RU2800278C2 - Impurities - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to compounds of formula I, where the values A, B, C, L, R², R³, R⁷-R⁹, m, p are specified in the claims, which are selective allosteric inhibitors of EGFR mutant variants containing T790M/L858R, T790M/L858R/C797S, L858R, L858R/C797S and to pharmaceutical compositions containing these compounds.

EFFECT: compounds can be used in the preparation of an agent for the therapeutic and/or prophylactic treatment of non-small cell lung cancer characterized by mutations activating EGFR.

15 cl, 8 tbl, 68 ex

Description

Field of invention

The present invention provides compounds that are selective allosteric inhibitors of EGFR mutant variants containing T790M/L858R, T790M/L858R/C797S, L858R, L858R/C797S, their manufacture, pharmaceutical compositions containing them, and their use as therapeutically active substances.

State of the art

Receptor tyrosine kinases of the HER family are mediators of cell growth, differentiation, and survival. The receptor family includes four distinct members, i.e. epidermal growth factor receptor (EGFR, ErbB1 or HER1) HER2 (ErbB2), HER3 (ErbB3) and HER4 (ErbB4). Upon ligand binding, the receptors form homo- and heterodimers, and subsequent activation of intrinsic tyrosine kinase activity results in receptor autophosphorylation and activation of signaling molecules (Yarden et al. ¹ ). Dysregulation of EGFR by overexpression or mutation has been implicated in various types of human cancers, including colorectal cancer, pancreatic cancer, gliomas, head and neck and lung cancers, in particular non-small cell lung cancer (NSCLC, NSCLC), and several agents targeting EGFR have been developed in recent years (Ciardiello et al. ² ). Erlotinib (Tarceva ^® ), a reversible EGFR tyrosine kinase inhibitor, has been approved in many countries for the treatment of recurrent NSCLC.

A strong effect of monotherapy with EGFR tyrosine kinase inhibitors is observed in a subgroup of patients with NSCLC, whose tumors have somatic mutations of the kinase domain, while the clinical benefit in patients with wild-type EGFR is greatly reduced (Paez et al. ³ ). The most common somatic EGFR mutations are deletions in exon 19, with the most common mutation being deletion 746-750, and amino acid substitutions in exon 21, with the most common mutation being L858R (Sharma et al. ⁴ ).

Treatment resistance often occurs, usually due to a secondary T790M mutation at the ATP receptor site. Some of the developed mutation-selective irreversible inhibitors are highly active against the T790M variant, but their effectiveness may be impaired when the C797S mutation appears, i.e. a cysteine residue with which they form a key covalent bond (Thress et al. ⁵ ). As further reported by Wang, the C797S mutation is the main mechanism for resistance to T790M-targeted EGFR inhibitors (Wang et al. ⁶ ). Additional mutations that confer resistance to osimertinib are described by Yang, eg L718Q. (Yang et al. ⁷ ). Lu et al. ⁸ in their review describe the targeting of EGFR ^L858E/T790M and EGFR ^{L858R/T790M/C797S} resistance mutations in the treatment of NSCLC.

Because the most common EGFR tyrosine kinase inhibitors target the ATP kinase site, there is a need for new therapeutic agents that act differently, for example by targeting drug-resistant EGFR mutant variants.

Recent studies suggest that targeted allosteric site targeting can lead to mutation-selective inhibitors (Jia et al. ⁹ )

There is a need to create selective molecules that specifically inhibit mutant EGFR variants containing T790M/L858R, T790M/L858R/C797S, E858R, L858R/C797S, suitable for therapeutic and/or prophylactic treatment of cancer, in particular EGFR mutant variants containing T790M and C797S.

WO 2009158369 ¹⁰ describes certain heterocyclic antibacterial agents. WO 2016183534 ¹¹ describes certain heterocyclic compounds useful as EBNA1 inhibitors. WO 2011128279 describes certain heterocyclic compounds useful as mGluR5 modulators.

The essence of the invention

The present invention provides compounds of formula I or pharmaceutically acceptable salts thereof,

where substituents and variables are as described below and in the claims.

These compounds are useful in the therapeutic and/or prophylactic treatment of cancer.

Detailed Description of the Invention

This invention provides a compound of formula I and pharmaceutically acceptable salts thereof, preparation from the above compounds, medicaments containing them and their manufacture, as well as the use of the above compounds in the therapeutic and/or prophylactic treatment of cancer, in particular non-small cell lung cancer.

The following definitions of the general terms used in this specification apply whether the terms in question appear alone or in combination with other groups.

Unless otherwise indicated, the following terms used in this application, including the description and claims, have the definitions indicated below. It should be noted that, as used herein and in the appended claims, singular forms include plural forms unless the context clearly dictates otherwise.

The term "C _1-6 -alkyl", alone or in combination with other groups, means a hydrocarbon radical which may be linear or branched, with one or more branches, and the alkyl group generally contains from 1 to 6 carbon atoms, for example, methyl (Me), ethyl (Et), propyl, isopropyl (i-propyl), n-butyl, i-butyl (isobutyl), 2-butyl (sec-butyl), t-butyl (tert-but yl), isopentyl, 2-ethylpropyl (2-methylpropyl), 1,2-dimethylpropyl and the like. Specific groups are methyl and ethyl.

The term "halo-C _1-6 -alkyl", alone or in combination with other groups, refers to C _1-6 -alkyl, as defined herein, which is substituted by one or more halogens, in particular 1-5 halogens, more specifically 1-3 halogens. A specific halogen is fluorine. Specific "halo-C _1-6 alkyl" is fluoro-C _1-6 alkyl, and specific "halo-C _1-3 alkyl" is fluoro-C _1-3 alkyl. Examples are trifluoromethyl, difluoromethyl, fluoromethyl and the like.

The term "cyano", alone or in combination with other groups, refers to N≡C-(NC-).

The term "amino", alone or in combination with other groups, refers to NH ₂ .

The term "hydroxy", alone or in combination with other groups, refers to OH.

The term "halogen", alone or in combination with other groups, means chlorine (Cl), iodine (I), fluorine (F) and bromine (Br). A specific group is F.

The term "heteroaryl", alone or in combination with other groups, refers to an aromatic carbocyclic group containing one 4-8-membered ring, in particular 5-8-membered, or several fused rings containing from 6 to 14, in particular from 6 to 10 ring atoms, and containing 1, 2 or 3 heteroatoms, individually selected from N, O and S, in particular 1N or 2N, and in the group at least one hetero the cyclic ring is aromatic. The term "5-membered heteroaryl" refers to a single 5-membered aromatic ring containing 1 or 2 heteroatoms selected from N, O and S, in particular one N atom and one S atom, for example thiazolyl. A specific group is thiazol-2-yl. The term "6-membered heteroaryl" refers to a single 6-membered aromatic ring containing 1 or 2 heteroatoms selected from N, O and S, in particular one N atom, for example pyridinyl. A particular group is 2-pyridyl. Examples of "heteroaryl" include benzofuryl, benzoimidazolyl, lH-benzoimidazolyl, benzoxazinyl, benzoxazolyl, benzothiazinyl, benzothiazolyl, benzothienyl, benzotriazolyl, furyl, imidazolyl, indazolyl, lH-indazolyl, indolyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxazolyl, pyra zinyl, pyrazolyl (pyrazyl), lH-pyrazolyl, pyrazolo[1,5-a]pyridinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl, thiazolyl, thienyl, triazolyl, 6,7-dihydro-5H-[1]pyridinyl and the like. Specific groups are pyridinyl and thiazolyl.

The term "C _1-6 -alkoxy", alone or in combination with other groups, denotes a -OC _1-6 -alkyl radical, which may be linear or branched, with one or more branches, while the alkyl group generally contains from 1 to 6 carbon atoms, for example methoxy (OMe, MeO), ethoxy (OEt), propoxy, isopropoxy (i-propoxy), n-butoxy, i-butoxy (isobutoxy), 2 -butoxy (sec-butoxy), t-butoxy (tert-butoxy), isopentyloxy (i-pentyloxy) and the like. Particular "C _1-6 -alkoxy" are groups with 1 to 4 carbon atoms. A specific group is methoxy.

The term "halo-C _1-6 -alkoxy", alone or in combination with other groups, refers to C _1-6 -alkoxy, as defined herein, which is substituted by one or more halogens, in particular 1-5 halogens, more specifically 1-3 halogens. A specific halogen is fluorine. Specific "halo-C _1-6 alkoxy" is fluoro-C _1-6 alkoxy, and specific "halo-C _1-3 alkoxy" is fluoro-C _1-3 alkoxy. A specific group is-O-CF ₃ .

The term "N-containing heterocyclyl" or "heterocyclyl" refers to a monovalent saturated or partially unsaturated mono- or bicyclic ring system of 4 to 9 ring atoms containing 1, 2, or 3 ring heteroatoms that are N and the remaining ring atoms are carbon. Bicyclic means consisting of two cycles containing two common ring atoms, i.e. the bridge separating the two rings is either a single bond or a chain of one or two ring atoms. Examples are piperidinyl and piperazinyl.

The term "aryl" means a monovalent aromatic carbocyclic mono - or bicyclic ring system containing from 6 to 10 carbon atoms in the ring. Examples of aryl moieties include phenyl and naphthyl. Specific "aryl" is phenyl.

The term "pharmaceutically acceptable" means a characteristic of a material that is used in the preparation of a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable, and acceptable for pharmaceutical use in animals and humans.

The term "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with human and animal tissues. Examples of suitable salts with inorganic and organic acids are, but are not limited to, acetic acid, citric acid, formic acid, fumaric acid, hydrochloric acid, lactic acid, maleic acid, malic acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, succinic acid, sulfuric acid, tartaric acid, trifluoro acetic acid and the like. Specific acids are formic acid, trifluoroacetic acid and hydrochloric acid. Specific acids are hydrochloric acid, trifluoroacetic acid and fumaric acid.

The terms "pharmaceutically acceptable excipient" refers to carriers and excipients, such as diluents or excipients, that are compatible with the other ingredients of the formulation.

The term "pharmaceutical composition" encompasses a product containing the specified ingredients in predetermined amounts or ratios, as well as any product that is formed, directly or indirectly, by combining the specified ingredients in the specified quantities. In particular, it covers a product containing one or more active ingredients and optionally a carrier containing inert ingredients, as well as any product that is formed, directly or indirectly, due to the combination, complexation or aggregation of any two or more ingredients, or due to the dissociation of one or more ingredients, or due to reactions or interactions of other types of one or more ingredients.

The term "inhibitor" means a compound that competes with, reduces or prevents the binding of a particular ligand to a particular receptor, or that reduces or inhibits the function of a particular protein.

The term "half-maximal inhibition concentration" (IC ₅₀ ) refers to the concentration of a particular compound required to achieve 50% inhibition of a biological process in vitro. IC ₅₀ values can be logarithmically converted to pIC ₅₀ values (-log IC ₅₀ ) when larger values indicate exponentially greater activity. The IC ₅₀ value is not an absolute value, but depends on the experimental conditions, such as the concentrations used. The IC ₅₀ value can be converted to an absolute inhibition constant (K _i ) using the Cheng-Prusoff equation ¹² .

"Therapeutically effective amount" means an amount of a compound which, when administered to a subject for the treatment of a disease state, is sufficient to effect such treatment of the disease state. A "therapeutically effective amount" will vary depending on the compound, the disease state being treated, the severity of the disease being treated, the age and underlying health of the subject, the route and form of administration, the judgment of the attending physician or veterinarian, and other factors.

The terms "as defined herein" and "as described herein" in relation to a variable include by reference the broad definition of the variable, as well as the specific, more specific, and most specific definitions, if any.

The term "treating", "contacting" or "reacting" in relation to a chemical reaction means the addition or mixing of two or more reactants under appropriate conditions to obtain the specified and/or desired product. It should be understood that a reaction that produces the indicated and/or desired product will not necessarily result directly from the combination of the two reactants that are added initially, i.e. there may be one or more intermediates that are formed in a mixture that ultimately leads to the formation of the specified and/or desired product.

The term "aromatic" refers to the generally accepted idea of aromaticity, as defined in the literature, in particular in IUPAC ¹³ .

The term "pharmaceutically acceptable excipient" means any ingredient that has no therapeutic activity and is non-toxic, such as disintegrants, binders, fillers, diluents, buffering agents, tonicity agents, stabilizers, antioxidants, surfactants, or lubricants used in the formulation of pharmaceutical products.

When a chiral carbon is present in a chemical structure, all stereoisomers associated with said chiral carbon are assumed to be encompassed by the structure as pure stereoisomers as well as mixtures thereof.

The invention also provides pharmaceutical compositions, methods of use and methods for preparing the above compounds.

All individual embodiments may be combined.

In one embodiment, the invention provides a compound of formula I,

Where

L is absent or is -(C≡C)-,

A represents

B is aryl or heteroaryl,

C is heteroaryl,

Y is N, C(OH) or CH,

each R ¹ is independently selected from the group consisting of

i) amino,

ii) C _1-6 -alkyl,

in) C _1-6 -alkoxy,

iv) cyano,

v) halogen,

vi) halo-C _1-6 -alkyl,

vii) halo-C _1-6 -alkoxy and

viii) hydroxy;

each R ² is independently selected from the group consisting of

i)-(CH ₂ ) _k -N(R ⁴ ,R ⁵ ),

ii)-(C=O)-N(R ⁴ ,R ⁵ ),

iii) halogen,

iv) halo-C _1-6 -alkyl,

v)-NH-(C=O)-C _1-6 -alkyl and

vi) C _1-6 alkyl optionally substituted with OH;

each R ³ is independently selected from the group consisting of

i) amino,

ii) C _1-6 -alkyl,

iii) C _1-6 -alkoxy,

iv) cyano,

v) halogen,

vi) halo-C _1-6 -alkyl,

vii) halo-C _1-6 -alkoxy and

viii) hydroxy;

each R ⁴ is independently selected from the group consisting of

i) H and

ii) C _1-6 alkyl;

each R ⁵ is independently selected from the group consisting of

i) H,

ii) C _1-6 -alkyl and

iii)-(C=O)-C _1-6 alkyl;

or R ⁴ and R ⁵ together with the N atom to which they are attached form a heterocyclyl, the heterocyclyl being optionally substituted with one to three R ⁶ ;

each R ⁶ is independently selected from the group consisting of

i)-OH,

ii) halogen,

iii) C _3-8 -cycloalkyl,

iv) halo-C _1-6 -alkyl,

v) C _1-6 -alkoxy-C _1-6 -alkyl,

vi) cyano-C _1-6 -alkyl,

vii) C _1-6 -alkyl and

viii)-(C=O)-C _1-6 alkyl;

each R ⁷ is independently selected from the group consisting of

i) H,

ii) halogen,

iii) halo-C _1-6 -alkoxy,

iv) C _1-6 -alkoxy and

v) C _1-6 alkyl;

each R ⁸ is independently selected from the group consisting of

i) H,

ii) halogen,

iii) C _1-6 -alkoxy and

iv) C _1-6 alkyl;

each R ⁹ is independently selected from the group consisting of

i) H,

ii) halogen,

iii) halo-C _1-6 -alkoxy,

iv) C _1-6 -alkoxy and

v) C _1-6 alkyl;

k is 0, 1 or 2,

n is 0, 1, 2, 3, or 4;

m is 0, 1 or 2;

p is 0 or 1;

or a pharmaceutically acceptable salt thereof.

