methoxy-3-oxoisoindolin-2-yl)methyl)phenyl)-2-methylpropanoate

A diastereomeric mixture at C-3 4-yl)propyl)-3-methoxyisoindolin-1-one (1 g, prepared as in Example 116, Step 2 (except for chiral resolution), methyltrimethylsilyl dimethylketene acetal (820 mg, 4.71 mmol), zinc fluoride (486 .6 mg, 4.71 mmol) and di-u-brombis(tri-t-butylphosphino) dipalladium (I) {[P(t-Bu) ₃ ]PdBr} (STREM) (243 mg, 0.314 mmol) were placed in round bottom flask under nitrogen atmosphere, then degassed DMF (20 ml) was added.The reaction mixture was degassed with nitrogen for another 5 minutes, then heated (using a preheated stirrer set at 70°C) for 18 hours. degassed for 10 minutes Additional methyltrimethylsilyldimethylketeneacetal (858 mg, 4.92 mmol), zinc fluoride (500 mg, 4.84 mmol) and {[P(t-Bu) ₃ ]PdBr} (250 mg, 0.32 mmol) then heated (using a preheated stirrer set at 70° C.) for 4 hours. The reaction mixture was left to cool and then the DMF was removed under reduced pressure. Water (20 ml) and EtOAc (50 ml) were added and the resulting black suspension filtered. The filtrate layers were separated and the organics were kept. The aqueous portion was extracted with EtOAc (20 ml), then the combined organic extracts were dried (MgO ₄ ) and concentrated under reduced pressure to obtain a black precipitate (1.5 g). The precipitate was dissolved in THF (15 ml) at RT with stirring and a 1M TBAF solution in THF (7.75 ml) was added. The reaction mixture was stirred for 15 min at RT. The reaction mixture was diluted with EtOAc (60 ml) and washed with water (20 ml). The organic portion was dried (MgO ₄ ) and concentrated under reduced pressure to give a black precipitate (1.4 g). The crude material was purified by column chromatography using an isocratic gradient of 75% diethyl ether in isohexane to give a foam (540 mg). The two diastereoisomers were separated by chiral SLC to give the title compound as the fast moving isomer (300 mg). MS [M - C3 Methoxy] ⁺ = 626.1

Step 2: 2-(5-chloro-2-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl) propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}phenyl)-2-methylpropanoic acid

Methyl-2-(5-chloro-2-(((R)-1-(4-chlorophenyl)-7-fluoro-5-((S)-1-hydroxy-1-(tetrahydro-2H-pyran-4 -yl)propyl)-1-methoxy-3-oxoisoindolin-2-yl)methyl)phenyl)-2-methylpropanoate (300 mg) was dissolved in THF (22 ml), then a solution of lithium hydroxide monohydrate (109.1 mg, 4.5 mmol) in water (7.5 ml) and methanol (4.5 ml) at RT with stirring. The reaction mixture was heated at 65°C for 4 days, then at 75°C for 1 day.

The reaction mixture was left to cool, then the volatiles were removed under reduced pressure. The resulting emulsion was diluted with ether (50 ml) and water (20 ml) and the pH was adjusted (by adding 2M aqueous HCl) to facilitate extraction of the product into the organic layer. The organic portion was passed through a phase separation cartridge and the volatiles were removed under reduced pressure to give a crude foam (200 mg). The crude material was purified by column chromatography eluting with a gradient of 0-100% diethyl ether in isohexane and then washed with 100% EtOAc with 0.1% formic acid to give a crude mixture (70 mg). Additional cleaning with prep. HPLC gave the title compound (46 mg) as a colorless foam. The product was then isolated as a TRIS salt by dissolution in MeOH, exposure to TRIS and evaporation. ' ¹ H NMR (400 MHz, CDCl ₃ ) 7.74 (1H, s), 7.31 (1H, s), 7.31-7.28 (1H, m), 7.24 (3H, s) , 7.17(2H, d), 7.08(1H, d), 7.01(1H, dd), 4.50-4.37(2H, m), 4.04(1H, dd), 3.92(1H, dd), 3.43(6H, s), 3.39-3.28(2H, m), 2.96(3H, s), 2.73(1H, dd), 2 .01-1.89(3H, m), 1.73(1H, s), 1.52-1.50(6H, m), 1.14-1.07(1H, m), 0.72 (3H, dd) (7 exchangeable protons were not observed). MS [M+H] ⁺ =644.

Example 122: 2-(5-chloro-2-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl) propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}phenyl)acetic acid (tris(hydroxymethyl)aminomethane salt)

Stage 1: Methyl-2-(5-chloro-2-(((R)-1-(4-chlorophenyl)-7-fluoro-5-((3)-1-hydroxy-1-(tetrahydro-2H- pyran-4-yl)propyl)-1-methoxy-3-oxoisoindolin-2-yl)methyl)phenyl)acetate

1-(tert-Butyldimethylsilyloxy)-1-methoxyethene (1270.3 mg, 6.75 mmol), zinc fluoride (697.5 mg, 6.75 mmol), tri-t-butylphosphine (136 mg, 0.67 mmol ) and bis(dibenzylideneacetone)palladium(0) (193.9 mg, 0.337 mmol) were equally divided between two reaction tubes. Degassed solution of the diastereomeric mixture at C-3 pyran-4-yl)propyl)-3-methoxyisoindolin-1-one (860 mg, 1.35 mmol, obtained as in Example 116, Step 2 except for chiral separation) in DMF (20 mL) was equally divided between the two reaction tubes. The mixture in each tube was degassed with nitrogen for an additional 30 s, then sealed, then stirred under heat (using a preheated stirrer set at 70°C) for 18 h. The reaction mixture was allowed to cool to RT and the DMF was removed under reduced pressure. Water (20 ml) and EtOAc (50 ml) were added and the resulting black suspension filtered. The filtrate layers were separated and the organics were kept. The aqueous portion was extracted with EtOAc (20 ml), then the combined organic extracts were dried (MgO ₄ ) and concentrated under reduced pressure to obtain a black precipitate (1.5 g). The crude material was purified by column chromatography with a gradient of 50-90% diethyl ether in isohexane to give a colorless foam (510 mg). The two diastereoisomers were separated by chiral SLC to give the title compound as a fast moving isomer (140 mg, 33% yield). MS [M-C3 methoxy] ⁺ =598.1

Step 2: 2-(5-chloro-2-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl) propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}phenyl)acetic acid (tris(hydroxymethyl)aminomethane salt)

Step 2 was carried out using conditions similar to those described for Substance 52, Step 3 to give the title compound. ¹ H NMR (400 MHz, CDCl ₃ ) 7.78 (1H, s), 7.25-7.18 (4H, m), 7.14 (1H, d), 7.06-6.97 (3H , m), 4.70(1H, d), 4.21(1H, d), 4.00(1H, d), 3.86(1H, d), 3.70(1H, d), 3 .59 (6H, s), 3.54 (1H, d), 3.38-3.22 (3H, m), 2.74 (3H, s), 1.89-1.78 (2H, m ), 1.69 (1H, d), 1.48-1.34 (2H, m), 1.05 (1H, d), 0.64 (3H, dd), seven exchangeable protons were not observed. MS [M+H] ⁺ =616

Example 123: 2-(5-chloro-2-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1R)-1-hydroxy-1-(oxan-4-yl) propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}phenyl)acetic acid

The title compound was prepared in a similar manner to Example 122, but from (+)-(R)-2-(4-chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-(tetrahydro-2H-pyran-4-yl )propyl)benzoic acid (prepared in a similar manner to Compound 52).

¹ H NMR (400 MHz, CDCl ₃ ) 7.67 (s, 2H), 7.30-7.10 (m, 7H), 4.71 (d, 1H), 4.15 (d, 1H), 4.03(dd, 1H), 3.88(dd, 1H), 3.80(d, 1H), 3.72(d, 1H), 3.37(t, 1H), 3.25(t , 1H), 2.72 (s, 3H), 1.95-1.82 (m), 1.71 (d, 1H), 1.48-1.32 (m, 2H), 1.10- 0.98 (m, 1H), 0.91-0.80 (m, 1H), 0.65 (t, 3H). MS [M-OMe ^- ] ⁺ =584

Example 124: (2S,3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-( oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]-2-methylpropanoic acid

Step 1: Prop-2-en-1-yl-(2S,3S)-3-(4-chlorophenyl)-3-[1-(4-chlorophenyl)-7-fluoro-1-hydroxy-5-[( 1S)-1-hydroxy-1-(oxan-4-yl)propyl]-3-oxo-2,3-dihydro-1H-isoindol-2-yl]-2-methylpropanoate

To a solution of (S)-2-(4-chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-(tetrahydro-2H-pyran-4-yl)propyl)benzoic acid (Compound 52) (0.686 g, 1.6 mmol), prop-2-en-1-yl-(2S,3S)-3-amino-3-(4-chlorophenyl)-2-methylpropanoate (Compound 62) (0.54 g, 2.12 mmol) and diisopropylethylamine (0.83 ml, 4.8 mmol) in DMF (15 ml) was added HATU (0.91 g, 2.4 mmol) and the reaction mixture was stirred for 2 h. Water was added and extracted with ethyl acetate. The organic phase was washed with saturated NaHCO ₃ , brine, dried and the solvent was evaporated. The crude product was purified by chromatography to give the title compound (0.75 g, 72%). MS: [M-N] ^- = 654.