In one embodiment, the invention provides a compound of formula I,

Where

L is absent or is -(C≡C)-,

A represents

B is aryl or heteroaryl,

C is heteroaryl,

Y is N, C(OH) or CH,

each R ¹ is independently selected from the group consisting of

i) amino,

ii) C _1-6 -alkyl,

iii) C _1-6 -alkoxy,

iv) cyano,

v) halogen,

vi) halo-C _1-6 -alkyl,

vii) halo-C _1-6 -alkoxy and

viii) hydroxy;

each R ² is independently selected from the group consisting of

i)-(CH ₂ ) _k -N(R ⁴ ,R ⁵ ),

ii)-(C=O)-N(R ⁴ ,R ⁵ ),

iii) halogen,

iv)-NH-(C=O)-C _1-6 -alkylai

v) C _1-6 alkyl optionally substituted with OH;

each R ³ is independently selected from the group consisting of

i) amino,

ii) C _1-6 -alkyl,

iii) C _1-6 -alkoxy,

iv) cyano,

v) halogen,

vi) halo-C _1-6 -alkyl,

vii) halo-C _1-6 -alkoxy and

viii) hydroxy;

each R ⁴ is independently selected from the group consisting of

i) H and

ii) C _1-6 alkyl;

each R ⁵ is independently selected from the group consisting of

i) H,

ii) C _1-6 -alkyl and

iii)-(C=O)-C _1-6 alkyl;

or R ⁴ and R ⁵ together with the N atom to which they are attached form a heterocyclyl, the heterocyclyl being optionally substituted with R ⁶ ;

each R ⁶ is independently selected from the group consisting of

i) OH,

ii) C _1-6 -alkyl and

iii)-(C=O)-C _1-6 alkyl;

each R ⁷ is independently selected from the group consisting of

i) H,

ii) halogen,

iii) halo-C _1-6 -alkoxy,

iv) C _1-6 -alkoxy and

v) C _1-6 alkyl;

each R ⁸ is independently selected from the group consisting of

i) H,

ii) halogen,

iii) C _1-6 -alkoxy and

iv) C _1-6 alkyl;

each R ⁹ is independently selected from the group consisting of

i) H,

ii) halogen,

iii) halo-C _1-6 -alkoxy,

iv) C _1-6 -alkoxy and

v) C _1-6 alkyl;

k is 0, 1 or 2,

n is 0; 1, 2, 3 or 4;

m is 0, 1 or 2;

p is 0 or 1;

or a pharmaceutically acceptable salt thereof.

A specific embodiment of the invention relates to a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein

L is absent or is -(C≡C)-,

A represents

B is aryl or heteroaryl,

C is heteroaryl,

Y is N or CH,

each R ² is independently selected from the group consisting of

i)-(CH ₂ ) _k -N(R ⁴ ,R ⁵ ),

ii) halo-C _1-6 -alkyl and

iii) C _1-6 alkyl optionally substituted with OH;

R ⁴ and R ⁵ together with the N atom to which they are attached form a heterocyclyl, the heterocyclyl being optionally substituted with one to three R ⁶ ;

each R ⁶ is independently selected from the group consisting of

i)-OH,

ii) halogen,

iii) C _3-8 -cycloalkyl,

iv) halo-C _1-6 -alkyl,

v) C _1-6 -alkoxy-C _1-6 -alkyl,

vi) cyano-C _1-6 -alkyl and

vii) C _1-6 alkyl;

R ⁷ is H or halogen;

R ⁸ is H;

R ⁹ is halogen;

k is 0 or 1;

n is 0;

m is 1;

r is 0.

A specific embodiment of the invention relates to a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein

L is absent or is -(C≡C)-,

A represents

B is aryl or heteroaryl,

C is heteroaryl,

Y is N or CH,

each R ² is independently selected from the group consisting of

i)-(CH ₂ ) _k -N(R ⁴ ,R ⁵ ) and

ii) C _1-6 alkyl optionally substituted with OH;

R ⁴ and R ⁵ together with the N atom to which they are attached form a heterocyclyl, the heterocyclyl being optionally substituted with R ⁶ ;

each R ⁶ is independently selected from the group consisting of

i)-OH and

ii) C _1-6 alkyl;

R ⁷ is H or halogen;

R ⁸ is H;

R ⁹ is halogen;

k is 0 or 1;

n is 0;

m is 1;

r is 0.

A specific embodiment of the invention relates to a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein A is

Where

Y is N or CH, and

each R ^a , R ^b , R ^c or R ^d is independently selected from the group consisting of

i) H,

ii) amino,

iii) C _1-6 -alkyl,

iv) C _1-6 -alkoxy,

v) cyano,

vi) halogen,

vii) halo-C _1-6 -alkyl,

viii) halo-C _1-6 -alkoxy and

ix) hydroxyl;

more specifically, where A is 6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl or 6,7-dihydro-5H-pyrrolisin-1-yl.

A specific embodiment of the invention relates to a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein A is

and Y is N or CH.

A specific embodiment of the invention relates to a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein A is 6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl.

A specific embodiment of the invention relates to a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein B is aryl, in particular phenyl.

A specific embodiment of the invention relates to a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein B is aryl.

A specific embodiment of the invention relates to a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein B is phenyl.

A specific embodiment of the invention relates to a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein B is heteroaryl, in particular pyridinyl.

A specific embodiment of the invention relates to a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein B is heteroaryl.

A specific embodiment of the invention relates to a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein B is pyridinyl.

A specific embodiment of the invention relates to a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein B is phenyl or pyridinyl.

A specific embodiment of the invention relates to a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein C is heteroaryl, in particular thiazolyl.

A specific embodiment of the invention relates to a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein C is heteroaryl.

A specific embodiment of the invention relates to a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein C is thiazolyl.

A specific embodiment of the invention relates to a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2.

A specific embodiment of the invention relates to a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, where n is 0.

A certain embodiment of the invention relates to a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, where m is 1.

A specific embodiment of the invention relates to a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein p is 0.

A certain embodiment of the invention relates to a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein R ² is -(CH ₂ ) _k -N(R ⁴ ,R ⁵ ), k is 0 or 1, and R ⁴ and R ⁵ together with the N atom to which they are attached form a heterocyclyl, wherein the heterocyclyl is optionally substituted with one or two R ⁶ .

A certain embodiment of the invention relates to a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein R is -(CH ₂ ) _k -N(R ⁴ ,R ⁵ ), k is 0 or 1, and R ⁴ and R ⁵ together with the N atom to which they are attached form a heterocyclyl, with the heterocyclyl optionally substituted with one R ⁶ .

A specific embodiment of the invention relates to a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein R is -(CH ₂ ) _k -N(R ⁴ ,R ⁵ ), k is 0 or 1, and R ⁴ and R ⁵ together with the N atom to which they are attached form a heterocyclyl, wherein the heterocyclyl is optionally substituted with methyl, ethyl or OH, in particular R ² is (ethyl)piperazinyl, (hydroxy)pi peridinyl, -CH ₂ -(hydroxy)piperidinyl, -CH ₂ -(methyl)piperazinyl or -piperazinyl.

A specific embodiment of the invention relates to a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein R ² is -(CH ₂ ) _k -N(R ⁴ ,R ⁵ ), k is 0 or 1, and R ⁴ and R ⁵ together with the N atom to which they are attached form a heterocyclyl, wherein the heterocyclyl is optionally substituted with methyl, ethyl, or OH.

A specific embodiment of the invention relates to a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein R ² is -(CH ₂ ) _k -N(R ⁴ ,R ⁵ ), k is 0, and R ⁴ and R ⁵ together with the N atom to which they are attached form a heterocyclyl, wherein the heterocyclyl is optionally substituted with methyl, ethyl, or OH.

A specific embodiment of the invention relates to a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein R is -(CH ₂ ) _k -N(R ⁴ ,R ⁵ ), k is 1, and R ⁴ and R ⁵ together with the N atom to which they are attached form a heterocyclyl, wherein the heterocyclyl is optionally substituted with methyl, ethyl, or OH.

A certain embodiment of the invention relates to a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein R ² is -(CH ₂ ) _k -N(R ⁴ ,R ⁵ ), k is 0 or 1, and R ⁴ and R ⁵ together with the N atom to which they are attached form piperazinyl, piperidinyl or morpholino, wherein piperazinyl, piperidinyl or morpholino is optionally substituted with one or two R ⁶ .

A specific embodiment of the invention relates to a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein R ² is -(CH ₂ ) _k -N(R ⁴ ,R ⁵ ), k is 0 or 1, and R ⁴ and R ⁵ together with the N atom to which they are attached form piperazinyl, piperidinyl or morpholino, wherein piperazinyl, piperidinyl or morpholino is optionally substituted with one R ⁶ .

A specific embodiment of the invention relates to a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein R ² is (ethyl)piperazinyl, (hydroxy)piperidinyl, _-CH2 -(hydroxy)piperidinyl, _-CH2 -(methyl)piperazinyl, or piperazinyl.

A specific embodiment of the invention relates to a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein R ⁹ is halogen.

A specific embodiment of the invention relates to a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein R ⁹ is F.

A specific embodiment of the invention relates to a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein R ⁶ is selected from

i) OH,

ii) halogen,

iii) C _3-8 -cycloalkyl,

iv) halo-C _1-6 -alkyl,

v) C _1-6 -alkoxy-C _1-6 -alkyl,

vi) cyano-C _1-6 -alkyl and

vii) C _1-6 alkyl.

A specific embodiment of the invention relates to a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein R ⁶ is selected from

i) C _3-8 -cycloalkyl,

ii) halo-C _1-6 -alkyl,

iii) C _1-6 -alkoxy-C _1-6 -alkyl,

iv) cyano-C _1-6 -alkyl and

v) C _1-6 alkyl.

A certain embodiment of the invention relates to a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, which are selected from the group consisting of

(2RS)-2-(6,7-dihydro-5H-pyrrolisin-1-yl)-2-[4-fluoro-6-[2-[4-[(4-hydroxy-1-piperidyl)methyl]phenyl]ethynyl]-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide,

(2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-6-[2-[4-[(4-methylpiperazin-1-yl)methyl]phenyl]ethynyl]-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide,

(2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-6-[2-[4-[(4-hydroxy-1-piperidyl)methyl]phenyl]ethynyl]-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide,

(2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-1-oxo-6-(4-piperazin-1-ylphenyl)isoindolin-2-yl]-N-thiazol-2-ylacetamide,

(2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-6-[4-(4-hydroxy-1-piperidyl)phenyl]-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide,

(2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-6-[2-[4-(hydroxymethyl)phenyl]ethynyl]-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide,

(2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-1-oxo-6-[2-[4-(1-piperidylmethyl)phenyl]ethynyl]isoindolin-2-yl]-N-thiazol-2-ylacetamide,

(2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[4-(4-ethylpiperazin-1-yl)phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide,

(2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[6-(4-ethylpiperazin-1-yl)-3-pyridyl]-4-fluoro-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide,

(2RS)-2-[4-chloro-6-[2-[4-[(4-hydroxy-1-piperidyl)methyl]phenyl]ethynyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide,

(2RS)-2-[4-chloro-6-[4-(4-ethylpiperazin-1-yl)phenyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide,

(2RS)-2-[4-chloro-6-[4-(4-hydroxy-1-piperidyl)phenyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide,

(2RS)-2-[4-chloro-6-[6-(4-hydroxy-1-piperidyl)-3-pyridyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide and

(2RS)-2-[7-chloro-4-fluoro-6-[2-[4-[(4-hydroxy-1-piperidyl)methyl]phenyl]ethynyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide.

A certain embodiment of the invention relates to a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, which are selected from the group consisting of

(2RS)-2-(6,7-dihydro-5H-pyrrolisin-1-yl)-2-[4-fluoro-6-[2-[4-[(4-hydroxy-1-piperidyl)methyl]phenyl]ethynyl]-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide,

(2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-6-[2-[4-[(4-methylpiperazin-1-yl)methyl]phenyl]ethynyl]-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide,

(2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-6-[2-[4-[(4-hydroxy-1-piperidyl)methyl]phenyl]ethynyl]-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide,

(2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-1-oxo-6-(4-piperazin-1-ylphenyl)isoindolin-2-yl]-N-thiazol-2-ylacetamide,

(2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-6-[4-(4-hydroxy-1-piperidyl)phenyl]-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide,

(2RS8)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-1-oxo-6-[2-[4-(1-piperidylmethyl)phenyl]ethynyl]isoindolin-2-yl]-N-thiazol-2-ylacetamide,

(2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[4-(4-ethylpiperazin-1-yl)phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide,

(2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[6-(4-ethylpiperazin-1-yl)-3-pyridyl]-4-fluoro-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide,

(2RS)-2-[4-chloro-6-[2-[4-[(4-hydroxy-1-piperidyl)methyl] phenyl]ethynyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide,

(2RS)-2-[4-chloro-6-[4-(4-ethylpiperazin-1-yl)phenyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide,

(2RS)-2-[4-chloro-6-[4-(4-hydroxy-1-piperidyl)phenyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide,

(2RS)-2-[4-chloro-6-[6-(4-hydroxy-1-piperidyl)-3-pyridyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide and

(2RS)-2-[7-chloro-4-fluoro-6-[2-[4-[(4-hydroxy-1-piperidyl)methyl]phenyl]ethynyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide.

A certain embodiment of the invention relates to a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, which are selected from the group consisting of

2-[4-chloro-1-oxo-6-[2-[4-(1-piperidylmethyl)phenyl]ethynyl]isoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide;

2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[4-(1-ethyl-4-piperidyl)phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide;

2-[4-fluoro-6-[2-[4-[(4-hydroxy-1-piperidyl)methyl]phenyl]ethynyl]-1-oxoisoindolin-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide;

2-[6-[3-chloro-4-(4-ethylpiperazin-1-yl)phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide;

2-[6-[3-chloro-4-[rac-(3R)-3-methylpiperazin-1-yl]phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide;

2-[6-[3-chloro-4-[rac-(3R)-4-ethyl-3-methylpiperazin-1-yl]phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide;

2-[4-chloro-6-[4-[(1-ethyl-4-piperidyl)oxy]phenyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide;

2-[6-(3-chloro-4-morpholinophenyl)-4-fluoro-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide;

2-[6-[3-chloro-4-(4-ethylpiperazin-1-yl)phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide;

2-[6-(3-chloro-4-morpholinophenyl)-4-fluoro-1-oxoisoindolin-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide;

2-[6-[3-chloro-4-[rac-(3R)-4-ethyl-3-methylpiperazin-1-yl]phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide;

2-[6-[4-(1-Ethyl-4-piperidyl)-3-fluorophenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide;

2-[6-[4-(1-cyclopropyl-4-piperidyl)phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide;

2-[4-chloro-6-[4-(1-cyclopropyl-4-piperidyl)phenyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide;

2-[4-chloro-6-[4-(1-ethyl-4-piperidyl)phenyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide;

2-[6-[3-chloro-4-(1-ethyl-4-piperidyl)phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide;

2-[6-[4-(1-ethyl-4-piperidyl)phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide;

2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-1-oxo-6-[4-[rac-(3R,4R)-1-ethyl-3-fluoro-4-piperidyl]phenyl]isoindolin-2-yl]-N-thiazol-2-ylacetamide;

2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[4-(1-ethyl-4-piperidyl)-3-fluorophenyl]-4-fluoro-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide;

2-[6-[4-[1-(2,2-difluoroethyl)-4-piperidyl]phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide;

2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-6-[4-[1-(2-methoxyethyl)-4-piperidyl]phenyl]-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide;

2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-6-[4-[1-(2-fluoroethyl)-4-piperidyl]phenyl]-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide;

2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[3-ethyl-4-(1-ethyl-4-piperidyl)phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide;

2-[6-[4-(4-cyclopropylpiperazin-1-yl)-3-fluorophenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide;

2-[6-[3-chloro-4-(4-cyclopropylpiperazin-1-yl)phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide;

2-[4-chloro-6-[4-(4-cyclopropylpiperazin-1-yl)-3-fluorophenyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-acetamide;

2-[6-[3-chloro-4-[4-(2,2-difluoroethyl)piperazin-1-yl]phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide;

2-[6-[4-(4-cyclopropylpiperazin-1-yl)-3-fluorophenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide;

2-[6-[2-(2-chlorophenyl)ethynyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide;

2-[6-[2-[4-[(4,4-difluoro-1-piperidyl)methyl]phenyl]ethynyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide;

2-(6,7-dihydro-5H-pyrrolisin-1-yl)-2-[4-fluoro-6-(3-fluoro-4-morpholinophenyl)-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide;

2-[6-[3-chloro-4-(4-cyclopropylpiperazin-1-yl)phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide;

2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-1-oxo-6-[2-[4-(trifluoromethyl)phenyl]ethynyl]isoindolin-2-yl]-N-thiazol-2-ylacetamide;

2-(6,7-dihydro-5H-pyrrolisin-1-yl)-2-[6-[4-(1-ethyl-4-piperidyl)phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide;

2-[6-[3-chloro-4-[4-(2-fluoroethyl)piperazin-1-yl]phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide;

2-[6-[3-ethyl-4-(1-ethyl-4-piperidyl)phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide;

2-[7-chloro-4-fluoro-6-(4-morpholinophenyl)-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide;

2-[4-chloro-6-[3-ethyl-4-(1-ethyl-4-piperidyl)phenyl]-1-oxoisoindolin-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide;

2-[4-chloro-6-[4-(1-ethyl-4-piperidyl)phenyl]-1-oxoisoindolin-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide;

2-[4-chloro-6-[4-(1-cyclopropyl-4-piperidyl)phenyl]-1-oxoisoindolin-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide;

2-[4-chloro-6-[4-[1-(2-fluoroethyl)-4-piperidyl]phenyl]-1-oxoisoindolin-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide;

2-[4-chloro-6-[4-[1-(2-cyanoethyl)-4-piperidyl]phenyl]-1-oxoisoindolin-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide;

2-[4-chloro-6-[3-ethyl-4-[1-(2-fluoroethyl)-4-piperidyl]phenyl]-1-oxoisoindolin-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide;

2-[4-chloro-6-[4-[1-(2-fluoroethyl)-4-piperidyl]phenyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide;

2-[4-chloro-6-[4-[1-(2,2-difluoroethyl)-4-piperidyl]phenyl]-1-oxoisoindolin-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide;

2-[4,7-dichloro-6-[4-(1-ethyl-4-piperidyl)phenyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide;

2-[4,7-dichloro-6-[4-(1-ethyl-4-piperidyl)phenyl]-1-oxoisoindolin-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide;

2-[4,7-dichloro-6-[4-[1-(2-fluoroethyl)-4-piperidyl]phenyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide;

2-[4,7-dichloro-6-[4-[1-(2-fluoroethyl)-4-piperidyl]phenyl]-1-oxoisoindolin-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide;

2-[4,7-dichloro-6-(4-morpholinophenyl)-1-oxoisoindolin-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide;

2-[4-chloro-1-oxo-6-[4-[rac-(3R,4R)-1-ethyl-3-fluoro-4-piperidyl]phenyl]isoindolin-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide;

2-[4-fluoro-6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-1-oxoisoindolin-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide;

2-[4-chloro-6-[4-(1-ethyl-3,3-difluoro-4-piperidyl)phenyl]-1-oxoisoindolin-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide;

2-[4-chloro-6-[4-[1-(2-hydroxyethyl)-4-piperidyl]phenyl]-1-oxoisoindolin-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide.

A more specific embodiment of the invention relates to a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, which are selected from the group consisting of

2-[4-chloro-6-[3-ethyl-4-[1-(2-fluoroethyl)-4-piperidyl]phenyl]-1-oxoisoindolin-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide;

2-[4-chloro-1-oxo-6-[4-[rac-(3R,4R)-1-ethyl-3-fluoro-4-piperidyl]phenyl]isoindolin-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide.

A certain embodiment of the invention relates to a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

A certain embodiment of the invention relates to a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, for use in the therapeutic and/or prophylactic treatment of cancer, in particular non-small cell lung cancer.

A specific embodiment of the invention relates to a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, for use in the therapeutic and/or prophylactic treatment of non-small cell lung cancer.

A certain embodiment of the invention relates to a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the therapeutic and/or prophylactic treatment of cancer, in particular non-small cell lung cancer.

A certain embodiment of the invention relates to a pharmaceutical composition containing a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

A specific embodiment of the invention relates to a method for the therapeutic and/or prophylactic treatment of cancer, in particular non-small cell lung cancer, by administering to a patient a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof.

A certain embodiment of the invention relates to a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, for use as a drug in the therapeutic and/or prophylactic treatment of a patient with EGFR activating mutations suffering from cancer, in particular non-small cell lung cancer, comprising determining the status of EGFR activating mutations in said patient, and then administering to said patient a compound of formula I, as described herein, or a pharmaceutically acceptable salt thereof.

A certain embodiment of the invention relates to a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, for use as a drug in the therapeutic and/or prophylactic treatment of a patient with EGFR mutations: T790M/L858R, T790M/L858R/C797S, L858R and/or L858R/C797S suffering from cancer, in particular non-small cell lung cancer, comprising the definition status of EGFR activating mutations in said patient, and then administering to said patient a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof.

A certain embodiment of the invention relates to a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, for use as a drug in the therapeutic and/or prophylactic treatment of a patient with EGFR activating mutations, as determined by the cobas®, v2 EGFR mutation detection test, suffering from cancer, in particular non-small cell lung cancer, comprising determining the status of EGFR activating mutations in said patient, and then administering to said patient a compound of formula I, as described herein, or a pharmaceutically acceptable salt thereof.

In addition, the invention includes all substituents of the compounds of formula I in their corresponding deuterated form, where applicable.

In addition, the invention includes all optical isomers, i.e. diastereomers, diastereomeric mixtures, racemic mixtures, all their respective enantiomers and/or tautomers, as well as their solvates, of the compounds of formula I, where applicable.

The compounds of formula I may contain one or more asymmetric centers and therefore may exist as racemates, racemic mixtures, single enantiomers, diasteremeric mixtures and single diastereomers. Additional asymmetric centers may be present depending on the nature of the various substituents on the molecule. Each such asymmetric center will independently give rise to two optical isomers, and it is intended that all possible optical isomers and diastereomers in the mixture, as well as pure or partially purified compounds, be included in this invention. This invention is intended to cover all such isomeric forms of these compounds. Independent syntheses of these diastereomers or their chromatographic separation can be accomplished, as is known in the art, by appropriate modification of the methodology described herein. Their absolute stereochemistry can be determined by X-ray diffraction crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. If necessary, racemic mixtures of compounds can be separated to isolate the individual enantiomers. Separation can be carried out by methods well known in the art, for example by coupling a racemic mixture of compounds with an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods such as fractional crystallization or chromatography.

In an embodiment of the invention, when optically pure enantiomers are provided, optically pure enantiomer means that the compound contains >90% of the desired isomer by weight, in particular >95% of the desired isomer by weight, or more specifically >99% of the desired isomer by weight, with the specified percentage based on the total weight of the isomer(s) of the compound. Chirally pure or chirally enriched compounds can be obtained by chirally selective synthesis or by separation of enantiomers. Separation of enantiomers can be carried out with the final product or alternatively with a suitable intermediate.

The compounds of formula I can be obtained in accordance with the schemes described in the examples. The starting material is commercially available or can be prepared according to known methods.

Scheme 1

An isoindoline compound of formula I' can be prepared, for example, by cyclizing the ring of a preformed amino ester 1 with a suitably substituted methyl-2-(bromomethyl)benzoate of formula 2 to give the desired isoindole ester 3. Hydrolysis and amide coupling with a suitably substituted amine of formula 4 with a crosslinking agent such as HATU affords the desired isoindole compound of formula I' (Scheme 1).

In general, the sequence of steps used to synthesize compounds of formula I', which is a compound of formula I, and additional functionalization can also be modified in some cases.

Appropriate pharmaceutically acceptable acid salts can be prepared by standard methods known to the person skilled in the art, for example by dissolving a compound of formula I in a suitable solvent such as, for example, dioxane or tetrahydrofuran, and by adding an appropriate amount of the appropriate acid. Products can usually be isolated by filtration or by chromatography.

The conversion of a compound of formula I into a pharmaceutically acceptable salt with a base can be accomplished by treating such a compound with the base. One possible way to prepare such a salt is, for example, adding 1/n equivalents of a basic salt, such as, for example, M(OH) _n , where M = metal or ammonium cation, and n = amount of hydroxide anions, to a solution of the compound in a suitable solvent (for example, ethanol, ethanol-water mixture, tetrahydrofuran-water mixture) and remove the solvent by evaporation or lyophilization. Specific salts are hydrochloride, formate, and trifluoroacetate.

In the event that their preparation is not described in the examples, the compounds of formula I, as well as all intermediates, can be obtained in accordance with similar methods or in accordance with the methods presented herein. Starting materials are commercially available, known in the art, or can be obtained using methods known in the art, or similar.

It is understood that the compounds of general formula I in this invention can be functionally derivatized to give derivatives that are capable of being converted back to the parent compound in vivo. Pharmacological tests

The compounds of formula I and their pharmaceutically acceptable salts have valuable pharmacological properties. Compounds were tested according to the test given hereinafter.

Phospho-EGFR TMLR HTRF Assay (Cell) Cell Line and Medium

The H1975 cell line (CRL-5908; batch BA70803) was obtained from the American Type Culture Collection (Manassas, VA, USA). Cells were maintained at 37°C, 5% CO ₂ in RPMI 1640 complete medium without phenol red containing 0.3 mg/mL glutamine, 100 IU/mL penicillin, and 100 mg/mL streptomycin (Gibco, 15140-122) supplemented with 10% fetal bovine serum (PBS, Gibco, 100 91-148). Compounds were diluted with RPMI 1640 deficient medium (Gibco, 11835-030) without phenol red containing 0.3 mg/ml glutamine, 100 IU/ml penicillin and 100 mg/ml streptomycin (Gibco). Protocol Cells were cultured for 24 hours in a 384-well plate (Greiner Bio-One, Nr. 784-080; 5000 cells/well) using 8 μl of complete medium/well. Then, 4 μl/well of compound solution, 3x serially diluted 3 times compound or DMSO in nutrient deficient medium (0.33% DMSO final concentration) was added to the cells. After 16 hours at 37°C, 5% CO ₂ , 95% rel. cells were lysed by adding 4 μl/well of supplemented lysis buffer (Cis-bio, phospho-EGFR kit, HTRF, 64EG1PEH) to the compound mixture, followed by incubation for 30 min at room temperature with shaking (400 rpm). Then 4 μl of a mixture of anti-phospho-EGFR cryptate and anti-phospho-EGFR-d2 antibody solutions prepared in detection buffer was added. The plates were then incubated for 4 hours at room temperature until the fluorescence emission at 620 and 665 nm was read using an Envision reader (Perkin Elmer). Cell line and medium

The BaF3-TMLRCS cell line was obtained from Crownbio (San Diego, California, USA). Cells were stored at 37° C., 5% CO ₂ in RPMI ATCC (Gibco 31870) + 2 mM glutamine + 0.5 μg/ml puromycin supplemented with 10% fetal bovine serum (FBS) (Gibco). Protocol

The cells were transferred as above into a Greiner Bio-One microtiter plate, Nr. 784-08 at 20,000 cells/well in 12.5 µl of growth medium/well after the plates were prefilled with 12.5 µl of test compound solutions (dose-dependently) or DMSO alone. After rotating the plates at 300xg for 30 seconds, the cells were incubated for 4 hours at 37°C, 5% CO ₂ , 95% humidity. Cells were lysed by adding 4 µ/well of supplemented lysis buffer (Cis-bio, phospho-EGFR kit, HTRF, 64EG1PEH) to the compound mixture, followed by incubation for 30 min at room temperature with shaking (400 rpm). The plates were then frozen and stored overnight at -80°C. The day after the plates were thawed, 4 µl of a mixture of anti-phospho-EGFR cryptate and anti-phospho-EGFR-c12 antibody solutions prepared in the supplied detection buffer was added to each well. The lidded plates were then incubated for 4 hours at room temperature until the fluorescence emission at 616 and 665 nm was read using an Envision reader (Perkin Elmer). The data was analyzed as above using a normalized signal ratio of 665 to 616 times 10,000.

Pharmaceutical compositions

The compounds of formula I and pharmaceutically acceptable salts can be used as therapeutically active substances, for example in the form of pharmaceutical preparations. Pharmaceutical preparations can be administered orally, for example in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions. However, administration can be done rectally, eg in the form of suppositories, or parenterally, eg in the form of injectable solutions.