Step 2: Prop-2-en-1-yl-(2S,3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[( 1S)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]-2-methylpropanoate

The title compound was prepared from ethyl-(2S,3S)-3-(4-chlorophenyl)-3-[1-(4-chlorophenyl)-7-fluoro-1-hydroxy-5-[(1S)-1-hydroxy- 1-(oxan-4-yl)propyl]-3-oxo-2,3-dihydro-1H-isoindol-2-yl]-2-methylpropanoate and methanol in a manner similar to Compound 10, but using MeOH instead 1,1-bis(hydroxymethyl)cyclopropane. The diastereoisomers were separated by chiral SLC, the title compound being the more rapidly eluting isomer. MS: [M+H] ⁺ =670.

Step 3: (2S,3S)-3-(4-Chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-( oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]-2-methylpropanoic acid

The title compound was prepared from prop-2-en-1-yl-(2S,3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[ (1S)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]-2-methylpropanoate in a manner analogous to that described in Example 90, step 4. 1H NMR (400 MHz, DMSO-d6): 12.56-12.00 (1H, m), 7.71 (1H, s), 7.42 (1H, d), 7 .02 (4H, d), 6.88 (3H, d), 4.91 (1H, s), 4.23 (1H, d), 3.99-3.85 (2H, m), 3. 75(1H, dd), 3.25-3.10(5H, m), 2.02-1.90(1H, m), 1.90-1.78(2H, m), 1.67( 1H, d), 1.43-1.17(6H, m), 0.95(1H, d), 0.58(3H, t). MS: [M+H] ⁺ =630.

Example 124a: (2S,3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-( oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]-2-methylpropanoic acid (tris(hydroxymethyl)aminomethane salt)

Example 124 was dissolved in EtOH and 1 mol was added. equiv. tris(hydroxymethyl)aminomethane.

The solvent was removed under vacuum to give a colorless solid. ¹ H NMR (500 MHz, DMSO-d6) δ 7.69 (s, 1H), 7.39 (d, J=10.7 Hz, 1H), 7.01 (broad s, 4H), 6.96 -6.88 (m, 4H), 4.92 (wide s, 1H), 4.34-4.22 (m, 1H), 3.88 (dd, J=10.9, 4.2 Hz, 1H), 3.74 (dd, J=11.1, 4.2 Hz, 1H), 3.71-3.61 (m, 1H), 3.29 (s, 6H), 3.33-3 .22 (m, 1H), 3.21-3.14 (m, 1H), 3.13 (s, 3H), 1.94 (tt, J=12.2, 3.6 Hz, 1H), 1.89-1.78 (m, 2H), 1.66 (d, J=12.8 Hz, 1H), 1.41-1.24 (m, 2H), 1.19 (d, J= 6.8 Hz, 3H), 0.93 (d, J=13.2 Hz, 1H), 0.57 (t, J=7.3 Hz, 3H). MS: [M+H] ⁺ =630.

Example 125 and 126: (3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-1-[(3-fluoroxetan-3-yl)methoxy] -5-(2-Hydroxybutan-2-yl)-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoic acid (*both isomers were separated and isolated)

Step 1: Ethyl-(S)-3-((R)-5-bromo-1-(4-chlorophenyl)-7-fluoro-1-((3-fluoroxetan-3-yl)methoxy)-3-oxoisoindoline -2-yl)-3-(4-chlorophenyl)propanoate

The title compound was prepared from (3S)-ethyl-3-(5-bromo-1-(4-chlorophenyl)-1-hydroxy-3-oxoisoindolin-2-yl)-3-(4-chlorophenyl)propanoate (Compound 36, 7.19 g, 12.7 mmol) and (3-fluoroxetan-3-yl)methanol (4.00 g, 38 mmol) in a manner similar to Compound 10. The diastereoisomers were separated by column chromatography eluting with DCM. The title compound was obtained as a colorless solid (1.93 g). MS: [M-(3-fluoroxetan-3-yl)methanol] ⁺ =550.

Stage 2: Stage 2 was carried out using procedures similar to those described for Example 21, Stage 3, to obtain ethyl-(S)-3-((R)-5-acetyl-1-(4-chlorophenyl)-7-fluoro -1-((3-Fluoroxetan-3-yl)methoxy)-3-oxoisoindolin-2-yl)-3-(4-chlorophenyl)propanoate (1.29 g) as a yellow solid. MS: [M-(3-fluoroxetan-3-yl)methanol] ⁺ =512.

Step 3: (S)-3-((R)-5-Acetyl-1-(4-chlorophenyl)-7-fluoro-1-((3-fluoroxetan-3-yl)methoxy)-3-oxoisoindoline-2 -yl)-3-(4-chlorophenyl)propanoic acid

The title compound was prepared from ethyl-(S)-3-((R)-5-acetyl-1-(4-chlorophenyl)-7-fluoro-1-((3-fluoroxetan-3-yl)methoxy)-3- oxoisoindolin-2-yl)-3-(4-chlorophenyl)propanoate (1.19 g, 1.92 mmol) using procedures similar to those described for Compound 52, Step 3. The crude product was obtained as a sticky orange solid ( 1.26 g). MS: [M+H] ⁺ =590.

Step 4: (3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-1-[(3-fluoroxetan-3-yl)methoxy]-5 -(2-hydroxybutan-2-yl)-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoic acid

The title compound was prepared using procedures similar to those described for Example 41, Step 3; except for the use of ethyl magnesium chloride instead of (tetrahydro-2H-pyran-4-yl) magnesium chloride.

Example 125: *fast moving isomer: ¹ H NMR (400 MHz, CDCl ₃ ) 7.73 (1H, d), 7.38 (1H, dd), 7.04-6.94 (8H, m), 4 .93-4.72(3H, m), 4.68-4.59(2H, m), 3.73-3.62(2H, m), 3.52-3.36(2H, m) , 1.89-1.80(2H, m), 1.59(3H, s), 0.80(3H, dd); OH and COOH are absent. MS: [M+H] ⁺ =620.

Example 126: * Slow moving isomer: ¹ H NMR (400 MHz, CDCl ₃ ) 7.74 (1H, s), 7.37 (1H, d), 7.02-6.95 (8H, m), 4 .93-4.59(5H, m), 3.72-3.63(2H, m), 3.52-3.37(2H, m), 1.89-1.81(2H, m) , 1.58 (3H, s), 0.82 (3H, dd); OH and COOH are absent. MS: [M+H] ⁺ =620.

Examples 127 and 128: (3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(pyridine-2- yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoic acid

(*both isomers were separated and isolated)

Step 1: Ethyl-(3S)-3-(4-chlorophenyl)-3-[1-(4-chlorophenyl)-7-fluoro-1-hydroxy-3-oxo-5-(pyridine-2-carbonyl)- 2,3-dihydro-1H-isoindol-2-yl]propanoate

To a stirred solution of 2-(4-chlorobenzoyl)-3-fluoro-5-(pyridine-2-carbonyl)benzoic acid (Compound 61) (0.48 g, 1.25 mmol), (S)-ethyl-3 hydrochloride -amino-3-(4-chlorophenyl)propanoate (0.47 g, 1.87 mmol) and diisopropylethylamine (0.9 ml, 5.0 mmol) in DMF (15 ml) was added N-propylphosphonic anhydride, cyclic trimer (50% w/w, 1.211 ml, 1.87 mmol) and the reaction mixture was stirred for 1 hour. Water was added and the product was extracted with ethyl acetate. The crude product was purified by chromatography eluting with ethyl acetate 0-50% to give the title compound (0.36 g, 39%). MS: [M+H] ⁺ =384.

Step 2: Ethyl (3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-1-methoxy-3-oxo-5-(pyridine-2- carbonyl)-2,3-dihydro-1H-isoindol-2-yl]propanoate

The title compound was prepared from ethyl-(3S)-3-(4-chlorophenyl)-3-[1-(4-chlorophenyl)-7-fluoro-1-hydroxy-3-oxo-5-(pyridine-2-carbonyl) -2,3-dihydro-1H-isoindol-2-yl]propanoate and methanol in a manner similar to that described for Compound 10. The diastereoisomers were separated by column chromatography [M+H] ⁺ =607.

Stage 3: (3S)-3-(4-Chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-1-methoxy-3-oxo-5-(pyridine-2-carbonyl )-2,3-dihydro-1H-isoindol-2-yl]propanoic acid

The title compound was obtained from ethyl-(3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-1-methoxy-3-oxo-5-(pyridine- 2-carbonyl)-2,3-dihydro-1H-isoindol-2-yl]propanoate in a manner analogous to that described for Compound 40. [M+H] ⁺ =579.

Step 4: (3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(pyridin-2-yl) propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoic acid

To a solution of (3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-1-methoxy-3-oxo-5-(pyridine-2-carbonyl) -2,3-dihydro-1H-isoindol-2-yl]propanoic acid (0.5 g, 0.86 mmol) in THF 10 ml) was added ZnCl ₂ (1.7 ml, 0.5 M in THF, 0 .85 mmol) and the mixture was stirred for 30 min, cooled to -30°C, and EtMgCl (1.29 ml, 2 M in THF, 2.58 mmol) was added and stirred for 30 min. Saturated NH ₄ Cl solution was added, acidified to pH=4.5 and extracted with ethyl acetate. The diastereoisomers were separated by chiral SLC.

Example 127 Fast moving isomer

¹ H NMR (400 MHz, DMSO-d ₆ ): 12.36 (1H, s), 8.61-8.55 (1H, m), 7.85 (1H, d), 7.82-7, 70 (2H, m), 7.63-7.56 (1H, m), 7.30-7.23 (1H, m), 7.17-7.04 (4H, m), 7.04- 6.88(4H, m), 6.08(1H, s), 4.60(1H, dd), 3.46(1H, dd), 3.18(1H, dd), 3.08-3 .00 (3H, m), 2.44-2.34 (1H, m), 2.34-2.24 (1H, m), 0.71 (3H, t). MS: [M+H] ⁺ =609.