The compounds of formula I and their pharmaceutically acceptable salts can be treated with pharmaceutically inert inorganic or organic carriers to obtain pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acid or salts thereof and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatin capsules. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols, and the like. However, depending on the nature of the active substance, carriers are generally not necessary in the case of soft gelatin capsules. Suitable carriers for preparing solutions and syrups are, for example, water, polyols, glycerol, vegetable oils and the like. Suitable carriers for suppositories are, for example, natural or hydrogenated oils, waxes, fats, semi-solid and liquid polyols, and the like.

In addition, pharmaceutical preparations may contain pharmaceutically acceptable excipients such as preservatives, solubility enhancers, stabilizers, wetting agents, emulsifiers, sweeteners, colors, flavors, osmotic salts, buffering agents, or antioxidants. They may also contain therapeutically valuable substances.

Medicinal products containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier are also provided in this invention, as well as a method for their preparation, which includes giving one or more compounds of formula I and / or their pharmaceutically acceptable salts and, if necessary, one or more other therapeutically valuable substances, a dosage form for administration together with one or more therapeutically inert carriers.

The dosage may vary within wide limits and must of course be adjusted to individual requirements in each individual case. In the case of oral administration, the dosage for adults may vary from about 0.01 mg to about 1000 mg per day of the compound of General formula I or the appropriate amount of its pharmaceutically acceptable salt. The daily dosage can be administered as a single dose or multiple doses, and in addition, you can exceed the upper limit, when it is found that there is an indication.

The following examples illustrate the invention without limiting it, but may serve only as an illustration. Pharmaceutical preparations typically contain about 1-500 mg, especially 1-100 mg, of a compound of formula I. Examples of compositions according to the invention are presented below.

Example A

Tablets with the following composition are made in the traditional way:

Cooking method

1. Mix ingredients 1, 2, 3 and 4 and granulate using purified water.

2. Dry the pellets at 50°C.

3. Pass the pellets through suitable grinding equipment.

4. Add ingredient 5 and mix for three minutes; press on a suitable press.

Example B-1

Capsules are made with the following composition:

Cooking method

1. Mix ingredients 1, 2 and 3 in a suitable mixer for 30 minutes.

2. Add ingredients 4 and 5 and mix for 3 minutes.

3. Put into a suitable capsule.

The compound of formula I, lactose and cornstarch are first mixed in a mixer and then in a grinder. The mixture is returned to the mixer; talc is added to it and mixed thoroughly. The mixture is filled into suitable capsules, for example hard gelatine capsules, by means of a device.

Example B-2

Soft gelatin capsules are made with the following composition:

Cooking method

The compound of formula I is dissolved in the warm melt of the other ingredients and the mixture is filled into suitably sized soft gelatin capsules. Filled soft gelatin capsules are processed in accordance with conventional techniques.

Example C

Suppositories are made with the following composition:

Cooking method

The mass for the suppository is melted in a glass or steel vessel, thoroughly mixed and cooled to 45°C. After that, a finely ground compound of formula I is added to it and stirred until complete disappearance. The mixture is poured into suitable size suppository molds, left to cool; the suppositories are then removed from the molds and individually packaged in wax paper or metal foil.

Example D

Prepare injection solutions with the following composition:

Cooking method

The compound of formula I is dissolved in a mixture of polyethylene glycol 400 and water for injection (part). The pH is adjusted to 5.0 with acetic acid. The volume is adjusted to 1.0 ml by adding the residual amount of water. The solution is filtered, poured into vials with the necessary excess and sterilized.

Example E

Sachets are made with the following composition:

Cooking method

The compound of formula I is mixed with lactose, microcrystalline cellulose and sodium carboxymethylcellulose and granulated with a mixture of polyvinylpyrrolidone and water. The granulate is mixed with magnesium stearate and flavor additives and placed in a sachet.

experimental part

The following examples are presented to illustrate the invention. They should not be considered as limiting the scope of the invention, but only as an illustration of it.

Example 1

(2RS)-2-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-6-[2-[4-[(4-methylpiperazin-1-yl)methyl]phenyl]ethynyl]-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide

Step 1: Ethyl 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxoacetate

To a solution of ethyl 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate ¹⁴ (20.0 g, 102.97 mmol) dissolved in 200 ml of 1,4-dioxane was added selenium dioxide (22.85 g, 205.94 mmol, 2 eq.). The reaction mixture was stirred for 5 hours at 80°C. The reaction mixture was concentrated in vacuo to give a residue. The crude product was purified by flash chromatography on a silica gel column eluting with a gradient of petroleum ether:ethyl acetate 2:1 to ethyl acetate:ethanol 10:1 to give the desired ethyl 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxoacetate (quant, yield) as light brown oil, MS: m/e=209 ,1 (M+H ⁺ ).

Step 2: Ethyl 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-hydroxyiminoacetate

To a solution of ethyl 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxoacetate (Example 1, step 1) (17.5 g, 84.05 mmol) dissolved in 145 ml of ethanol was added hydroxylamine hydrochloride (6.42 g, 92.45 mmol, 1.1 eq.) and sodium acetate (13 .79 g, 168.1 mol, 2 eq.) at room temperature. The reaction mixture was stirred for 3.5 hours at 80°C. The reaction mixture was concentrated and extracted with water and five times with ethanol/THF/ethyl acetate 1:1:8. The organic layers were concentrated to dryness. The desired ethyl 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-hydroxyiminoacetate (15 g, 80% yield) was obtained as a yellow solid, MS: m/e=224.1 (M+H ⁺ ) and used directly in the next step.

Step 3: Ethyl-(2RS)-2-amino-2-(6,7-dihydro-5H-pyrrolo[1,2-c1imidazol-1-yl)acetate

Pd/C (30.0 g, 67.2 mmol, 1 eq., 10 %) at room temperature. The mixture was hydrogenated with H ₂ for 24 hours at 45°C. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The desired ethyl-(2RS)-2-amino-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate (quant, yield) was obtained as a brown oil, MS: m/e=210.1 (M+H ⁺ ) and used directly in the next step.

Stage 4: Ethyl-(2RS)-2-amino-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate hydrochloride

A solution of ethyl (2RS)-2-amino-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate (Example 1, step 3) (15.0 g, 82.79 mmol) in HCl/EtOH (300 ml, 1200 mmol, 14.5 eq., 2.5 mol/l) was stirred at 25°C within 36 hours. The reaction mixture was concentrated in vacuo below 25° C. to give a brown oil residue. 150 ml of acetonitrile was added to the residue and the precipitated yellow solid was collected and dried under vacuum at below 25°C to give the desired ethyl (2RS)-2-amino-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate hydrochloride (quant, yield) as a yellow solid, MS: m/e=210.1 ( M+H ⁺ ).

Step 5: Methyl 5-bromo-2-(bromomethyl)-3-fluorobenzoate

Methyl 5-bromo-3-fluoro-2-methylbenzoate ¹⁵ (5.91 g, 23.9 mmol) was dissolved in 100 ml of trifluorotoluene and N-bromosuccinimide (4.26 g, 23.9 mmol, 1 eq.) and AIBN (393 mg, 2.39 mmol, 0.1 eq.) were added at room temperature. The mixture was stirred at 110°C for 3 hours. The reaction mixture was cooled, extracted with water and twice with ethyl acetate. The organic layers were dried over sodium sulfate and concentrated to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with a gradient of 0:100 to 50:50 ethyl acetate:heptane to give the desired methyl 5-bromo-2-(bromomethyl)-3-fluorobenzoate (7.29 g, 94% yield) as a light yellow liquid, MS: m/e=326.8 (M+H ⁺ ).

Step 6: Ethyl-(2RS)-2-(6-bromo-4-fluoro-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate

Ethyl (2RS)-2-amino-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate hydrochloride (Example 1, Step 4) (4.15 g, 16.9 mmol, 1 eq) was dissolved in 35 ml DMF. Methyl 5-bromo-2-(bromomethyl)-3-fluorobenzoate (Example 1, step 5) (5.0 g, 15.3 mmol) and triethylamine (10.7 ml, 76.7 mmol, 5 eq.) were added at room temperature. The mixture was stirred at 80°C for 16 hours. The reaction mixture was extracted with water and twice with ethyl acetate. The organic layers were extracted with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with a dichloromethane:methanol gradient from 100:0 to 90:10 to give the desired ethyl (2RS)-2-(6-bromo-4-fluoro-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate (2, 6 g, 40% yield) as a yellow solid, MS: m/e=422.1/424.1 (M+H ⁺ ).

Step 7: Lithium (2RS)-2-(6-bromo-4-fluoro-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate

(2RS)-2-(6-Bromo-4-fluoro-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate (Example 1, step 6) (1.96 g, 4.64 mmol) was dissolved in 16 ml of ethanol. LiOH (1 M in water) (5.57 ml, 5.57 mmol, 1.2 eq.) was added at room temperature. The mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated in vacuo to give the desired crude (2RS)-2-(6-bromo-4-fluoro-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl) lithium acetate (1.92 g, quant.) as a light brown solid, MS: m/e=394.1/396.1 (M+H ⁺ ).

Step 8: (2RS)-2-(6-Bromo-4-fluoro-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide

Lithium ((2RS)-2-(6-Bromo-4-fluoro-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate (Example 1, step 7) (2.53 g, 6.32 mmol) was dissolved in 10 ml DMF. Thiazol-2-amine (760 mg, 7.59 mmol, 1.2 eq.), Hunig's base (5.5 ml, 31.6 mmol, 5 eq.) and HATU (2.89 g, 7.59 mmol, 1.2 eq.). The mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with water and twice with 9:1 dichloromethane:methanol. The organic layers were extracted with water, dried over sodium sulfate and conc. The crude product was purified by flash chromatography on a silica gel column eluting with a dichloromethane:methanol gradient from 100:0 to 80:20 to give the desired (2RS)-2-(6-bromo-4-fluoro-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N- thiazol-2-ylacetamide (1.8 g, 60% yield) as light brown solid, MS: m/e=476.1/478.1 (M+H⁺).

Step 9: (2RS)-2-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-6-[2-(4-formylphenyl)ethynyl]-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide

(2RS)-2-(6-Bromo-4-fluoro-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide (Example 1, step 8) (140 mg, 0.29 mmol) and 4-ethynylbenzaldehyde (49.7 mg, 0.382 mmol, 1.3 eq.) was dissolved in 12 ml of DMF. Triethylamine (89 mg, 0.123 ml, 0.882 mmol, 3 eq.), bis(triphenylphosphine)palladium(II) dichloride (10 mg, 0.015 mmol, 0.05 eq.), triphenylphosphine (8 mg, 0.03 mmol, 0.1 eq.) and copper(I) iodide (3 mg, 0.015 mmol) were added. , 0.05 eq.), and the mixture was stirred for 4 hours at 80°C. The reaction mixture was extracted with water and twice with ethyl acetate. The organic layers were extracted with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with a dichloromethane:methanol gradient from 100:0 to 90:10 to give the desired (2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-6-[2-(4-formylphenyl)ethynyl]-1-oxoisoindoline -2-yl]-N-thiazol-2-ylacetamide (130 mg, 86% yield) as yellow solid, MS: m/e=526.1 (M+H ⁺ ).

Step 10: (2RS)-2-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-6-[2-[4-[(4-methylpiperazin-1-yl)methyl1phenyl]ethynyl]-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide

(2RS)-2-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-6-[2-(4-formylphenyl)ethynyl]-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide (Example 1, step 9) (40 mg, 0.076 mmol) was dissolved in 1 ml dichloromethane . 1-methylpiperazine (11 mg, 0.114 mmol, 1.5 eq.) and sodium triacetoxyhydroborate (24 mg, 0.114 mmol, 1.5 eq.) were added at room temperature. The mixture was stirred at room temperature for 16 hours. The reaction mixture was extracted with water and twice with dichloromethane. The organic layers were extracted with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with a dichloromethane:methanol gradient from 100:0 to 85:15 to give the desired (2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-6-[2-[4-[(4-methylpiperazin-1-yl)methyl]phenyl] ethynyl]-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide (17 mg, 37% yield) as white solid, MS: m/e=610.4 (M+H ⁺ ).

Example 2

(2RS)-2-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-6-[2-[4-[(4-hydroxy-1-piperidyl)methyl]phenyl]ethynyl]-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide

The title compound was obtained as a white solid, MS: m/e=611.3 (M+H ⁺ ) using chemical reactions similar to those described in Example 1, step 10, starting from (2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-6-[2-(4-formylphenyl)ethynyl]-1-oxoisoindoline -2-yl]-N-thiazol-2-ylacetamide (Example 1, step 9) and piperidin-4-ol.

Example 3

(2RS)-2-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-1-oxo-6-(4-piperazin-1-ylphenyl)isoindolin-2-yl]-N-thiazol-2-ylacetamide Step 1: tert-Butyl-4-[4-[7-fluoro-3-oxo-2-[(1RS)- 1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-ethoxy-2-oxoethyl]isoindolin-5-yl]phenyl]piperazine-1-carboxylate

Ethyl (2RS)-2-(6-bromo-4-fluoro-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate (Example 1, step 6) (56 mg, 0.133 mmol) and (4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)boronic acid ¹⁶ (41 mg, 0.133 mmol, 1.0 eq.) was dissolved in 1.0 ml of 1,2-dimethoxyethane and 2 M aq. Na ₂ CO ₃ solution (0.199 ml, 0.398 mmol, 3.0 eq.). Tetrakis(triphenylphosphine)palladium (0) (15 mg, 0.0133 mmol, 0.1 eq.) was added and the reaction mixture was stirred at 80° C. for 4 hours. The reaction mixture was cooled to room temperature and then extracted with ethyl acetate and saturated NaHCO ₃ solution. The aqueous layer was back extracted with ethyl acetate. The organic layers were washed with water and saturated aqueous sodium chloride. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with an ethyl acetate:heptane gradient from 5:95 to 100:0. The desired tert-butyl 4-[4-[7-fluoro-3-oxo-2-[(1RS)-1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-ethoxy-2-oxoethyl]isoindolin-5-yl]phenyl]piperazin-1-carboxylate (48 mg, 60% yield) was obtained as light brown oil, MS: m/e=6 04.4 (M+H ⁺ ).

Stage 2: tert-Butyl-4-[4-[7-fluoro-3-oxo-2-[(1RS)-1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl]isoindolin-5-yl]phenyl]piperazin-1-carboxylate

tert-Butyl 4-[4-[7-fluoro-3-oxo-2-[(1RS)-1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-ethoxy-2-oxoethyl]isoindolin-5-yl]phenyl]piperazin-1-carboxylate (Example 3, step 1) (48 mg, 0.0795 mmol) was combined with 11 ml of ethanol, which gave a light yellow solution. LiOH (1 M in water) (0.0954 ml, 0.0954 mmol, 1.2 eq) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo. The residue was taken up in ethanol and concentrated in vacuo and then dissolved in 7 ml DMF. Thiazol-2-amine (9.55 mg, 0.0954 mmol, 1.2 eq.) and Hunig's base (0.0694 ml, 0.398 mmol, 5 eq.) were added, followed by HATU (36.3 mg, 0.0954 mmol, 1.2 eq.). The mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with ethyl acetate and saturated NaHCO ₃ solution. The aqueous layer was back extracted with ethyl acetate. The organic layers were washed with water and saturated aqueous sodium chloride. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with a dichloromethane:methanol gradient from 100:0 to 90:10 to give the desired tert-butyl-4-[4-[7-fluoro-3-oxo-2-[(1RS)-1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-( thiazol-2-ylamino)ethyl]isoindolin-5-yl]phenyl]piperazine-1-carboxylate (22 mg, 42% yield) as yellow oil, MS: m/e=658.3 (M+H ⁺ ).

Step 3: (27RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-1-oxo-6-(4-piperazin-1-ylphenyl)isoindolin-2-yl]-N-thiazol-2-ylacetamide

tert-Butyl 4-[4-[7-fluoro-3-oxo-2-[(1RS)-1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl]isoindolin-5-yl]phenyl]piperazin-1-carboxylate (Example 3, step 2) (26 mg, 0.0 395 mmol) [dissolved/suspended] in 0.5 ml dichloromethane and 0.25 ml methanol. HCl (4 M in dioxane) (0.099 ml, 0.395 mmol, 10 eq.) was added at room temperature and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was extracted with saturated NaHCO ₃ solution and twice with dichloromethane. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness. The desired (2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-1-oxo-6-(4-piperazin-1-ylphenyl)isoindolin-2-yl]-N-thiazol-2-ylacetamide (22 mg, 99.8% yield) was obtained as a light yellow oil, MS: m/e=558.2 (M +H ⁺ ).

Example 4

(2RS)-2-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[6-(4-ethylpiperazin-1-yl)-3-pyridyl]-4-fluoro-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide

Stage 1: tert-Butyl-4-[5-[7-fluoro-3-oxo-2-[(1RS)-1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-ethoxy-2-oxoethyl]isoindolin-5-yl]-2-pyridyl]piperazine-1-carboxylate

The title compound was obtained as a brown oil, MS: m/e=605.3 (M+H ⁺ ) using chemical transformations similar to those described in Example 3, step 1, starting from ethyl-(2RS)-2-(6-bromo-4-fluoro-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate (When mer 1, step 6) and (6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-3-yl)boronic acid ¹⁷ .

Stage 2: tert-Butyl-4-[5-[7-fluoro-3-oxo-2-[(1RS)-1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl]isoindolin-5-yl]-2-pyridyl]piperazine-1-carboxylate

The title compound was obtained as a yellow oil, MS: m/e=659.1 (M+H ⁺ ) using chemical transformations similar to those described in Example 3, step 2, starting from tert-butyl-4-[5-[7-fluoro-3-oxo-2-[(1RS)-1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-ethoxy-2-oxo -ethyl]isoindolin-5-yl]-2-pyridyl]piperazine-1-carboxylate (Example 4, step 1) and thiazole-2-amine.

Step 3: (2RS)-2-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-1-oxo-6-(6-piperazin-1-yl-3-pyridyl)isoindolin-2-yl]-N-thiazol-2-ylacetamide

The title compound was obtained as a light brown solid, MS: m/e=559.1 (M+H ⁺ ) using chemical transformations similar to those described in Example 3, step 3, starting from tert-butyl-4-[5-[7-fluoro-3-oxo-2-[(1RS)-1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo- 2-(thiazol-2-ylamino)ethyl]isoindolin-5-yl]-2-pyridyl]piperazine-1-carboxylate (Example 4, step 2).

Step 4: (2RS)-2-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[6-(4-ethylpiperazin-1-yl)-3-pyridyl]-4-fluoro-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide

(2RS)-2-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-1-oxo-6-(6-piperazin-1-yl-3-pyridyl)isoindolin-2-yl]-N-thiazol-2-ylacetamide (Example 4, step 3) (45 mg, 0.0806 mmol) was dissolved in 1, 0 ml DMF. Ethyl iodide (13.8 mg, 7.16 μl, 0.0886 mmol, 1.1 eq.) and Hunig's base (41.6 mg, 56.3 μl, 0.322 mmol, 4 eq.) were added at room temperature. The reaction mixture was stirred at 60°C for 1 hour. The reaction mixture was cooled to room temperature and then extracted with ethyl acetate and water. The aqueous layer was back extracted with ethyl acetate. The organic layers were washed with saturated aqueous sodium chloride. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with a gradient of dichloromethane:methanol from 100:0 to 85:15 to give the desired 1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide (24 mg, 51% yield) as light yellow solid, MS: m/e=587.3 (M+H ⁺ ).

Example 5

(2RS)-2-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[4-(4-ethylpiperazin-1-yl)phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide

The title compound was obtained as a light yellow solid, MS: m/e=586.3 (M+H ⁺ ) using chemical reactions similar to those described in Example 4, step 4, starting from (2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-1-oxo-6-(4-piperazin-1-ylphenyl)isoindoline -2-yl]-N-thiazol-2-ylacetamide (Example 3, step 3) and ethyl iodide.

Example 6

(2RS)-2-[4-Chloro-6-[4-(4-ethylpiperazin-1-yl)phenyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide

Step 1: Methyl 5-bromo-2-(bromomethyl)-3-chlorobenzoate

The title compound was obtained as a colorless solid, MS: m/e=343.4 (M+H ⁺ ), using chemical transformations similar to those described in Example 1, step 5, starting from methyl 5-bromo-3-chloro-2-methylbenzoate ¹⁸ .

Step 2: Ethyl-(2RS)-2-(6-bromo-4-chloro-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate

The title compound was obtained as a red amorphous substance, MS: m/e=438.0/440.0 (M+H ⁺ ) using chemical transformations similar to those described in Example 1, step 6, starting from ethyl-(2RS)-2-amino-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate (Example 1, step 3) and methyl-5 -bromo-2-(bromomethyl)-3-chlorobenzoate (Example 6, step 1).

Stage 3: Ethyl-(2RS)-2-[4-chloro-6-[4-(4-ethylpiperazin-1-yl)phenyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate

The title compound was obtained as a yellowish white amorphous substance, MS: m/e=548.3 (M+H ⁺ ) using chemical transformations similar to those described in Example 3, step 1, starting from ethyl-(2RS)-2-(6-bromo-4-chloro-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-1- yl)acetate (Example 6, step 2) and 1-ethyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine ¹⁹ .

Step 4: (2RS)-2-[4-Chloro-6-[4-(4-ethylpiperazin-1-yl)phenyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide

The title compound was obtained as a light yellow solid, MS: m/e=602.2 (M+H ⁺ ), using chemical transformations similar to those described in Example 3, step 2, starting from ethyl-(2RS)-2-[4-chloro-6-[4-(4-ethylpiperazin-1-yl)phenyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-yl)acetate (Example 6, step 3) and thiazol-2-amine.

Example 7

(2RS)-2-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-6-[4-(4-hydroxy-1-piperidyl)phenyl]-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide

Step 1: Ethyl-(2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-6-[4-(4-hydroxy-1-piperidyl)phenyl]-1-oxoisoindolin-2-yl]acetate

The title compound was obtained as a yellow solid, MS: m/e=519.2 (M+H ⁺ ) using chemical transformations similar to those described in Example 3, step 1, starting from ethyl-(2RS)-2-(6-bromo-4-fluoro-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate ( Example 1, step 6) and 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidin-4-ol ²⁰ .

Step 2: (2RS)-2-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-6-[4-(4-hydroxy-1-piperidyl)phenyl]-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide

The title compound was obtained as a light brown solid, MS: m/e=573.1 (M+H ⁺ ) using chemical transformations similar to those described in Example 3, step 2, starting from ethyl-(2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-6-[4-(4-hydroxy-1-piperidyl)phenyl] -1-oxoisoindolin-2-yl]acetate (Example 7, step 1) and thiazol-2-amine.

Example 8

(2RS)-2-[4-Chloro-6-[6-(4-hydroxy-1-piperidyl)-3-pyridyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide

Step 1: (2RS)-2-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-6-[6-(4-hydroxy-1-piperidyl)-3-pyridyl]-1-oxoisoindolin-2-yl]acetic acid

The title compound was obtained as a dark gray solid, MS: m/e=508.3/510.3 (M+H ⁺ ), using chemical transformations similar to those described in Example 3, step 1, starting from ethyl-(2RS)-2-(6-bromo-4-fluoro-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazole- 1-yl)acetate (Example 1, step 6) and (6-(4-hydroxypiperidin-1-yl)pyridin-3-yl)boronic acid by isolating the corresponding acid formed.

Step 2: (2RS)-2-[4-Chloro-6-[6-(4-hydroxy-1-piperidyl)-3-pyridyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide

The title compound was obtained as a light brown solid, MS: m/e=590.1/592.1 (M+H ⁺ ), using chemical transformations similar to those described in Example 1, step 8, starting from (2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-6-[6-(4-hydroxy-1-piperidyl )-3-pyridyl]-1-oxoisoindolin-2-yl]-acetic acid (Example 8, step 1) and thiazol-2-amine.

Example 9

(2RS)-2-[4-Chloro-6-[2-[4-[(4-hydroxy-1-piperidyl)methyl]phenyl]ethynyl]-1-oxoisoindolin-2-yl]-2-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide

Step 1: 1-[(4-Ethynylphenyl)methyl]piperidin-4-ol

The title compound was obtained as a yellow solid, MS: m/e=216.2 (M+H ⁺ ), using chemical transformations similar to those described in Example 1, step 10, starting from 4-ethynylbenzaldehyde and piperidin-4-ol.

Step 2: Methyl 3-chloro-5-iodo-2-methylbenzoate

3-Chloro-5-iodo-2-methylbenzoic acid ²¹ (1 g, 3.37 mmol) was dissolved in 20 ml of methanol and sulfuric acid (33.1 mg, 0.018 ml, 0.337 mmol, 0.1 eq.) was added at room temperature. The mixture was stirred at 70°C for 4 hours. Sulfuric acid (0.18 ml, 3.37 mmol, 1.0 eq.) was added and the mixture was stirred at 80° C. for 16 hours. The reaction mixture was concentrated to a volume of ~5 ml, and then was extracted with ethyl acetate and saturated NaHCO ₃ solution. The aqueous layer was back extracted with ethyl acetate. The organic layers were washed with water. The organic layers were combined, dried over sodium sulfate, filtered and concentrated on Isolute® to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with an ethyl acetate:heptane gradient from 0:100 to 50:50. The desired methyl 3-chloro-5-iodo-2-methylbenzoate (941 mg, 90% yield) was obtained as a white solid, MS: m/e=309.1 (M-H ^- ).

Step 3: Methyl 2-(bromomethyl)-3-chloro-5-iodobenzoate

The title compound was obtained as a white solid, MS: m/e=388.4 (M-H ^- ), using chemical transformations similar to those described in Example 1, step 5, starting from methyl 3-chloro-5-iodo-2-methylbenzoate (Example 9, step 2).

Step 4: Ethyl-(2RS)-2-(4-chloro-6-iodo-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate

The title compound was obtained as a dark brown semi-solid, MS: m/e=486.1/488.0 (M+H ⁺ ), using chemical transformations similar to those described in Example 1, step 6, starting from ethyl-(2RS)-2-amino-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate hydrochloride (Example 1, step 4 ) and methyl 2-(bromomethyl)-3-chloro-5-iodobenzoate (Example 9, step 3).

Stage 5: Ethyl-(2RS)-2-[4-chloro-6-[2-[4-[(4-hydroxy-1-piperidyl)methyl]Phenyl]ethynyl]-1-oxoisoindolin-2-yl1-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate

The title compound was obtained as a yellow solid, MS: m/e=573.2/575.2 (M+H ⁺ ), using chemical transformations similar to those described in Example 1, step 9, starting from ethyl-(2RS)-2-(4-chloro-6-iodo-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-1 -yl)acetate (Example 9, step 4) and 1-[(4-ethynylphenyl)methyl]piperidin-4-ol (Example 9, step 1).

Step 6: (2RS)-2-[4-Chloro-6-[2-[4-[(4-hydroxy-1-piperidyl)methyl]phenyl]ethynyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide

The title compound was obtained as a light yellow solid, MS: m/e=627.5/629.5 (M+H ⁺ ), using chemical transformations similar to those described in Example 3, step 2, starting from ethyl-(2RS)-2-[4-chloro-6-[2-[4-[(4-hydroxy-1-piperidyl)methyl]phenyl]ethynyl]-1-oxoisoindolin-2-yl]-2 -(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate (Example 9, step 5) and thiazol-2-amine.

Example 10

(2RS)-2-(6,7-Dihydro-5H-pyrrolisin-1-yl)-2-[4-fluoro-6-[2-[4-[(4-hydroxy-1-piperidyl)methyl]phenyl]ethynyl]-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide

Step 1: Methyl 5-bromo-3-fluoro-2-(3,5,7-triaza-1-azoniumtricyclo[3.3.1.13.7]decan-1-ylmethyl)benzoate bromide

Methyl 5-bromo-2-(bromomethyl)-3-fluorobenzoate (Example 1, step 4) (300 mg, 0.920 mmol) was dissolved in 5 ml of chloroform and 1,3,5,7-tetraazatricyclo[3.3.1.13.7]decane (135 mg, 0.966 mmol, 1.05 eq.) was added at room temperature. The reaction mixture was stirred at 70°C for 2 hours. The resulting suspension was filtered and washed twice with dichloromethane. The filter cake was dried to give the desired methyl 5-bromo-3-fluoro-2-(3,5,7-triaza-1-azoniumtricyclo[3.3.1.13.7]decan-1-ylmethyl)benzoate bromide (369 mg, 86% yield) as a white solid, MS: m/e=385.2/387.2 (M+H ⁺ ).