Example 128: slow moving isomer

¹ H NMR (400 MHz, DMSO-d ₆ ): 12.29 (1H, d), 8.59-8.53 (1H, m), 7.86 (1H, d), 7.83-7, 70(2H, m), 7.59(1H, dd), 7.28-7.22(1H, m), 7.17-7.05(4H, m), 7.05-6.92( 4H, m), 6.07(1H, s), 4.61(1H, dd), 3.49-3.41(1H, m), 3.22-3.09(1H, m), 3 .03 (3H, s), 2.41 (1H, dd), 2.34-2.26 (1H, m), 0.71 (3H, t).

MS: [M+H] ⁺ =609.

Example 129: (3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[1-(4-fluoropiperidin-4-yl)-1 -hydroxypropyl]-3-methoxy-2,3-dihydro-1H-isoindol-1-one (Example isolated as single isomer at position shown*)

The title compound was prepared from (-)-5-(1-(1-(tert-butoxycarbonyl)-4-fluoropiperidin-4-yl)-1-hydroxypropyl)-2-(4-chlorobenzoyl)-3-fluorobenzoic acid (Substance 57) and (4-chloro-2-(methylsulfonyl)phenyl)methanamine (Example 35, Step 3) using procedures similar to those described in Example 87 (Steps 1-2). ¹ H NMR (400 MHz, CDCl3) 7.93 (1H, d), 7.78 (1H, s), 7.49 (1H, d), 7.45-7.38 (2H, m), 7 .32(2H, d), 7.24(2H, d), 4.96(2H, q), 3.02(3H, s), 2.96(3H, s), 2.95-2, 83 (4H, m), 2.26-2.16 (2H, m), 2.09-1.95 (2H, m), 1.86-1.62 (3H, m), 1.44- 1.25 (1H, m), 0.71 (3H, dd); MS [M+H]+=653.

Example 130 4-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(1-methylpiperidin-4-yl)propyl]-3- oxo-1-[cis-3-hydroxycyclobutoxy]-2,3-dihydro-1H-isoindol-2-yl]methyl}benzonitrile

The title compound was prepared from (S)-5-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1-hydroxypropyl)-2-(4-chlorobenzoyl)-3-fluorobenzoic acid (Compound 60), 4-aminomethylbenzonitrile and cis-3-((tert-butyldimethylsilyl)oxy)cyclobutan-1-ol using procedures similar to those described in Example 87 (Steps 1-3). Purification by chiral SLC gave the title compound (slow moving isomer): ¹ H NMR (400 MHz, CDCl ₃ ) 7.62 (1H, d), 7.50 (2H, d), 7.34 (2H, d ), 7.30(1H, dd), 7.28-7.24(4H, m), 4.62(1H, d), 4.12(1H, d), 3.61-3.53( 1H, m), 3.08-3.00(1H, m), 2.91(1H, d), 2.80(1H, d), 2.22(3H, s), 1.94-7 .75 (9H, m), 1.73-1.66 (3H, m), 1.43-1.20 (3H, m), 0.67 (3H, dd). MS: [M+H] ⁺ =618.

Example 131: (3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-(4-fluoro-1-methylpiperidine-4- yl)-1-hydroxypropyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoic acid

(*single isomer separated and isolated)

Step 1 and 2: From (-)-5-(1-(1-(tert-butoxycarbonyl)-4-fluoropiperidin-4-yl)-1-hydroxypropyl)-2-(4-chlorobenzoyl)-3-fluorobenzoic acid (Substance 57), Steps 1 and 2 were carried out using methods similar to those described in Example 105. MS: [M+H] ⁺ =661.1.

Stage 3: ethyl-(3S)-3-(4-chlorophenyl)-3-(1-(4-chlorophenyl)-7-fluoro-5-(1-(4-fluoro-1-methylpiperidin-4-yl) -1-hydroxypropyl)-1-methoxy-3-oxoisoindolin-2-yl)propanoate

Step 3 was performed using procedures similar to those described for Example 81, Step 5. The desired diastereoisomer was isolated using chiral SLC as the fastest eluting isomer. MS: [M+H] ⁺ =675.1.

Step 4: (3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-(4-fluoro-1-methylpiperidine-4- yl)-1-hydroxypropyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoic acid

Step 4 was carried out using methods similar to those described for Substance 52, Step 3 to give the title compound which precipitated and was collected by filtration during extraction. ¹ H NMR (400 MHz, DMSO) 7.70 (1H, s), 7.42 (1H, d), 7.16 (2H, d), 7.09 (3H, d), 7.05 (1H , s), 6.98(2H, d), 5.53(1H, s), 4.63(1H, dd), 3.48(1H, dd), 3.18(1H, dd), 3 .08 (3H, s), 2.70-2.67 (1H, m), 2.13 (3H, s), 2.05-1.99 (1H, m), 1.95-1.80 (5H, m), 1.78-1.69 (1H, m), 1.11-1.05 (1H, m), 0.55 (3H, t), OH and COOH were not observed. MS: [M+H] ⁺ =647.3.

Example 132: tert-Butyl-2-{4-[(1S)-1-[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-7-fluoro-1-methoxy -3-oxo-2,3-dihydro-1H-isoindol-5-yl]-1-hydroxypropyl]piperidin-1-yl}acetate

Example 133: tert-Butyl-2-{4-[(1R)-1-[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-7-fluoro-1-methoxy -3-oxo-2,3-dihydro-1H-isoindol-5-yl]-1-hydroxypropyl]piperidin-1-yl}acetate

(*both isomers were separated and isolated)

Stages 1-2. From 5-(1-(tert-butoxycarbonyl)piperidine-4-carbonyl)-2-(4-chlorobenzoyl)-3-fluorobenzoic acid (Examples 80 and 81, step 2), steps 1-2 were performed using methods similar to with those described in Example 73, Steps 3 and 4, respectively, with the exception of using T ₃ P instead of HATU in Step 1 and MeOH instead of 1-(hydroxymethyl)cyclopropane-1-carboxamide in Step 2 to obtain 3-(4-chlorophenyl)-2 -[(4-chlorophenyl)methyl]-4-fluoro-3-methoxy-6-(piperidine-4-carbonyl)-2,3-dihydro-1H-isoindol-1-one. MS [M+H] ⁺ =527

Stage 3: tert-butyl-2-{4-[1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-7-fluoro-1-methoxy-3-oxo-2,3-dihydro- 1H-isoindole-5-carbonyl]piperidin-1-yl}acetate

To a reaction flask containing 3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-4-fluoro-3-methoxy-6-(piperidine-4-carbonyl)-2,3-dihydro-1H- isoindol-1-one (1.729 g, 3.28 mmol), K ₂ CO ₃ (1.80 g, 13.0 mmol) and DMF (30 ml), tert-butyl bromoacetate (0.53 ml, 3.57 mmol). The reaction mixture was stirred at room temperature for 90 minutes when analysis by LCMS showed complete absorption of the starting material. Then the solvent was removed and the residue was mixed with EtOAc (10 ml) and sat. _NaHC03 . The aqueous layer was further extracted with EtOAc (3×50 ml). The combined organics were dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to an oily residue. This material was then purified with SiO ₂ (petroleum ether: EtOAc) to give 1.505 g (72%) of the racemic product. The racemic material was then subjected to chiral preparative resolution to give the enantiomers as white solids.

Fast enantiomer: ¹ H NMR (400 MHz, CDCl ₃ ): 8.22 (1H, d), 7.75 (1H, dd), 7.28 (5H, d), 7.26-7.18 (4H , m), 4.66 (1H, d), 4.07 (1H, d), 3.31-3.20 (1H, m), 3.19 (2H, s), 3.04 (2H, d), 2.77(3H, s), 2.50-2.34(2H, m), 1.99-1.84(4H, m), 1.49(9H, s). MS [M+NH ₄ ] ⁺ =641.

Slow enantiomer: ¹ H NMR (400 MHz, CDCl ₃ ): 8.22 (1H, s), 7.75 (1H, d), 7.28 (5H, s), 7.26-7.17 (4H , m), 4.66 (1H, d), 4.07 (1H, d), 3.31-3.21 (1H, m), 3.19 (2H, s), 3.04 (2H, d), 2.77(3H, s), 2.50-2.34(2H, m), 2.00-1.84(4H, m), 1.50(9H, s). MS [M+NH ₄ ] ⁺ =641.

Step 4: Using the slow eluting isomer from Step 3, Step 4 was performed using a method similar to that described for Compound 52, Step 1. Purification by preparative chiral HPLC afforded the title compounds.

Example 132 - fast diastereomer: ¹ H NMR (400 MHz, CDCl ₃ ): 7.64 (1H, s), 7.32-7.15 (9H, m), 4.61 (1H, d), 4, 05 (1H, d), 3.05 (2H, s), 3.01 (1H, d), 2.89 (1H, d), 2.72 (3H, s), 2.16-1.96 (2H, m), 1.91 (2H, q), 1.82 (1H, d), 1.74 (1H, s), 1.71-1.54 (2H, m), 1.44 ( 10H, s), 1.41-1.31(1H, m), 0.68(3H, t). MS [M+H] ⁺ =671.

Example 133 - slow diastereomer: ¹ H NMR (400 MHz, CDCl ₃ ): 7.68 (1H, s), 7.33-7.17 (9H, m), 4.64 (1H, d), 4, 06 (1H, d), 3.07 (2H, s), 3.04 (1H, d), 2.90 (1H, d), 2.75 (3H, s), 2.19-2.02 (2H, m), 2.02-1.89 (2H, m), 1.89-1.77 (2H, m), 1.77-1.59 (2H, m), 1.59-1 .45 (9H, m), 1.45-1.36 (2H, m), 0.70 (3H, t). MS [M+H] ⁺ =671.