Step 2: Methyl 2-(aminomethyl)-5-bromo-3-fluorobenzoate hydrochloride

Methyl 5-bromo-3-fluoro-2-(3,5,7-triaza-1-azoniumtricyclo[3.3.1.13,7]decan-1-ylmethyl)benzoate bromide (Example 10, step 1) (369 mg, 0.792 mmol) was suspended in 5 ml of methanol and HCl (25% in water) (0.618 ml, 4.7 5 mmol, 6 eq.). The reaction mixture was stirred at 75°C for 2 hours. The reaction mixture was concentrated to dryness and used without further purification. The desired methyl 2-(aminomethyl)-5-bromo-3-fluorobenzoate hydrochloride (393 mg, quantitatively, 60% pure) was obtained as a white solid, MS: m/e=262.1 (M-H ^- ). Step 3: (2RS)-2-(6-Bromo-4-fluoro-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolisin-1-yl)acetonitrile

A mixture of 6,7-dihydro-5H-pyrrolizine-1-carbaldehyde ²² (100 mg, 0.740 mmol), methyl 2-(aminomethyl)-5-bromo-3-fluorobenzoate hydrochloride (Example 10, step 2) (379 mg, 0.888 mmol, purity=70%, 1.2 eq.) in 3.0 ml of acetonitrile was stirred at 70°C for 16 hours. Trimethylsilyl cyanide (89.9 mg, 0.113 ml, 0.888 mmol, 1.2 eq.) was added at room temperature and the reaction mixture was stirred at 70° C. for 2 hours. Hunig's base (191 mg, 0.258 ml, 1.48 mmol, 2.0 eq.) was added at room temperature and the reaction mixture was stirred at 70° C. for 4 hours. The reaction mixture was extracted with saturated NaHCO ₃ solution and twice with ethyl acetate. The organic layers were washed with water and saturated aqueous sodium chloride, dried over sodium sulfate and concentrated to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with a 0:100 to 100:0 ethyl acetate:heptane gradient to give the desired (2RS)-2-(6-bromo-4-fluoro-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolisin-1-yl)acetonitrile (70 mg, 25% yield) in as a yellow solid, MS: m/e=374.0/375.9 (M+H ⁺ ).

Step 4: (2RS)-2-(6-Bromo-4-fluoro-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolisin-1-yl)acetate sodium

(2RS)-2-(6-Bromo-4-fluoro-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolisin-1-yl)acetonitrile (Example 10, step 3) (110 mg, 0.294 mmol) was dissolved in 1.0 ml of ethanol. NaOH (2 M in water) (0.294 ml, 0.588 mmol, 2 eq) was added at room temperature. The mixture was stirred at 85°C for 16 hours. The reaction mixture was cooled to room temperature and then concentrated to dryness. The desired (2RS)-2-(6-bromo-4-fluoro-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolisin-1-yl)acetate sodium (165 mg, 95% yield, 70% purity) was obtained as a yellow solid, MS: m/e=393.0/395.0 (M+H ⁺ ) and used in the next step without further purification. Step 5: (2RS)-2-(6-Bromo-4-fluoro-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolisin-1-yl)-N-thiazol-2-ylacetamide

The title compound was obtained as a light brown solid, MS: m/e=474.9/476.9 (M+H ⁺ ), using chemical transformations similar to those described in Example 1, step 7, starting from (2RS)-2-(6-bromo-4-fluoro-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolisin-1-yl) sodium acetate (Example 10, step 4) and thiazol-2-amine.

Step 6: (2RS)-2-(6,7-Dihydro-5H-pyrrolisin-1-yl)-2-[4-fluoro-6-[2-[4-[(4-hydroxy-1-piperidyl)methyl]phenyl]ethynyl]-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide

The title compound was obtained as a yellow solid, MS: m/e=610.4 (M+H ⁺ ), using chemical transformations similar to those described in Example 1, step 9, starting from (2RS)-2-(6-bromo-4-fluoro-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolisin-1-yl)-N-thiazol-2-ylacetamide (When mer 10, step 5) and 1-[(4-ethynylphenyl)methyl]piperidin-4-ol (Example 9, step 1).

Example 11

(2RS)-2-[4-Chloro-6-[4-(4-hydroxy-1-piperidyl)phenyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide

Step 1: Ethyl-(2RS)-2-[4-chloro-6-[4-(4-hydroxy-1-piperidyl)phenyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate

The title compound was obtained as a brown solid, MS: m/e=535.2/537.2 (M+H ⁺ ) using chemical transformations similar to those described in Example 3, step 1, starting from ethyl-(2RS)-2-(4-chloro-6-iodo-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazole 1-yl)acetate (Example 9, step 4) and 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidin-4-ol ²⁰ .

Step 2: (2RS)-2-[4-Chloro-6-[4-(4-hydroxy-1-piperidyl)phenyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide

The title compound was obtained as a white solid, MS: m/e=589.2/591.2 (M+H ⁺ ), using chemical transformations similar to those described in Example 3, step 2, starting from ethyl-(2RS)-2-[4-chloro-6-[4-(4-hydroxy-1-piperidyl)phenyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyr rolo[1,2-c]imidazol-1-yl)acetate (Example 11, step 1) and thiazol-2-amine.

Example 12

(2RS)-2-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-6-[2-[4-(hydroxymethyl)phenyl]ethynyl]-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide

The title compound was obtained as a light yellow solid, MS: m/e=526.1 (M+H ⁺ ), using chemical transformations similar to those described in Example 1, step 9, starting from (2RS)-2-(6-bromo-4-fluoro-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-ti azol-2-ylacetamide (Example 1, step 8) and (4-ethynylphenyl)methanol.

Example 13

(2RS)-2-[7-Chloro-4-fluoro-6-[2-[4-[(4-hydroxy-1-piperidyl)methyl]phenyl]ethynyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide

Stage 1: 2-Chloro-3-iodo-6-methyl-5-nitrobenzoic acid

6-Chloro-2-methyl-3-nitrobenzoic acid ²³ (3.8 g, 15.9 mmol) was dissolved in 18 ml of sulfuric acid. 1,3-diiodo-5,5-dimethylimidazolidine-2,4-dione (6.9 g, 18.2 mmol, 1.15 eq) was added at room temperature. The mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water and the resulting precipitate was filtered off. The solid was dried to give the desired 2-chloro-3-iodo-6-methyl-5-nitrobenzoic acid (5.37 g, quant, yield) as a brown foam, MS: m/e=339.8/341.7 (M+H ⁺ ).

Step 2: Methyl 2-chloro-3-iodo-6-methyl-5-nitrobenzoate

2-Chloro-3-iodo-6-methyl-5-nitrobenzoic acid (Example 13, step 1) (5.37 g, 14.2 mmol) was dissolved in 25 ml of DMF. Potassium carbonate (3.9 g, 28.3 mmol, 2 eq.) and iodomethane (2.1 g, 14.9 mmol, 1.05 eq.) were added at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with saturated sodium hydrogen carbonate solution and twice with ethyl acetate. The organic layers were extracted with water and 10% lithium chloride solution. The organic layers were combined, dried over sodium sulfate and concentrated to dryness. Неочищенный продукт очищали флэш-хроматографией на колонке с силикагелем, элюируя градиентом гептан:этилацетат от 100:0 до 60:40, чтобы получить необходимый метил-2-хлор-3-йод-6-метил-5-нитробензоат (2,89 г, выход 57%) в виде светло-желтого твердого вещества, МС: m/е=353,9/355,9 (М+Н ⁺ ).

Step 3: Methyl 3-amino-6-chloro-5-iodo-2-methylbenzoate

Methyl 2-chloro-3-iodo-6-methyl-5-nitrobenzoate (Example 13, step 2) (2.89 g, 8.13 mmol) was dissolved in 30 ml of methanol and 15 ml of water. Ammonium chloride (4.35 g, 81.3 mmol, 10 eq.) and iron (2.72 g, 48.8 mmol, 6 eq.) were added at room temperature. The mixture was stirred at 70°C for 16 hours. The reaction mixture was filtered and evaporated to dryness. The residue was extracted with saturated sodium hydrogen carbonate solution and twice with ethyl acetate. The organic layers were extracted with water and saturated aqueous sodium chloride. The organic layers were combined, dried over sodium sulfate and concentrated to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with a gradient of 100:0 to 30:70 ethyl acetate:heptane to give the desired methyl 3-amino-6-chloro-5-iodo-2-methylbenzoate (1.9 g, 72% yield) as an orange oil, MS: m/e=324.9/326.9 (M+H ⁺ ).

Stage 4: Methyl 2-chloro-5-fluoro-3-iodo-6-methylbenzoate (696 mg, 2.12 mmol, 49.1% yield)

Methyl 3-amino-6-chloro-5-iodo-2-methylbenzoate (Example 13, step 3) (1.4 g, 4.3 mmol) was dissolved in 10 ml of dioxane. Nitrosonium tetrafluoroborate (0.55 g, 4.74 mmol, 1.1 eq.) was added portionwise while cooling on ice at room temperature. The mixture was stirred at room temperature for 30 minutes and at 110°C for 90 minutes. The reaction mixture was poured into water and extracted twice with ethyl acetate. The organic layers were extracted with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with a gradient of heptane:ethyl acetate from 100:0 to 75:25 to give the desired methyl 2-chloro-5-fluoro-3-iodo-6-methylbenzoate (696 mg, 49% yield) as a colorless oil, MS: m/e=327.1/329.1 (M-H ⁺ ).

Step 5: Methyl 2-(bromomethyl)-6-chloro-3-fluoro-5-iodobenzoate

The title compound was obtained as a colorless solid, MS: m/e=409.0 (M+H ⁺ ), using chemical transformations similar to those described in Example 1, step 5, starting from methyl 2-chloro-5-fluoro-3-iodo-6-methylbenzoate (Example 13, step 4).

Step 6: Ethyl-(2RS)-2-(7-chloro-4-fluoro-6-iodo-1-oxoisoindolin-2-yl)-2-(b,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate

The title compound was obtained as a brown solid, MS: m/e=504.1/506.1 (M+H ⁺ ), using chemical transformations similar to those described in Example 1, step 6, starting from ethyl-(2RS)-2-amino-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate hydrochloride (Example 1, step 4) and methyl 2-(bromomethyl)-6-chloro-3-fluoro-5-iodobenzoate (Example 13, step 5).

Step 7: (2RS)-2-(7-Chloro-4-fluoro-6-iodo-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide

The title compound was obtained as a light yellow solid, MS: m/e=558.1/560.1 (M+H ⁺ ), using chemical transformations similar to those described in Example 3, step 2, starting from ethyl-(2RS)-2-(7-chloro-4-fluoro-6-iodo-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c ]imidazol-1-yl)acetate (Example 13, step 6) and thiazol-2-amine.

Step 8: (2RS)-2-[7-Chloro-4-fluoro-6-[2-[4-[(4-hydroxy-1-piperidyl)methyl]Phenyl]ethynyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide

The title compound was obtained as a light brown solid, MS: m/e=645.3/647.3 (M+H ⁺ ), using chemical transformations similar to those described in Example 1, step 9, starting from (2RS)-2-(7-chloro-4-fluoro-6-iodo-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imide zol-1-yl)-N-thiazol-2-ylacetamide (Example 13, step 7) and 1-[(4-ethynylphenyl)methyl]piperidin-4-ol (Example 9, step 1).

Example 14

(2RS)-2-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-1-oxo-6-[2-[4-(1-piperidylmethyl)phenyl]ethynyl]isoindolin-2-yl]-N-thiazol-2-ylacetamide

The title compound was obtained as a light yellow semi-solid, MS: m/e=595.4 (M+H ⁺ ), using chemical reactions similar to those described in Example 1, step 10, starting from (2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-6-[2-(4-formylphenyl)ethynyl]-1-oc soisoindolin-2-yl]-N-thiazol-2-ylacetamide (Example 1, step 9) and piperidine.

Example 15

(2RS)-2-[4-Chloro-1-oxo-6-[2-[4-(1-piperidylmethyl)phenyl]ethynyl]isoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide

Step 1: (2RS)-2-(4-Chloro-6-iodo-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide

The title compound was obtained as a yellow foam, MS: m/e=540.1/542.1 (M+H ⁺ ), using chemical transformations similar to those described in Example 3, step 2, starting from ethyl-(2RS)-2-(4-chloro-6-iodo-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-1- yl)acetate (Example 9, step 4) and thiazol-2-amine.

Step 2: (2RS)-2-[4-Chloro-6-[2-(4-formylphenyl)ethynyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide

The title compound was obtained as a yellow foam, MS: m/e=542.3/544.3 (M+H ⁺ ), using chemical transformations similar to those described in Example 1, step 9, starting from (2RS)-2-(4-chloro-6-iodo-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)- N-thiazol-2-ylacetamide (Example 15, step 1) and 4-ethynylbenzaldehyde.

Step 3: (2RS)-2-[4-Chloro-1-oxo-6-[2-[4-(1-piperidylmethyl)phenyl]ethynyl]isoindolin-2-yl-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide

The title compound was obtained as a light yellow solid, MS: m/e=611.5/613.5 (M+H ⁺ ), using chemical transformations similar to those described in Example 1, step 10, starting from (2RS)-2-[4-chloro-6-[2-(4-formylphenyl)ethynyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo [1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide (Example 15, step 2) and piperidine.

Example 16

(2RS)-2-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[4-(1-ethyl-4-piperidyl)phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide

Stage 1: tert-Butyl-4-[4-[2-[(1RS)-1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl]-7-fluoro-3-oxoisoindolin-5-yl]phenyl]piperidine-1-carboxylate

The title compound was obtained as a brown solid, MS: m/e=657.5 (M+H ⁺ ), using chemical transformations similar to those described in Example 3, step 1, starting from (2RS)-2-(6-bromo-4-fluoro-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolisin-1-yl)-N-thiazol-2-ylacetamide ( Example 10, step 5) and (4-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)boronic acid.

Step 2: (2RS)-2-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-1-oxo-6-[4-(4-piperidyl)phenyl]isoindolin-2-yl]-N-thiazol-2-ylacetamide hydrochloride

The title compound was obtained as a yellow solid, MS: m/e=557.4 (M+H ⁺ ) using chemical transformations similar to those described in Example 3, step 3, starting from tert-butyl-4-[4-[2-[(1RS)-1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylami no)ethyl]-7-fluoro-3-oxoisoindolin-5-yl]phenyl]piperidine-1-carboxylate (Example 16, step 1).

Step 3: (2RS)-2-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[4-(1-ethyl-4-piperidyl)phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide

The title compound was obtained as a white solid, MS: m/e=585.4 (M+H ⁺ ) using chemical reactions similar to those described in Example 4, step 4, starting from (2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-1-oxo-6-[4-(4-piperidyl)phenyl]isoindoline-2 -yl]-N-thiazol-2-ylacetamide hydrochloride (Example 16, step 2) and ethyl iodide.