Example 134 2-{4-[(1S)-1-[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-7-fluoro-1-methoxy-3-oxo -2,3-dihydro-1H-isoindol-5-yl]-1-hydroxypropyl]piperidin-1-yl}acetic acid

Example 135 2-{4-[(1R)-1-[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-7-fluoro-1-methoxy-3-oxo -2,3-dihydro-1H-isoindol-5-yl]-1-hydroxypropyl]piperidin-1-yl}acetic acid (*obtained and isolated as single isomers)

Examples 134: and 135 were prepared from Examples 132 and 133, respectively, using procedures similar to those described for Example 121, Step 2.

Example 134: ¹ H NMR (400 MHz, DMSO-d ₆ ): 7.68 (1H, s), 7.43-7.32 (3H, m), 7.32-7.21 (4H, m) , 7.17(2H, d), 4.93(1H, s), 4.45(1H, d), 4.14(1H, d), 3.12(1H, d), 3.00( 1H, d), 2.92(2H, S), 2.73(3H, s), 2.33-2.14(3H, m), 1.86(2H, q), 1.82-1 .67 (2H, m), 1.42-1.23 (2H, m), 1.16 (1H, d), 0.58 (3H, t). MS [M+H] ⁺ =615.

Example 135 1H NMR (400 MHz, DMSO-d6): 7.69 (1H, s), 7.39 (1H, d), 7.34 (2H, d), 7.31-7.21 (4H, m), 7.18(2H, d), 5.15-4.87(1H, m), 4.46(1H, d), 4.13(1H, d), 3.19(1H, d ), 3.03(3H, s), 2.73(3H, s), 2.45-2.26(3H, m), 1.95-1.69(4H, m), 1.47- 1.31 (2H, m), 1.16 (1H, d), 0.59 (3H, t). MS [M-H ⁺ ] ^- =613.

Example 136: Methyl-3-{4-[(1S)-1-[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-7-fluoro-1-methoxy-3 -oxo-2,3-dihydro-1H-isoindol-5-yl]-1-hydroxypropyl]piperidin-1-yl}propanoate

The title compound was prepared from (S)-5-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1-hydroxypropyl)-2-(4-chlorobenzoyl)-3-fluorobenzoic acid (Compound 60) and 4-chlorobenzylamine using methods similar to those described for Example 87 (Steps 1-3) except using methyl methacrylate/DBU instead of NaBH ₃ CN in Step 3. ¹ H NMR (400 MHz, CDCl ₃ ): 7.63 (1H , d), 7.31-7.15(9H, m), 4.61(1H, d), 4.05(1H, d), 3.66(3H, s), 2.96(1H, d), 2.84(1H, d), 2.72(3H, s), 2.69-2.56(2H, m), 2.47(2H, t), 2.07-1.79 (5H, m), 1.79-1.55 (3H, m), 1.40-1.28 (2H, m), 0.67 (3H, t). MS [M+H] ⁺ =643.

Example 137 3-{4-[(1S)-1-[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-7-fluoro-1-methoxy-3-oxo -2,3-dihydro-1H-isoindol-5-yl]-1-hydroxypropyl]piperidin-1-yl}propanoic acid

The title compound was prepared from Example 136 using a procedure similar to that described for Compound 52 (Step 3). ¹ H NMR (400 MHz, DMSO): 7.69 (1H, s), 7.40 (1H, d), 7.35 (2H, d), 7.31-7.21 (3H, m), 7.18(2H, d), 4.89(1H, s), 4.46(1H, d), 4.13(1H, d), 3.01(1H, d), 2.87(1H , d), 2.74 (3H, s), 2.58-2.52 (3H, m), 2.36-2.25 (2H, m), 2.06-1.73 (5H, m ), 1.71 (1H, d), 1.35-1.18 (2H, m), 1.09 (1H, d), 0.57 (3H, t). MS [M-H] ^- = 627.

BIOLOGICAL ANALYSIS

MDM2-p53 interaction using 96-well binding assay (ELISA)

An ELISA assay was performed on streptavidin-coated plates that had been pre-incubated with 200 μl per well of 1 μg ml ^-1 biotinylated IP3 protein. The plates were ready for use for MDM2 binding after washing the plates with PBS.

Compounds and controls in DMSO, aliquoted into 96-well plates, were pre-incubated in a final DMSO concentration of 2.5-5% (v/v) at room temperature (eg, 20° C.) for 20 minutes. with 190 µl aliquots of optimized concentrations of in vitro translated MDM2 before transferring the MDM2-compound mixture to streptavidin-coated b-IP3 plates and incubating at 4°C for 90 min. After washing three times with PBS to remove unbound MDM2, each well was incubated at 20°C for 1 hour with TBS-Tween (50 mM Tris pH 7.5; 150 mM NaCl; 0.05% non-ionic detergent Tween 20)-buffered primary monoclonal antibody anti-MDM2 mice (Ab-5, Calbiochem, used at 1/10,000 or 1/200 dilution depending on antibody stock used), then washed three times with TBS-Tween before incubation for 45 min. at 20°C with TBS-Tween-buffered solution of secondary goat antibodies against mouse antigens conjugated with horseradish peroxidase (HRP) (used in a dilution of 1/20000 or 1/2000 depending on the stock solution of the antibody used). Unbound secondary antibody was removed by washing three times with TBS-Tween. Bound HRP activity was measured by enhanced chemiluminescence (ECL™, Amersham Biosciences) using oxidation of the diacylhydrazide substrate, luminol, to generate a measurable light signal. The percentage inhibition of MDM2 at a particular concentration is calculated as [1 - (RLU (Luminescence Signal Intensity) set in compound treated sample - RLU-negative DMSO control) ÷ (RLU of DMSO-positive and negative controls)] × 100 or as (RLU found in compound-treated sample - RLU of DMSO-control samples) x 100. IC ₅₀ was measured using a % MDM2 inhibition versus concentration curve and is the average of two to three independent experiments.

Western blotting

SJSA cells were exposed to 5, 10 and 20 μm compounds in 0.5% DMSO for 6 hours. Cells, along with controls containing only 0.5% DMSO, were washed with ice-cold phosphate-buffered saline (PBS) and protein extracts were prepared by lysing the cells in SDS buffer (62.5 mM Tris pH 6.8; 2% sodium dodecyl sulfate ( SDS); 10% glycerol) with sonication for 2×5 seconds (Soniprep 150 IU) to destroy high molecular weight DNA and reduce sample viscosity. Protein concentration in the samples was assessed using a Pierce BCA analytical system (Pierce, Rockford, IL) and 50 μg aliquots of protein were analyzed using standard denaturing polyacrylamide gel electrophoresis (SDS-PAGE) and Western blot methods. Added β-mercaptoethanol (5%) and bromophenol blue (0.05%) to the samples, which were then boiled for 5 minutes, after which they were subjected to a short centrifugation, before being loaded into the prepared SDS-polyacrylamide gel (Invitrogen), buffered Tris-glycine with a gradient of 4-20%. Molecular weight standards (SeeBlue™, Invitrogen) were included in each gel and electrophoresis was performed in a Novex XL reservoir (Invitrogen) at 180 volts for 90 minutes. Separated proteins were transferred by overnight gel electrophoresis to a Hybond C nitrocellulose membrane (Amersham) using a BioRad electrophoresis reservoir and transfer buffer of 25 mM Tris, 190 mM glycine, and 20% methanol at 30 volts or for two hours at 70 volts. . The primary antibodies used for the enzyme immunoassay of the transferred proteins were: mouse monoclonal antibody NCL-p53DO-7 (Novocastra) at 1:1000; MDM2 (Ab-1, clone IF2) (Oncogene) at 1:500; WAF1 (Ab-1, clone 4D10) (Oncogene) at 1:100; Actin (AC40) (Sigma) at 1:1000. The secondary antibody used was affinity purified goat anti-mouse conjugated to peroxidase (Dako) at 1:1000. Detection and visualization of proteins was performed by enhanced chemiluminescence (ECL™, Amersham) with light detection using blue light sensitive autoradiography film (Super RX, Fuji).

Protocol A: SJSA-1 and SN40R2 Assays

The MDM2-amplified cell lines tested were an isogenic matched pair of wild-type p53 and mutated osteosarcoma (SJSA-1 and SN40R2, respectively). All cell cultures were grown in RPMI 1640 medium (Gibco, Paisley, UK) supplemented with 10% fetal bovine serum and routinely tested for and confirmed free of mycoplasmal infection. Cell growth and its inhibition was measured using the method using sulforodamine B (SRB), indicated earlier. 100 μl of 3×10 ⁴ /ml and 2×10 ⁴ /ml SJSA-1 and SN40R2 cells, respectively, were plated on 96-well culture plates and incubated at 37°C in a humid chamber with 5% CO ₂ for 24 hours, after which the medium was replaced with 100 µl of test medium containing a range of concentrations of the MDM2-p53 antagonist and incubated for another 72 hours to allow cells to grow, before adding 25 µl of 50% trichloroacetic acid (TCA) to fix the cells for 1 hour at 4°C. TCA was washed off with distilled water and 100 μl of SRB dye (0.4% w/v in 1% acetic acid) (Sigma-Aldrich, Poole, Dorset) was added to each well of the plate. After incubation with SRB dye at room temperature for 30 minutes, the plates were washed with 1% acetic acid and left to dry. The SRB-stained protein, which is a measure of the number of cells per well, was then resuspended in 100 μl of 10 mM Tris-HCl (pH 10.5), and the absorbance in each well was measured at λ=570 nm using a FluoStar Omega plate reader. The GI ₅₀ value was calculated by non-linear regression analysis of the data using Prism v4.0 statistical software.

Protocol B: SJSA-1 and SN40R2 assays

The CellTiter-Glo® Luminescent Cell Viability Assay is a homogeneous method for determining the number of viable cells in a culture based on the quantification of ATP present, which signals the presence of metabolically active cells. SJSA-1 and SN40R2 were grown in RPMI 1640 medium (Life Technologies #61870) supplemented with 10% PBS (PAA #A15-204) and 10 U/ml penicillin/streptomycin. 2000 cells in 75 μl were seeded in each well of a 96-well plate and left at 37°C in a humid chamber with 5% CO ₂ for 24 hours. After that, a range of concentrations of the MDM2-p53 antagonist in DMSO was added to the cells at a final concentration of DMSO 0 .3% and incubated for an additional 72 hours to allow the cells to grow. 100 µl of CTG reagent (Promega #G7573) was added to all wells and luminescence was measured in multivariate terms. EC ₅₀ values were determined by 4-parameter sigmoidal curve fitting using XLfit in conjunction with Activity Base (IDBS; Guildford, Surrey, UK).

Antiproliferative activity

Cell growth inhibition is measured using the alamar blue assay (Nociari, MM, Shalev, A., Benias, P., Russo, C. Journal of Immunological Methods 1998, 213, 157-167). The method is based on the ability of viable cells to reduce resazurin to its fluorescent product, resorufin. For each proliferation assay, cells are placed in 96-well plates and left to recover for 16 hours, after which inhibitory compounds (in 0.1% DMSO v/v) are added for an additional 72 hours. At the end of the incubation period, 10% (v/v) alamar blue is added and incubated for an additional 6 hours until the fluorescent product is detected at 535 nM ex/590 nM em. The antiproliferative activity of the compounds of the present invention can be determined by evaluating the ability of the compounds to inhibit growth in cancer cell lines, such as those available from DSMZ, ECACC or ATCC.

results

For cases where more than one data point was acquired, the table above shows the mean (i.e. geometric or arithmetic mean) of those data points.

Of course, it should be understood that the present invention is not intended to be limited to the details of the above embodiments, which are described by way of example only.

Combined protocol for cell proliferation

The effect of a compound of formula (I) (Compound 1) in combination with an anticancer agent (Compound II) can be measured by the following method. Cells from human cell lines (eg, SJSA-1) were seeded in 96-well culture plates at a concentration of 2.5×10 ³ , 6.0×10 ³ , or 4.0×10 ³ cells/well, respectively. Cells were allowed to recover for 24-48 hours before addition of compound(s) or vehicle control (0.35-0.5% DMSO) as described below:

Compounds were added in parallel over 72-96 hours. After complete compound incubation for 72-96 hours, cells were fixed with ice-cold 10% (w/v) trichloroacetic acid for 1 hour on ice and then washed four times with dH ₂ 0 using a plate washer (Labsystems Wellwash Ascent) and dried in air. Cells were then stained with 0.4% (w/v) sulforodamine-B (Sigma) in 1% acetic acid for 20 minutes. at room temperature and then washed four times with 1% (v/v) acetic acid and air dried before adding 10 mM Tris buffer to solubilize the dye. The colorimetric product was counted by reading at Abs490 nm or Abs570 nm on a Wallac Victor ² plate reader (1420 multi-channel reader, Perkin Elmer Life Sciences). IC ₅₀ was determined for Compound II in the presence of varying doses of Compound I. Synergy was determined when the IC ₅₀ value decreased in the presence of sub-effective doses of Compound I. Additivity was determined when the response to Compound II and Compound I together resulted in an effect equivalent to the sum of the two compounds separately . Antagonistic effects were defined as effects causing an upward shift in the IC ₅₀ ie. those in which the response to the two compounds was less than the sum of the effect of the two compounds taken separately.

EXAMPLES OF PHARMACEUTICAL COMPOSITIONS

(i) Composition in the form of tablets

A tablet composition containing a compound of formula (I) is prepared by mixing a suitable amount of the compound (eg 50-250 mg) with a suitable diluent, disintegrant, compressive agent and/or glidant. One possible tablet contains 50 mg of the compound and 197 mg of lactose (BP) as a diluent and 3 mg of magnesium stearate as a lubricant, compressed to form a tablet in a known manner. The compressed tablet may optionally be film-coated.

(ii) Formulation in the form of capsules

A capsule formulation is prepared by mixing 100-250 mg of a compound of formula (I) with an equivalent amount of lactose and filling the resulting mixture into standard hard gelatin capsules. If necessary, a suitable disintegrant and/or glidant may be included in suitable amounts.

(iii) Formulation I for injection

A parenteral composition for administration by injection can be obtained by dissolving a compound of formula (I) (eg in the form of a salt) in water containing 10% propylene glycol to provide an active compound concentration of 1.5% by weight. The solution is then made isotonic, sterilized by filtration or terminal sterilization, filled into an ampoule or vial or pre-filled syringe and sealed.

(iv) Formulation II for injection

A parenteral composition for administration by injection is prepared by dissolving a compound of formula (I) (eg, in the form of a salt) (2 mg/ml) and mannitol (50 mg/ml) in water, sterile filtration of the solution or final sterilization, and filling it into resealable vials. or ampoules or pre-filled syringes with a capacity of 1 ml.

(v) Composition III for injection

A formulation for intravenous delivery by injection or infusion can be prepared by dissolving a compound of formula (I) (eg in salt form) in water at 20 mg/mL and then adjusting for isotonicity. The vial is then sealed and sterilized by autoclaving or the formulation is filled into an ampoule or vial or pre-filled syringe, sterilized by filtration and sealed.

(vi) Formulation IV for injection

A formulation for intravenous delivery by injection or infusion can be prepared by dissolving a compound of formula (I) (eg in the form of a salt) in water containing a buffer (eg 0.2 M acetate pH 4.6) at 20 mg/ml. The vial, ampoule or pre-filled syringe is then sealed and sterilized by autoclaving or sterilized by filtration and sealed.

(vii) Composition for subcutaneous or intramuscular injection

The composition for subcutaneous or intramuscular administration is prepared by mixing the compound of formula (I) with pharmaceutical grade corn oil to provide a concentration of 5-50 mg/ml. The composition is sterilized and placed in a suitable container.

(viii) Lyophilized Formulation I

Aliquots of the formulated compound of formula (I) are placed in 50 ml vials and lyophilized. During lyophilization, the compositions are frozen using a one-step freezing protocol at (-45°C). The temperature is raised to -10°C for annealing, then lowered to freeze at -45°C followed by primary drying at +25°C for about 3400 minutes and then secondary drying with increasing temperature steps up to 50°C. The pressure during primary and secondary drying is set at 80 millitors.

(ix) Lyophilized Formulation II

Aliquots of the formulated compound of formula (I) or a salt thereof are placed in 50 ml vials and lyophilized. During lyophilization, the compositions are frozen using a one-step freezing protocol at (-45°C). The temperature is raised to -10°C for annealing, then lowered to freeze at -45°C followed by primary drying at +25°C for about 3400 minutes and then secondary drying with increasing temperature steps up to 50°C. The pressure during primary and secondary drying is set at 80 millitors.

(x) Lyophilized formulation III for intravenous use

An aqueous buffered solution is prepared by dissolving a compound of formula I in a buffer. The buffered solution is placed, filtered to remove particulate matter, into a container (such as a type 1 glass vial) which is then partially sealed (eg with a Fluorotec stopper). If the compound and formulation are sufficiently stable, the formulation is sterilized by autoclaving at 121° C. for the desired period of time. If the composition is not stable for autoclaving, it can be sterilized using a suitable filter and placed in sterile vials under sterile conditions. The solution is freeze-dried using a suitable cycle. After the freeze-drying cycle is complete, the vials are refilled with nitrogen to atmospheric pressure, sealed and secured (eg with an aluminum cap). For intravenous administration, the freeze-dried solid may be diluted with a pharmaceutically acceptable diluent such as 0.9% saline or 5% dextrose. The solution may be administered as is or may be further diluted in an infusion bag (containing a pharmaceutically acceptable diluent such as 0.9% saline or 5% dextrose) prior to administration.

(xii) Powder in a bottle

A composition for oral administration is prepared by filling a bottle or vial with a compound of formula (I). The composition is then diluted with a suitable diluent, for example water, fruit juice or a commercially available carrier such as OraSweet or Syrspend. The diluted solution may be dispensed into measuring cups or oral syringes for administration.