Example 17

(2RS)-2-[(6R)-6-Fluoro-6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-2-[4-fluoro-6-[2-[4-[(4-hydroxy-1-piperidyl)methyl]phenyl]ethynyl]-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide

Step 1: tert-Butyl-(2RS,4R)-2-(2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-carbonyl)-4-fluoropyrrolidine-1-carboxylate

To a solution of (2S,4R)-1-tert-butoxycarbonyl-4-fluoropyrrolidine-2-carboxylic acid (450.0 g, 1.93 mol, 1.00 eq.) and 2,2-dimethyl-1,3-dioxane-4,6-dione (278.0 g, 1.93 mol, 1.00 eq.) in dichloromethane (3.00 l) DMAP (471.4 g, 3.86 mol, 2.00 eq.) was added and the mixture was cooled to 0°C. DCC (398.0 g, 1.93 mol, 390.3 ml, 1.00 eq.) was added in several portions and the reaction mixture was stirred at 25°C for 12 hours. The reaction mixture was filtered and then the filtrate was washed with 1 M HCl (2.00 L), after which the organic layer was concentrated in vacuo to give the desired product (1.20 kg, 3.34 mol, 86.5% yield) as a yellow solid, which was used directly in the next step.

Step 2: tert-Butyl-(2RS,4R)-2-(3-ethoxy-3-oxopropanoyl)-4-fluoropyrrolidine-1-carboxylate

A mixture of tert-butyl-(2RS,4R)-2-(2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-carbonyl)-4-fluoropyrrolidine-1-carboxylate (Example 17, Step 1) (650.0 g, 1.81 mol, 1.00 eq.) in EtOH (2.00 L) was stirred at 95°C for 12 o'clock. The reaction mixture was concentrated under reduced pressure to give the desired product as a light yellow oil (1.00 kg, 3.30 mol, 91.1% yield), which was used directly in the next step.

Stage 3: Ethyl 3-[(2RS,4R)-4-fluoropyrrolidin-2-yl1-3-oxopropanoate hydrochloride

A mixture of tert-butyl-(2RS,4R)-2-(3-ethoxy-3-oxopropanoyl)-4-fluoropyrrolidine-1-carboxylate (320.0 g, 1.05 mol, 1.00 eq) and HCl/EtOAc (4.00 M, 800.0 ml, 3.03 eq) was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to give the desired product (603.0 g, 2.97 mol, 93.8% yield) as a red oil which was used directly for the next reaction without further purification.

Step 4: Ethyl 2-[(6R)-6-fluoro-3-thioxo-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazol-1-yl]acetate

KSCN (89.20 g, 917.9 mmol, 89.2 ml, 1.10 eq.) and the mixture was heated to 90° C. and stirred for 12 hours. The mixture was concentrated in vacuo to give a crude solid. The crude solid was washed with EtOAc (5.00 L) and H ₂ O (3.00 L) and concentrated in vacuo to give compound 5 (555.0 g, 2.27 mol, 90.7% yield) as a white solid.

Step 5: Ethyl 2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate

H ₂ O ₂ (529.1 g, 4.67 mol, 44 8.4 ml, 30% purity, 4.00 eq.) at 0-25°C. The reaction mixture was stirred at 25°C for 30 minutes. The reaction mixture was diluted with water (4.00 l), and then brought to pH=9 by adding solid NaHCO ₃ at 0°C. The mixture was extracted six times with DCM (1.00 L each). The combined organic layers were washed with saturated NaCl solution (3.00 L) and the combined organic layers were washed three times with saturated Na ₂ S ₂ O ₃ solution (2.00 L each). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the desired product (156.0 g, crude) as a brown oil.

Step 6: Ethyl 2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-2-oxoacetate

SeO ₂ (44.2 g, 398.6 mmol, 43.3 ml, 2.00 eq.), and the mixture was heated to 80°C and stirred for 2 hours. Silica gel was added to the mixture and concentrated to give a residue which was purified by silica gel chromatography using pure EtOAc to give the desired product (54.0 g, 238.7 mmol, 59.8% yield) as a black-brown oil.

Step 7: Ethyl 2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-2-hydroxyiminoacetate

To a solution of ethyl 2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-2-oxoacetate (18.6 g, 82.2 mmol, 1.00 eq.) in EtOH (90.0 ml) was added NaOAc (13.5 g, 164.5 mmol, 2.00 eq.) and NH ₂ OHHCl (6.30 g, 90.5 mmol, 1.10 eq.) The reaction mixture was stirred at 80° C. for 2 hours. The mixture was cooled to 25°C and filtered, then concentrated to give a residue which was diluted with EtOAc:EtOH (20:1) (300.0 ml) and washed with water (200.0 ml) and saturated NaCl solution (200.0 ml), dried with anhydrous Na ₂ SO ₄ to give the desired product (18.0 g, 74.6 mmol, 90.8% yield) in as a black-brown oil, which was used directly without further purification.

Step 8: Ethyl-(2RS)-2-amino-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate

A solution of ethyl 2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-2-hydroxyiminoacetate (18.0 g, 70.9 mmol, 1.00 eq.) and Pd/C (36.0 g, 10% purity) in THF (90.0 ml) and EtOH (180.0 ml) was stirred at 50°C for 16 hours under H ₂ (15.0 psi). The mixture was filtered and the filter cake washed with EtOAc. The filtrate was concentrated to give the desired product (11.0 g, 43.3 mmol, 61.1% yield, 89.5% purity) as a green oil.

Stage 9: Ethyl-(2RS)-2-(6-bromo-4-fluoro-1-oxoisoindolin-2-yl)-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate

The title compound was obtained as a dark brown oil, MS: m/e=442.0 (M+H ⁺ ), using chemical transformations similar to those described in Example 1, step 6, starting from ethyl-(2RS)-2-amino-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate (Example 17, step 8) and methyl 5-bromo-2-(bromomethyl)-3-fluorobenzoate (Example 1, step 5).

Step 10: (2RS)-2-(6-Bromo-4-fluoro-1-oxoisoindolin-2-yl)-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide

The title compound was obtained as a dark brown solid, MS: m/e=494.2/496.2 (M+H ⁺ ), using chemical transformations similar to those described in Example 3, step 2, starting from ethyl-(2RS)-2-(6-bromo-4-fluoro-1-oxoisoindolin-2-yl)-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-yl]acetate (Example 17, step 9) and thiazol-2-amine.

Step 11: (2RS)-2-[(6R)-6-Fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-2-[4-fluoro-6-[2-[4-[(4-hydroxy-1-piperidyl)methyl]phenyl]ethynyl]-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide

The title compound was obtained as a white solid, MS: m/e = 627.5 (M+H ⁺ ), using chemical transformations similar to those described in Example 1, step 9, starting from (2RS)-2-(6-bromo-4-fluoro-1-oxoisoindolin-2-yl)-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-1 -yl]-N-thiazol-2-ylacetamide (Example 17, step 10) and 1-[(4-ethynylphenyl)methyl]piperidin-4-ol (Example 9, step 1).

Example 18

(2RS)-2-[6-[3-Chloro-4-(4-ethylpiperazin-1-yl)phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide

Step 1: Ethyl-(2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-b-iodo-1-oxoisoindolin-2-yl)acetate

The title compound was obtained as a white solid using chemical transformations similar to those described in Example 1, steps 5 and 6, starting from ethyl (2RS)-2-amino-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate hydrochloride (Example 1, step 4) and methyl 5-iodo-3-fluoro-2-methylbenzoate instead of methyl 5-bromo- 3-fluoro-2-methylbenzoate.

Stage 2: tert-Butyl-4-[2-chloro-4-[2-[(1RS)-1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-ethoxy-2-oxoethyl]-7-fluoro-3-oxoisoindolin-5-yl]phenyl]piperazine-1-carboxylate

Ethyl (2RS)-2-(6-iodo-4-fluoro-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate (Example 18, step 1) (400 mg, 0.85 mmol) and (4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-chlorophenyl) boronic acid (348 mg, 1.02 mmol, 1.2 eq.) was dissolved in toluene. Cesium carbonate (830 mg, 2.56 mmol, 3.0 eq.) and PdCl ₂ (DPPF)-CH ₂ Cl ₂ adduct (62 mg, 0.085 mmol, 0.1 eq.) were added and the reaction mixture was stirred at 100°C for 1 hour. The reaction mixture was cooled to room temperature and then extracted with ethyl acetate and saturated NaHCO ₃ solution. The aqueous layer was back extracted with ethyl acetate. The organic layers were washed with water and saturated aqueous sodium chloride. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with a dichloromethane:methanol gradient from 100:0 to 90:10. The desired tert-butyl 4-[2-chloro-4-[2-[(1RS)-1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-ethoxy-2-ocoethyl]-7-fluoro-3-oxoisoindolin-5-yl]phenyl]piperazin-1-carboxylate (580 mg, 96% yield) was obtained as light brown oil, MS: m /e = 638.3/640.3 (M + H ⁺ ).

Stage 3: tert-Butyl-4-[2-chloro-4-[2-[(1RS)-1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl]-7-fluoro-3-oxoisoindolin-5-yl]phenyl]piperazin-1-carboxylate

The title compound was obtained as a light brown oil, MS: m/e = 692.3/694.3 (M+H ⁺ ), using chemical transformations similar to those described in Example 3, step 2, starting from tert-butyl-4-[2-chloro-4-[2-[(1S)-1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-ethoxy- 2-oxoethyl]-7-fluoro-3-oxoisoindolin-5-yl]phenyl]piperazine-1-carboxylate (Example 18, step 2) and thiazol-2-amine.

Step 4: (2RS)-2-[6-(3-Chloro-4-piperazin-1-ylphenyl)-4-fluoro-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide

The title compound was obtained as a white solid, MS: m/e = 592.4/594.3 (M+H ⁺ ), using chemical transformations similar to those described in Example 4, step 3, starting from tert-butyl-4-[2-chloro-4-[2-[(1RS)-1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2 -(thiazol-2-ylamino)ethyl]-7-fluoro-3-oxoisoindolin-5-yl]phenyl]piperazin-1-carboxylate (Example 18, step 3).

Step 5: (2RS)-2-[6-[3-Chloro-4-(4-ethylpiperazin-1-yl)phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide

The title compound was obtained as a light yellow solid, MS: m/e = 620.4/622.4 (M+H ⁺ ), using chemical transformations similar to those described in Example 4, step 4, starting from (2RS)-2-[6-(3-chloro-4-piperazin-1-ylphenyl)-4-fluoro-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyr rolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide (Example 18, step 4) and iodoethane.

Example 19

(2RS)-2-[6-[3-Chloro-4-[(3R)-3-methylpiperazin-1-yl]phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide

Stage 1: tert-Butyl-(2R)-4-(4-bromo-2-chlorophenyl)-2-methylpiperazine-1-carboxylate

4-Bromo-2-chloro-1-iodobenzene (3.1 g, 10 mmol) and tert-butyl-(R)-2-methylpiperazine-1-carboxylate (2.0 g, 10 mmol, 1.0 eq.) were dissolved in toluene. Sodium tert-butoxide (1.9 g, 20 mmol, 2.0 eq.), XantPhos (578 mg, 1 mmol, 0.1 eq.) and tris(dibenzylideneacetone)dipalladium (0) (457 mg, 0.5 mmol, 0.05 eq.) were added and the reaction mixture was stirred at 85°C for 16 hours. The reaction mixture was cooled to room temperature and then extracted with ethyl acetate and water. The aqueous layer was back extracted with ethyl acetate. The organic layers were washed with water and saturated aqueous sodium chloride. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with a gradient of heptane:ethyl acetate from 100:0 to 90:10. The desired product (1.9 g, 39% yield) was obtained as a yellow oil, MS: m/e = 389.1/391.1 (M+H ⁺ ).

Step 2: tert-Butyl-(2R)-4-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-methylpiperazine-1-carboxylate

tert-Butyl-(2R)-4-(4-bromo-2-chlorophenyl)-2-methylpiperazine-1-carboxylate (Example 19, step 1) (1.7 g, 3.85 mmol, 1.0 eq.) and bis(pinacolato)diboron (1.17 g, 4.6 mmol, 1.2 eq.) were dissolved in dioxane. Potassium acetate (1.1 g, 11.6 mmol, 3.0 eq.) and dichloro-1,1'-bis(diphenylphosphino)ferrocenepalladium (II) dichloromethane (315 mg, 0.39 mmol, 0.1 eq.) adduct were added and the reaction mixture was stirred at 90° C. for 16 hours. The reaction mixture was cooled to room temperature and concentrated to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with a gradient of heptane:ethyl acetate from 100:0 to 90:10. The desired product (930 mg, 53% yield) was obtained as a light yellow foam, MS: m/e = 437.4/439.4 (M+H ⁺ ).

Step 3: tert-Butyl-(2RS)-4-[2-chloro-4-[2-[(1S)-1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-ethoxy-2-oxoethyl]-7-fluoro-3-oxoisoindolin-5-yl]phenyl]-2-methylpiperazine-1-carboxylate

The title compound was obtained as a light brown foam, MS: m/e = 652.5/654.5 (M+H ⁺ ), using chemical transformations similar to those described in Example 18, step 2, starting from ethyl-(2RS)-2-(6-iodo-4-fluoro-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imide zol-1-yl)acetate (Example 18, step 1) and tert-butyl-(2R)-4-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-methylpiperazine-1-carboxylate (Example 19, step 2).

Stage 4: Through-Bullet- (2RS) -4- [2-chlor- 4- [2-[(1S) -1- (6.7-dihydro-5n-pyrrolo [1,2-С] imidazole-1-il) -2-ox-2- (thiazol-2-lamino) ethyl] -7-fluoroisoidolin-5-il] penil] -2-meter-meter -carboxylate

The title compound was obtained as a brown solid, MS: m/e = 706.4/708.3 (M+H ⁺ ), using chemical transformations similar to those described in Example 3, step 2, starting from tert-butyl-(2RS)-4-[2-chloro-4-[2-[(1S)-1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl) -2-ethoxy-2-oxoethyl]-7-fluoro-3-oxoisoindolin-5-yl]phenyl]-2-methylpiperazine-1-carboxylate (Example 19, step 3) and thiazol-2-amine.

Step 5: (2RS)-2-[6-[3-Chloro-4-[(3R)-3-methylpiperazin-1-yl]phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide

The title compound was obtained as a light yellow solid, MS: m/e = 606.3/608.3 (M+H ⁺ ) using chemical transformations similar to those described in Example 4, step 3, starting from tert-butyl-(2RS)-4-[2-chloro-4-[2-[(1S)-1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl )-2-oxo-2-(thiazol-2-ylamino)ethyl]-7-fluoro-3-oxoisoindolin-5-yl]phenyl]-2-methylpiperazin-1-carboxylate (Example 19, step 4).

Example 20

(2RS)-2-[6-[3-Chloro-4-[(3R)-4-ethyl-3-methylpiperazin-1-yl]phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide

The title compound was obtained as a white foam, MS: m/e=634.5/536.5 (M+H ⁺ ), using chemical transformations similar to those described in Example 4, step 4, starting from hydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide (Example 19, step 5) and iodoethane.