Claims (217)

1. Compound of formula (I):

or a tautomer or pharmaceutically acceptable salt thereof, wherein: R ¹ is independently selected from halogen, nitrile, C _1-4 alkyl, hydroxyC _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkynyl, -O _0.1 -(CR ^x R ^y ) _v -CO ₂ H , -S(O) _d -C _1-6 alkyl and -S(O) _d -heterocyclic group containing 6 ring members containing two heteroatoms selected from N and O; R ² is selected from hydrogen, C _1-4 alkyl, hydroxyC _1-4 alkyl, and -(CR ^x R ^y ) _u -CO ₂ H; s is chosen from 0 and 1; R ³ is hydrogen or -(A) _t -(CR ^x R ^y ) _q -X; t is selected from 0 and 1; q is selected from 0, 1 and 2; where when R ³ is -(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 equal to 1 and q is not equal to 0; A represents a C _3-6 cycloalkyl group or a heterocyclic group containing 4-5 ring members, wherein said heterocyclic group contains one or two heteroatoms selected from N and O; X is selected from hydrogen, halogen, -CN, -OR ⁹ , -(CH ₂ ) _v -CO ₂ H, -NHSO ₂ R ^x , and -C(=O)NR ^x R ^y ; R ⁴ and R ⁵ are halogen; R ⁶ and R ⁷ are independently selected from hydrogen, C _1-6 alkyl, hydroxyC _1-6 alkyl, -(CH ₂ ) _j -O-C _1-6 alkyl, -C _1-6 alkyl-NR ^x R ^y , - (CR ^x R ^y ) _p -CONR ^x R ^y , a heterocyclic group containing 5 or 6 ring members containing one or two heteroatoms selected from O and N, -CH ₂ -heterocyclic group containing 6 ring members containing two heteroatoms , which are N, and C _3-8 cycloalkyl, where said cycloalkyl or heterocyclic groups may be optionally substituted with one or more R ^z groups; R ⁹ is selected from hydrogen and C- _1-6 alkyl; R ^x and R ^y are independently selected from hydrogen, halogen, C _1-6 alkyl, and hydroxyC _1-6 alkyl; or groups R ^x and R ^y together with the nitrogen atom to which they are attached, can combine to form a saturated heterocyclyl group containing 5 ring members; R ^z is independently selected from halogen, C _1-6 alkyl, hydroxy, -(CH ₂ ) _r -CO ₂ C _1-6 alkyl, and -(CH ₂ ) _r -CO ₂ H; a, j, d, n, r and p are independently selected from 0, 1 and 2; m is independently selected from 1 and 2; u is selected from 0, 1, 2 and 3; And v is chosen from 0 and 1. 2. A compound according to claim 1 wherein R ¹ is halogen, nitrile, C _1-4 alkyl, C _2-4 alkynyl, or C _1-4 alkoxy. 3. A compound according to claim 1 or 2, wherein n is 1 and R ¹ is chlorine or nitrile. 4. A compound according to claim 3, wherein n is 1 and R ¹ is chlorine. 5. Connection according to any one of paragraphs. 1-3, in which n is 2 and R ¹ substituents are in the ortho and para positions of the phenyl ring. 6. The compound of claim 1 wherein R ¹ is independently selected from halogen, nitrile, C _1-4 alkyl, hydroxyC _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkynyl, -(CH ₂ ) _v - CO ₂ H, -S(O) _d -C _1-6 alkyl, and -S(O) _d -heterocyclic group containing 6 ring members, where the heterocyclic group contains two heteroatoms selected from N and O. 7. Connection according to any one of paragraphs. 1-6, in which R ² is selected from hydrogen, C _1-4 alkyl, and hydroxyC _1-4 alkyl. 8. Connection according to any one of paragraphs. 1-7, in which R ² is hydrogen or -(CR ^x R _y ) _u -CO ₂ H. 9. The compound of claim 8 wherein R ² is -COOH, -CH ₂ COOH, -CH ₂ CH ₂ -CO ₂ H, -(CH(CH ₃ ))-CO ₂ H, or -(C(CH ₃ ) ₂ )-CO ₂ H. 10. Connection according to any one of paragraphs. 1-9, in which R ³ is -(A) _t -(CR ^x R ^y ) _q -X, and A is a C _3-6 cycloalkyl group. 11. A compound according to claim 10, wherein A is a cyclopropyl group. 12. Connection according to any one of paragraphs. 1-9, in which R ³ represents -(A) _t -(CR ^x R ^y ) _q -X, and A represents a heterocyclic group containing 4-5 ring members. 13. A compound according to claim 12, wherein A is a heterocyclic group containing 5 ring members. 14. Connection according to any one of paragraphs. 1-13 where s is 0. 15. Connection according to any one of paragraphs. 1-13, where s is 1. 16. Connection according to any one of paragraphs. 1-15, in which X represents hydrogen, halogen, -CN, -OR ⁹ or -C(=O)NR ^x R ^y . 17. Connection according to any one of paragraphs. 1-11, in which the compound of formula (I) is a compound of formula

or a tautomer or pharmaceutically acceptable salt thereof. 18. Connection according to any one of paragraphs. 1-17, where a is 1. 19. Connection according to paragraphs. 1-18, in which the compound of formula (I) is a compound of formula (Ir):

or a tautomer or pharmaceutically acceptable salt thereof. 20. A compound according to claim 19, wherein the compound is a compound of formula (Is):

or a tautomer or pharmaceutically acceptable salt thereof. 21. Connection according to any one of paragraphs. 1-20, in which m is 1 and the substituent R ⁵ is in the para position of the phenyl group. 22. Connection according to any one of paragraphs. 1-21, in which R ⁵ represents chlorine. 23. Connection according to any one of paragraphs. 1-22, in which R ⁷ is selected from a heterocyclic group containing 5 or 6 ring members containing one or two heteroatoms selected from O and N, and -CH ₂ -heterocyclic group containing 6 ring members containing two heteroatoms, which are N, where said heterocyclic groups may be optionally substituted with one or more R ^z groups. 24. The compound of claim 23, wherein R ⁷ is selected from oxanyl, piperidinyl, pyrazolyl, or imidazolyl, optionally substituted with one or more R ^z , where R ^z is selected from halogen or C _1-4 alkyl. 25. A compound according to claim 24 wherein R ^z is selected from fluorine and methyl. 26. Connection according to any one of paragraphs. 1-25, in which R ⁶ represents methyl or ethyl. 27. Compound of formula (VIIf):

or a tautomer or pharmaceutically acceptable salt thereof, wherein: n is 1 and R ¹ is chlorine; R ² represents -CH ₂ COOH, -CH ₂ CH ₂ -CO ₂ H or -(CH(CH ₃ ))-CO ₂ H; R ⁴ and R ⁵ are halogen; R ⁶ is methyl or ethyl; And R ⁷ is oxanyl, piperidinyl or pyrazolyl, optionally substituted with one or more R ^z , where R ^z is halogen or C _1-4 alkyl. 28. Compound of formula (Iw):

or a tautomer or pharmaceutically acceptable salt thereof, wherein: n is 1 and R ¹ is chlorine; R ² represents -CH ₂ COOH, -CH ₂ CH ₂ -CO ₂ H or -(CH(CH ₃ ))-CO ₂ H; s is 1 and R ³ is hydrogen; R ⁴ is halogen; m is 1 and R ⁵ is halogen; And R ^z is hydrogen or fluorine. 29. A compound of formula (Iw) according to claim 28, wherein R ⁴ is fluorine. 30. Compound of formula (I):

or a tautomer or pharmaceutically acceptable salt thereof, wherein: n is 1 or 2 and R1 is halogen, or -O _0.1 (CR ^x R ^y ) _v COOH where v is 0 or 1; R ² is selected from hydrogen and -(CR ^x R ^y ) _u -CO ₂ H, where u is 0, 1 or 2; R ^x and R ^y are hydrogen or methyl; R ³ is hydrogen and s is 1; a is 1 and R ⁴ is halogen; m is 1 and R ⁵ is halogen; R ⁶ is C _1-6 alkyl; R ⁷ is a heterocyclic group containing 6 ring members containing one heteroatom selected from N, O, a heteroaryl group containing 5-6 ring members containing one or two heteroatoms selected from N, where the specified heterocyclic and heteroaryl group may be optionally substituted with one R ^z group selected from C _1-4 alkyl. 31. The compound or its tautomer or pharmaceutically acceptable salt, where the specified compound is selected from the following compounds: (3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-6-(2-hydroxypropan-2-yl)-2 ,3-dihydro-1H-isoindol-1-one; (3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-4-fluoro-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-6-(2-hydroxypropan-2- yl)-2,3-dihydro-1H-isoindol-1-one; (3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-3-(2-hydroxyethoxy)-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1Н -isoindol-1-one; (3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-3-{[3-(hydroxymethyl)oxetan-3-yl]methoxy}-6-(2-hydroxypropan-2- yl)-2,3-dihydro-1H-isoindol-1-one; 1-({[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-5-(2-hydroxypropan-2-yl)-3-oxo-2,3-dihydro- 1H-isoindol-1-yl]oxy}methyl)cyclopropane-1-carboxylic acid; (3R)-3-(4-chlorophenyl)-2-[(1S)-1-(4-chlorophenyl)ethyl]-3-(2,3-dihydroxy-2-methylpropoxy)-6-(2-hydroxypropane- 2-yl)-2,3-dihydro-1H-isoindol-1-one; (3R)-3-(4-chlorophenyl)-2-[(1S)-1-(4-chlorophenyl)ethyl]-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-6-(2-hydroxypropane- 2-yl)-2,3-dihydro-1H-isoindol-1-one; (3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-6-(1,2-dihydroxypropan-2-yl)-3-{[1-(hydroxymethyl)cyclopropyl]methoxy} -2,3-dihydro-1H-isoindol-1-one; (3R)-3-(4-chlorophenyl)-2-[(1S)-1-(4-chlorophenyl)ethyl]-6-(2-hydroxy-1-methoxypropan-2-yl)-3-{[1 -(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one; (3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-6-[1-(dimethylamino)-2-hydroxypropan-2-yl]-3-{[1-(hydroxymethyl) cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one; (3R)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-1-{[1-(hydroxymethyl)cyclopropyl]methoxy}-5-(2-hydroxypropan-2- yl)-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoic acid; (3R)-3-(4-chlorophenyl)-2-[(1S)-1-(4-chlorophenyl)ethyl]-6-(1,2-dihydroxypropan-2-yl)-3-{[1-( hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one; (3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-3-(3-hydroxy-3-methylbutoxy)-6-(2-hydroxypropan-2-yl)-2,3 -dihydro-1H-isoindol-1-one; (3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-6-(2-hydroxypropan-2-yl)-3-[(1H-pyrazol-4-yl)methoxy]- 2,3-dihydro-1H-isoindol-1-one; 1-({[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-5-(2-hydroxypropan-2-yl)-3-oxo-2,3-dihydro- 1H-isoindol-1-yl]oxy}methyl)cyclopropan-1-carbonitrile; N-{[1-({[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-5-(2-hydroxypropan-2-yl)-3-oxo-2, 3-dihydro-1H-isoindol-1-yl]oxy}methyl)cyclopropyl]methyl}methanesulfonamide; (3R)-3-(4-chlorophenyl)-2-[(4-ethynylphenyl)methyl]-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-6-(2-hydroxypropan-2-yl)-2 ,3-dihydro-1H-isoindol-1-one; (3R)-3-(4-chlorophenyl)-2-[(4-ethynylphenyl)methyl]-4-fluoro-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-6-(2-hydroxypropan-2- yl)-2,3-dihydro-1H-isoindol-1-one; (3R)-3-(4-chlorophenyl)-6-(1,2-dihydroxypropan-2-yl)-2-[(4-ethynylphenyl)methyl]-4-fluoro-3-{[1-(hydroxymethyl) cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one; 4-{[(1R)-1-(4-chlorophenyl)-7-fluoro-1-({1-[hydroxy(2H2)methyl]cyclopropyl}( ² H ₂ )methoxy)-5-(2-hydroxypropane- 2-yl)-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzonitrile; 4-{[(1R)-1-(4-chlorophenyl)-1-{[1-(hydroxymethyl)cyclopropyl]methoxy}-5-(2-hydroxypropan-2-yl)-3-oxo-2,3- dihydro-1H-isoindol-2-yl]methyl}benzonitrile; (3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-6-(2-hydroxypropan-2-yl)-3-[(3-methyloxetan-3-yl)methoxy]- 2,3-dihydro-1H-isoindol-1-one; 4-{[(1R)-1-(4-chlorophenyl)-5-(1,2-dihydroxypropan-2-yl)-1-{[1-(hydroxymethyl)cyclopropyl]methoxy}-3-oxo-2, 3-dihydro-1H-isoindol-2-yl]methyl}benzonitrile; (3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-3-[(1-hydroxycyclopropyl)methoxy]-6-(2-hydroxypropan-2-yl)-2,3- dihydro-1H-isoindol-1-one; 2-{[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-5-(2-hydroxypropan-2-yl)-3-oxo-2,3-dihydro-1H -isoindol-1-yl]oxy}-N,N-dimethylacetamide; (3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-6-(2-hydroxypropan-2-yl)-3-{[1-(methoxymethyl)cyclopropyl]methoxy}-2 ,3-dihydro-1H-isoindol-1-one; (3R)-3-(4-Chlorophenyl)-2-[(4-chlorophenyl)methyl]-3-{[1-(hydroxymethyl)cyclobutyl]methoxy}-6-(2-hydroxypropan-2-yl)-2 ,3-dihydro-1H-isoindol-1-one; 5-chloro-2-{[(1R)-1-(4-chlorophenyl)-1-{[1-(hydroxymethyl)cyclopropyl]methoxy}-5-(2-hydroxypropan-2-yl)-3-oxo- 2,3-dihydro-1H-isoindol-2-yl]methyl}benzoic acid; (3R)-2-{[4-chloro-2-(morpholine-4-sulfonyl)phenyl]methyl}-3-(4-chlorophenyl)-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-6- (2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one; 1-({[(1R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-1-(4-chlorophenyl)-7-fluoro-5-(2-hydroxypropan-2-yl)-3- oxo-2,3-dihydro-1H-isoindol-1-yl]oxy}methyl)cyclopropane-1-carboxamide; ( _3R )-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-3-({1-[hydroxy(2H2)methyl]cyclopropyl}( ^2H2 )methoxy)- 6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one; (3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-6-(2-hydroxypropan-2-yl)-3-(oxolan-3-yloxy)-2,3-dihydro -1H-isoindol-1-one; (3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-6-(2-hydroxypropan-2-yl)-3-[(oxolan-3-yl)methoxy]-2, 3-dihydro-1H-isoindol-1-one; (3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[1-hydroxy-1-(oxan-4-yl)ethyl]- 3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one; (3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[2-hydroxy-1-(piperazin-1-yl)propan-2 -yl]-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one; (3R)-3-(4-chlorophenyl)-2-[(1S)-1-(4-chlorophenyl)ethyl]-3-{[(3R,4Р)-4-hydroxyoxolan-3-yl]oxy}- 6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one; (3R)-3-(4-chlorophenyl)-2-[(1S)-1-(4-chlorophenyl)ethyl]-3-{[(3R,45)-4-hydroxyoxolan-3-yl]oxy}- 6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one; (3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-6-(2-hydroxypropan-2-yl)-3-methoxy-2,3-dihydro-1H-isoindole-1 -He; (3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-3-({1-[hydroxy( ² H ₂ )methyl] cyclopropyl}( ² H ₂ )methoxy)-6- (2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one; (3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-6-(2-hydroxypropan-2-yl)-3-(3-hydroxypropoxy)-2,3-dihydro-1H -isoindol-1-one; (3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-6-(2- hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one; (3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-3-(2,2-difluoro-3-hydroxypropoxy)-6-(2-hydroxypropan-2-yl)-2 ,3-dihydro-1H-isoindol-1-one; (3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-3-{[2-(hydroxymethyl)cyclobutyl]methoxy}-6-(2-hydroxypropan-2-yl)-2 ,3-dihydro-1H-isoindol-1-one; (3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-6-[2-hydroxy-1-oxo-1-(pyrrolidin-1-yl)propan-2-yl]- 3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one; 2-[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-1-{[1-(hydroxymethyl)cyclopropyl]methoxy}-3-oxo-2,3-dihydro- 1H-isoindol-5-yl]-2-hydroxy-N,N-dimethylpropanamide; 2-[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-1-{[1-(hydroxymethyl)cyclopropyl]methoxy}-3-oxo-2,3-dihydro- 1H-isoindol-5-yl]-2-hydroxy-N-methylpropanamide; (3R)-2-{[4-Chloro-2-(methylsulfanyl)phenyl]methyl}-3-(4-chlorophenyl)-4-fluoro-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-6- (2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one; (3R)-2-[(4-chloro-2-methanesulfinylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-6-(2- hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one; (3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-(2-hydroxy-1-methoxypropan-2-yl)-3-{ [1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one; (3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-6-(1,2-dihydroxypropan-2-yl)-4-fluoro-3-{[1 -(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one; (3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[2-hydroxy-1-(4-methylpiperazin-1-yl)propane -2-yl]-3-[(3R)-oxolan-3-yloxy]-2,3-dihydro-1H-isoindol-1-one; (3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[2-hydroxy-1-(4-methylpiperazin-1-yl)propane -2-yl]-3-[(3S)-oxolan-3-yloxy]-2,3-dihydro-1H-isoindol-1-one; (3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-(2-hydroxypropan-2-yl)-3-oxo-1-[ (3S)-oxolan-3-yloxy]-2,3-dihydro-1H-isoindol-2-yl]propanoic acid; 1-({[(1R)-2-{[4-chloro-2-(hydroxymethyl)phenyl]methyl}-1-(4-chlorophenyl)-7-fluoro-5-(2-hydroxypropan-2-yl) -3-oxo-2,3-dihydro-1H-isoindol-1-yl]oxy}methyl)cyclopropane-1-carbonitrile; 1-({[(1R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(1-methyl- 1H-pyrazol-4-yl)ethyl]-3-oxo-2,3-dihydro-1H-isoindol-1-yl]oxy}methyl)cyclopropan-1-carboxamide; (3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[1-hydroxy-1-(1-methyl-1H-pyrazole-4 -yl)ethyl]-3-[(1-hydroxycyclopropyl)methoxy]-2,3-dihydro-1H-isoindol-1-one; (3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[2-hydroxy-1-(4-methylpiperazin-1-yl)propane -2-yl]-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one; 5-chloro-2-{[(1R)-1-(4-chlorophenyl)-1-[(1-cyanocyclopropyl)methoxy]-7-fluoro-5-(2-hydroxypropan-2-yl)-3-oxo -2,3-dihydro-1H-isoindol-2-yl]methyl}benzoic acid; (3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[1-hydroxy-1-(1-methylpiperidin-4-yl)ethyl ]-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one; (3R)-2-{[4-Chloro-2-(dimethylphosphoryl)phenyl]methyl}-3-(4-chlorophenyl)-4-fluoro-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-6- (2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one; (3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[hydroxy(oxan-4-yl)methyl]-3-{[1 -(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one; 1-({[(1R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(oxan-4- yl)ethyl]-3-oxo-2,3-dihydro-1H-isoindol-1-yl]oxy}methyl)cyclopropan-1-carboxamide; 5-chloro-2-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(1-methylpiperidin-4-yl)ethyl]-1-methoxy-3 -oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzoic acid; (3R)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(oxan-4-yl)ethyl]- 1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoic acid; 4-[(1R)-1-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(1-methyl-1H-imidazol-4-yl)propyl] -3-oxo-1-[(3S)-oxolan-3-yloxy]-2,3-dihydro-1H-isoindol-2-yl]-2-hydroxyethyl]benzonitrile; 4-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(1-methyl-1H-imidazol-4-yl)propyl]-3-oxo-1 -[(3R)-oxolan-3-yloxy]-2,3-dihydro-1H-isoindol-2-yl]methyl}-3-(hydroxymethyl)benzonitrile; 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; 4-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(1-methyl-1H-imidazol-4-yl)propyl]-3-oxo-1 -[(3S)-oxolan-3-yloxy]-2,3-dihydro-1H-isoindol-2-yl]methyl}benzonitrile; (3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-(4-fluoroxan-4-yl)-1-hydroxyethyl] -1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoic acid; (4S)-4-(4-chlorophenyl)-4-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(1-methyl-1H-pyrazole-3 -yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]butanoic acid; (3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-(4-fluoroxan-4-yl)-1-hydroxypropyl] -1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoic acid; (3R)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-5-(1-cyclobutyl-1-hydroxyethyl)-7-fluoro-1-methoxy-3-oxo -2,3-dihydro-1H-isoindol-2-yl]propanoic acid; (3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl )propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoic acid; (3R)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1R)-1-hydroxy-1-(oxan-4-yl )propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoic acid; (4S)-4-(4-chlorophenyl)-4-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl )propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]butanoic acid; (4S)-4-(4-chlorophenyl)-4-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1R)-1-hydroxy-1-(oxan-4-yl )propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]butanoic acid; (4S)-4-(4-Chlorophenyl)-4-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1R)-1-(4-fluoroxan-4-yl)- 1-hydroxypropyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]butanoic acid; (3R)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1R)-1-(4-fluoroxan-4-yl)- 1-hydroxypropyl]-1-trideuteromethoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoic acid; (3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-1-ethoxy-7-fluoro-5-[(1R)-1-(4-fluoroxane-4 -yl)-1-hydroxypropyl]-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoic acid; (4S)-4-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1R)-1-(4-fluoroxan-4-yl)-1-hydroxypropyl]-1-methoxy -3-oxo-2,3-dihydro-1H-isoindol-2-yl]-4-(4-methoxyphenyl)butanoic acid; (4S)-4-(4-chlorophenyl)-4-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-{1-hydroxy-1-[trans-4-hydroxycyclohexyl]propyl}- 1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]butanoic acid; 2-(5-chloro-2-{[1-(4-chlorophenyl)-7-fluoro-5-[(1R)-1-(4-fluoroxan-4-yl)-1-hydroxypropyl]-1-methoxy -3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}phenoxy)acetic acid; 5-chloro-2-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy -3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzoic acid; 5-chloro-2-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1R)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy -3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzoic acid; 5-chloro-2-{[(1R)-1-(4-chlorophenyl)-1-ethoxy-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl] -3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzoic acid; 2-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1R)-1-(4-fluoroxan-4-yl)-1-hydroxypropyl]-1-methoxy-3- oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}-5-methylbenzoic acid; 2-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1R)-1-(4-fluoroxan-4-yl)-1-hydroxypropyl]-1-methoxy-3- oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}-5-methoxybenzoic acid; 2-(5-chloro-2-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl]- 1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}phenyl)-2-methylpropanoic acid; 2-(5-chloro-2-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl]- 1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}phenyl)acetic acid; 2-(5-chloro-2-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1R)-1-hydroxy-1-(oxan-4-yl)propyl]- 1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}phenyl)acetic acid; (2S,3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxane-4 -yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]-2-methylpropanoic acid; (3R)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-1-[(3-fluoroxetan-3-yl)methoxy]-5-(2 -hydroxybutan-2-yl)-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoic acid; (3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(pyridin-2-yl)propyl]- 1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoic acid; (3R)-2-[(4-Chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[1-(4-fluoropiperidin-4-yl)-1-hydroxypropyl] -3-methoxy-2,3-dihydro-1H-isoindol-1-one; 4-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(1-methylpiperidin-4-yl)propyl]-3-oxo-1 -[cis-3-hydroxycyclobutoxy]-2,3-dihydro-1H-isoindol-2-yl]methyl}benzonitrile; (3R)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-(4-fluoro-1-methylpiperidin-4-yl)- 1-hydroxypropyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoic acid; tert-Butyl-2-{4-[(1S)-1-[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-7-fluoro-1-methoxy-3- oxo-2,3-dihydro-1H-isoindol-5-yl]-1-hydroxypropyl]piperidin-1-yl}acetate; tert-butyl-2-{4-[(1R)-1-[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-7-fluoro-1-methoxy-3- oxo-2,3-dihydro-1H-isoindol-5-yl]-1-hydroxypropyl]piperidin-1-yl}acetate; 2-{4-[(1S)-1-[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-7-fluoro-1-methoxy-3-oxo-2, 3-dihydro-1H-isoindol-5-yl]-1-hydroxypropyl]piperidin-1-yl}acetic acid; 2-{4-[(1R)-1-[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-7-fluoro-1-methoxy-3-oxo-2, 3-dihydro-1H-isoindol-5-yl]-1-hydroxypropyl]piperidin-1-yl}acetic acid; methyl 3-{4-[(1S)-1-[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-7-fluoro-1-methoxy-3-oxo-2 ,3-dihydro-1H-isoindol-5-yl]-1-hydroxypropyl]piperidin-1-yl}propanoate; And 3-{4-[(1S)-1-[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-7-fluoro-1-methoxy-3-oxo-2, 3-dihydro-1H-isoindol-5-yl]-1-hydroxypropyl]piperidin-1-yl}propanoic acid. 32. A compound or a tautomer or pharmaceutically acceptable salt thereof, wherein the compound is (2S,3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5- [(1S)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]-2-methylpropanoic acid. 33. A compound or a tautomer or pharmaceutically acceptable salt thereof, wherein the compound is (3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1 -hydroxy-1-(oxan-4-yl)ethyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoic acid. 34. A compound or a tautomer or pharmaceutically acceptable salt thereof, wherein the compound is 2-(5-chloro-2-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1 -hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}phenyl)-2-methylpropanoic acid. 35. A compound or a tautomer or pharmaceutically acceptable salt thereof, wherein the compound is 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. 36. A combination that inhibits the interaction of MDM2-p53, containing an effective amount of the compound, as defined in any of paragraphs. 1-35, and one or more anticancer agents. 37. Pharmaceutical composition that inhibits the interaction of MDM2-p53, containing an effective amount of the compound, as defined in any of paragraphs. 1-35, or a combination as defined in claim 36, a pharmaceutically acceptable carrier and a pharmaceutically acceptable substance. 38. Connection, as defined in any of paragraphs. 1-35, the combination of claim 36, or the pharmaceutical composition of claim 37 for use in therapy to inhibit MDM2-p53 interaction. 39. Connection, as defined in any of paragraphs. 1-35, the combination of claim 36, or the pharmaceutical composition of claim 37 for use in the treatment of MDM2-p53 mediated cancer. 40. A compound, combination or pharmaceutical composition for use according to claim 39, where the cancer is: - tumors of epithelial origin; malignant tumors of the blood system and precancerous hematological disorders and disorders of borderline malignancy; tumors of mesenchymal origin; tumors of the central or peripheral nervous system; endocrine tumors; tumors of the eyes and their appendages; embryonic cell and trophoblastic tumors; pediatric and embryonic tumors; or syndromes, concomitant or otherwise, which make the patient vulnerable to malignancies; - carcinomas of the bladder and urinary tract, breast, gastrointestinal tract, liver, gallbladder and biliary system, exocrine pancreas, kidney, lung, head and neck, ovary, fallopian tubes, peritoneum, vagina, vulva, penis, testicles, cervix, myometrium, endometrium, thyroid gland, brain, adrenal glands, prostate gland, skin or adjacent organs; - malignant tumors of the blood system and similar conditions of lymphoid origin or malignant tumors of the blood system and related conditions of myeloid origin; - sarcomas of soft tissues, bones or cartilage; astrocytomas, neuromas and glioblastomas, meningiomas, ependymomas, pineal tumors and schwannomas; pituitary tumors, adrenal tumors, islet cell tumors, parathyroid tumors, carcinoid tumors and medullary thyroid cancer; retinoblastoma; teratomas, seminomas, dysgerminomas, chorioadenomas and choriocarcinomas; medulloblastoma, neuroblastoma, Wilms tumor and primitive neuroectodermal tumors or xeroderma pigmentosa; - leukemia; - acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL) or chronic myeloid leukemia (CML); - lymphoma; - Burkitt's lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma or diffuse large B-cell lymphoma; - brain tumor, skin cancer, lung cancer, gastrointestinal cancer, osteosarcoma, liposarcoma, Ewing's sarcoma, soft tissue sarcoma, esophageal cancer, colorectal cancer, breast cancer, lung cancer, brain cancer or childhood cancer; - hepatocellular carcinoma, lung cancer, sarcomas, osteosarcomas or Hodgkin's disease; - glioma or neuroblastoma; - melanoma; - mesothelioma; - malignant peritoneal mesothelioma or malignant pleural mesothelioma; - stromal tumor of the gastrointestinal tract, stomach cancer, colorectal cancer, colon cancer or bowel cancer; or - fibrosarcoma. 41. The use of a compound as defined in any of paragraphs. 1-35, the combination of claim 36, or the pharmaceutical composition of claim 37 for the preparation of a medicament for use in the treatment of MDM2-p53 mediated cancer. 42. A method of treating cancer mediated by MDM2-p53, comprising administering to a patient a compound as defined in any one of paragraphs. 1-35, the combination of claim 36, or the pharmaceutical composition of claim 37. 43. Connection, as defined in any of paragraphs. 1-35, or a pharmaceutical composition according to claim 37 for use in an effective amount for the treatment of an MDM2-p53 mediated cancer, wherein said compound is used in combination with one or more other anti-cancer compounds or anti-cancer therapies. 44. The method of obtaining compounds, as defined in any of paragraphs. 1-35, or a tautomer thereof, a pharmaceutically acceptable salt, wherein said method comprises reacting a compound of the following formula with an organometallic reagent:

where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁷ , a, s, m and n are as defined in any of paragraphs. 1-30. 45. The method of obtaining a pharmaceutically acceptable salt of the compounds, as defined in any of paragraphs. 1-35, or its tautomer, where this method includes obtaining a compound of formula (I) or a compound according to paragraphs. 31-35 and the formation of its pharmaceutically acceptable salt by reacting between the free acid or free base forms of the compounds of formula (I) or the compounds according to paragraphs. 31-35 and a base or acid in a solvent selected from water, an organic solvent, or a mixture of water and an organic solvent.