Example 21

(2RS)-2-[4-Chloro-6-[4-[(1-ethyl-4-piperidyl)oxy]phenyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide

The title compound was obtained as a white solid, MS: m/e = 617.4/619.4 (M+H ⁺ ) using chemical transformations similar to those described in Example 18, step 2, Example 3, step 2, Example 4, step 3 and step 4, starting from ethyl-(2RS)-2-(4-chloro-6-iodo-1-oxoisoindolin-2-yl)-2-(6, 7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate (Example 9, step 4) and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)piperidine-1-carboxylate.

Example 22

(2RS)-2-[6-(3-Chloro-4-morpholinophenyl)-4-fluoro-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide

The title compound was obtained as a white solid, MS: m/e = 593.3/595.3 (M+H ⁺ ), using chemical transformations similar to those described in Example 18, step 2 and Example 3, step 2, starting from ethyl-(2RS)-2-(6-bromo-4-fluoro-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-yl)acetate (Example 1, step 6) and (3-chloro-4-morpholinophenyl)boronic acid.

Example 23

(2RS)-2-[6-[3-Chloro-4-(4-ethylpiperazin-1-yl)phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide

The title compound was obtained as a light yellow solid, MS: m/e = 638.5/640.3 (M+H ⁺ ), using chemical transformations similar to those described in Example 18, step 2, Example 3, step 2, Example 4, step 3 and step 4, starting from ethyl-(2RS)-2-(6-bromo-4-fluoro-1-oxoisoindolin-2-yl)-2- [(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate (Example 17, step 9) and 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-chlorophenyl)boronic acid.

Example 24

(2RS)-2-[6-(3-Chloro-4-morpholinophenyl)-4-fluoro-1-oxoisoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide

The title compound was obtained as a yellow foam, MS: m/e = 611.3/613.3 (M+H ⁺ ), using chemical transformations similar to those described in Example 18, step 2 and Example 3, step 2, starting from ethyl-(2RS)-2-(6-bromo-4-fluoro-1-oxoisoindolin-2-yl)-2-[(6R)-6-fluoro-6,7-di hydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate (Example 17, step 9) and (3-chloro-4-morpholinophenyl)boronic acid.

Example 25

(2RS)-2-[6-[3-Chloro-4-[(3R)-4-ethyl-3-methylpiperazin-1-yl]phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide

The title compound was obtained as a yellow foam, MS: m/e=652.4/654.2 (M+H⁺), using chemical transformations similar to those described in Example 18, step 2, Example 3, step 2, Example 4, step 3 and step 4, starting from ethyl-(2RS)-2-(6-bromo-4-fluoro-1-oxoisoindolin-2-yl)-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl] acetate (Example 17, step 9) and tert-butyl-(2R)-4-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-methylpiperazine-1-carboxylate (Example 19, step 2).

Example 26

(2RS)-2-[6-[4-(1-Ethyl-4-piperidyl)-3-fluorophenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide

Stage 1: tert-Butyl-4-(4-bromo-2-fluorophenyl)-3,6-dihydro-2H-pyridine-1-carboxylate

4-Bromo-2-fluoro-1-iodobenzene (CAS 105931-73-5) (2.19 g, 7.28 mmol, 1.5 eq) and tert-Butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (CAS 286 961-14-6) (1.50 g, 4.85 mmol) was dissolved in 20 ml of dioxane. Sodium carbonate (2 M in water) (7.28 ml, 14.6 mmol, 3.0 eq.) and PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (355 mg, 0.485 mmol, 0.1 eq.) were added and the reaction mixture was stirred at 110°C for 2 hours. The reaction mixture was cooled to room temperature and then extracted with ethyl acetate and saturated NaHCO ₃ solution. The aqueous layer was back extracted with ethyl acetate. The organic layers were washed with water. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with an ethyl acetate:heptane gradient from 0:100 to 70:30. The desired tert-butyl 4-(4-bromo-2-fluorophenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (1.35 g, 78% yield) was obtained as a colorless oil, MS: m/e=300.0/302.0 (M-tert-Bu+H ⁺ ).

Stage 2: tert-Butyl-4-(4-bromo-2-fluorophenyl)piperidine-1-carboxylate

tert-Butyl-4-(4-bromo-2-fluorophenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (Example 26, step 1) (820 mg, 2.3 mmol) was dissolved in 5 ml of ethyl acetate and placed under argon. Platinum(IV) oxide (35 mg, 0.154 mmol, 0.07 eq., purity=80%) was added at room temperature. The mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. Platinum(IV) oxide (35 mg, 0.154 mmol, 0.07 eq., purity=80%) was added and hydrogenation continued for 4 hours. The reaction mixture was placed under argon, filtered and concentrated to dryness. The desired tert-butyl 4-(4-bromo-2-fluorophenyl)piperidine-1-carboxylate (820 mg, 85% yield, purity = 85%) was obtained as a colorless oil, MS: m/e = 302.0/304.0 (M-tert-Bu+H ⁺ ).

Stage 3: tert-Butyl-4-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine-1-carboxylate

The title compound was obtained as a colorless oil, MS: m/e = 350.0 (M-tert-Bu+H ⁺ ), using chemical transformations similar to those described in Example 19, step 2, starting from tert-butyl-4-(4-bromo-2-fluorophenyl)piperidine-1-carboxylate (Example 26, step 2).

Stage 4: tert-Butyl-4-[4-[2-[(1RS)-2-ethoxy-1-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-2-oxoethyl]-7-fluoro-3-oxoisoindolin-5-yl]-2-fluorophenyl]piperidine-1-carboxylate

The title compound was obtained as a yellow oil, MS: m/e = 639.7 (M+H ⁺ ), using chemical transformations similar to those described in Example 18, step 2, starting from ethyl-(2RS)-2-(6-bromo-4-fluoro-1-oxoisoindolin-2-yl)-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imide zol-1-yl]acetate (Example 17, step 9) and tert-butyl-4-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine-1-carboxylate (Example 26, step 3).

Stage 5: tert-Butyl-4-[2-fluoro-4-[7-fluoro-2-[(1RS)-1-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-2-oxo-2-(thiazol-2-ylamino)ethyl]-3-oxoisoindolin-5-yl]phenyl]piperidine-1-carboxy lat

The title compound was obtained as a light brown solid, MS: m/e = 693.5 (M+H ⁺ ), using chemical transformations similar to those described in Example 3, step 2, starting from tert-butyl-4-[4-[2-[(1RS)-2-ethoxy-1-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl] -2-oxoethyl]-7-fluoro-3-oxoisoindolin-5-yl]-2-fluorophenyl]piperidine-1-carboxylate (Example 26, step 4) and thiazole-2-amine.

Step 6: (2RS)-2-[(6R)-6-Fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-2-[4-fluoro-6-[3-fluoro-4-(4-piperidyl)phenyl]-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide

The title compound was obtained as a yellow solid, MS: m/e = 593.3 (M+H ⁺ ) using chemical transformations similar to those described in Example 3, step 3, starting from tert-butyl-4-[2-fluoro-4-[7-fluoro-2-[(1RS)-1-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl ]-2-oxo-2-(thiazol-2-ylamino)ethyl]-3-oxoisoindolin-5-yl]phenyl]piperidine-1-carboxylate (Example 26, step 5).

Step 7: (2RS)-2-[6-[4-(1-Ethyl-4-piperidyl)-3-fluorophenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide

The title compound was obtained as a yellowish white solid MS: m/e = 621.3 (M+H ⁺ ) using chemical reactions similar to those described in Example 4, step 4, starting from (2RS)-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-2-[4-fluoro-6-[3-fluoro-4-(4-pi peridyl)phenyl]-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide (Example 2 step 6) and ethyl iodide.

Example 27

(2RS)-2-[6-[4-(1-Cyclopropyl-4-piperidyl)phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide

Step 1: Ethyl-(2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl]acetate

The title compound was obtained as a brown oil, MS: m/e = 470, (M+H ⁺ ), using chemical transformations similar to those described in Example 19, step 2, starting from ethyl-(2RS)-2-(6-bromo-4-fluoro-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate

(Example 1, step 6).

Step 2: 4-(4-Bromophenyl)-1-cyclopropylpiperidine

4-(4-Bromophenyl)piperidine (0.6 g, 2.5 mmol) was dissolved in 5.6 ml THF and 5.6 ml methanol. (1-Ethoxycyclopropoxy)trimethylsilane (1.0 ml, 867 mg, 5.0 mmol, 2 eq.), sodium cyanoborohydride (239 mg, 3.8 mmol, 1.5 eq.) and acetic acid (0.24 ml, 4.2 mmol, 1.7 eq.) were added and the reaction mixture was stirred at 50°C for 16 hours. The reaction mixture was cooled to room temperature and then extracted with dichloromethane and 2N HCl. sodium hydroxide. The aqueous layer was back extracted with dichloromethane. The organic layers were washed with water and saturated aqueous sodium chloride. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with a gradient of heptane:ethyl acetate from 100:0 to 70:30. The desired product (609 mg, 83% yield) was obtained as a yellow solid, MS: m/e = 280.1/281.8 (M+H ⁺ ).

Step 3: (2RS)-2-[6-[4-(1-Cyclopropyl-4-piperidyl)phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide

The title compound was obtained as a brown foam, MS: m/e = 597.5 (M+H ⁺ ), using chemical transformations similar to those described in Example 18, step 2 and Example 3, step 2, starting from ethyl-(2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-1-oxo-6-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl]acetate (Example 27, step 1) and 4-(4-bromophenyl)-1-cyclopropylpiperidine (Example 27, step 2).

Example 28

(2RS)-2-[4-Chloro-6-[4-(1-cyclopropyl-4-piperidyl)phenyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide

Stage 1: 1-Cyclopropyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine

The title compound was obtained as a light brown solid, MS: m/e = 328.2 (M+H ⁺ ), using chemical transformations similar to those described in Example 19, step 2, starting from 4-(4-bromophenyl)-1-cyclopropylpiperidine (Example 27, step 2).

Step 2: (2RS)-2-[4-Chloro-6-[4-(1-cyclopropyl-4-piperidyl)phenyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide

The title compound was obtained as a yellow solid, MS: m/e = 613.3/615.3 (M+H ⁺ ), using chemical transformations similar to those described in Example 18, step 2 and Example 3, step 2, starting from ethyl-(2RS)-2-(4-chloro-6-iodo-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-yl)acetate (Example 9, step 4) and 1-cyclopropyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine (Example 28, step 1).

Example 29

(2RS)-2-[4-Chloro-6-[4-(1-ethyl-4-piperidyl)phenyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide

Step 1: 1-Ethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine

The title compound was obtained as a brown solid, MS: m/e = 316.2 (M+H ⁺ ), using chemical transformations similar to those described in Example 4, step 4 and Example 19, step 2, starting from 4-(4-bromophenyl)piperidine and iodoethane.

Step 2: (2RS)-2-[4-Chloro-6-[4-(1-ethyl-4-piperidyl)phenyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide

The title compound was obtained as a white solid, MS: m/e = 601.3/603.1 (M+H ⁺ ), using chemical transformations similar to those described in Example 18, step 2 and Example 3, step 2, starting from ethyl-(2RS)-2-(4-chloro-6-iodo-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1 ,2-c]imidazol-1-yl)acetate (Example 9, step 4) and 1-ethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (Example 29, step 1).

Example 30

(2RS)-2-[6-[3-Chloro-4-(1-ethyl-4-piperidyl)phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide

Stage 1: tert-Butyl-4-(2-chloro-4-nitrophenyl)-3,6-dihydro-2H-pyridine-1-carboxylate

The title compound was obtained as a yellow oil using chemical transformations similar to those described in Example 18, step 2, starting from 1-bromo-2-chloro-4-nitrobenzene (CAS 29682-39-1) and tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxyl and (CAS 286961-14-6).

Stage 2: tert-Butyl-4-(4-amino-2-chlorophenyl)piperidine-1-carboxylate

tert-Butyl 4-(2-chloro-4-nitrophenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (Example 30, step 1) (1.56 g, 4.6 mmol) was dissolved in 25 ml of ethyl acetate and Pd-C (0.160 g, 1.5 mmol, 0.327 eq.) was added at room temperature. The reaction mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. The reaction mixture was placed under argon, filtered and concentrated to dryness. Platinum (IV) oxide (160 mg) was placed in the reaction mixture as a catalyst. The mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. The reaction mixture was placed under argon, filtered and concentrated to dryness. The desired t-butyl 4-(4-amino-2-chlorophenyl)piperidine-1-carboxylate (1.20 g, 84% yield) was obtained as a colorless oil, MS: m/e = 255.1 (M-t-Bu+H ⁺ ).

Stage 3: tert-Butyl-4-(4-bromo-2-chlorophenyl)piperidine-1-carboxylate

tert-Butyl nitrite (CAS 540-80-7) (558 mg, 0.644 ml, 4.87 mmol, 1.5 eq.) and copper (II) bromide (CAS 7789-45-9) (871 mg, 3.9 mmol, 1.2 eq.) were suspended in 15 ml of acetonitrile. At 65°C, tert-butyl 4-(4-amino-2-chlorophenyl)piperidine-1-carboxylate (Example 30, step 2) (1.01 g, 3.25 mmol) dissolved in 2 ml of acetonitrile was added and the mixture was stirred at 65°C for 2 hours. The reaction mixture was cooled to room temperature and then extracted with ethyl acetate and saturated NaHCO ₃ solution. The aqueous layer was back extracted with ethyl acetate. The organic layers were washed with water and saturated aqueous sodium chloride. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with a gradient of heptane:ethyl acetate from 100:0 to 50:50 to give the desired tert-butyl 4-(4-bromo-2-chlorophenyl)piperidine-1-carboxylate (430 mg, 35% yield) as a colorless oil, MS: m/e = 318.0/320.0 (M -tert-Bu+H ⁺ ).

Stage 4: tert-Butyl-4-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine-1-carboxylate

The title compound was obtained as a colorless oil, MS: m/e = 366.1 (M-tert-Bu+H ⁺ ), using chemical transformations similar to those described in Example 19, step 2, starting from tert-butyl-4-(4-bromo-2-chlorophenyl)piperidine-1-carboxylate (Example 30, step 3).

Stage 5: tert-Butyl-4-[2-chloro-4-[2-[(1RS)-1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-ethoxy-2-oxoethyl]-7-fluoro-3-oxoisoindolin-5-yl]phenyl]piperidine-1-carboxylate

The title compound was obtained as a light brown solid, MS: m/e = 637.4 (M+H ⁺ ), using chemical transformations similar to those described in Example 18, step 2, starting from ethyl-(2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-6-iodo-1-oxoisoindolin-2-yl )acetate (Example 18, step 1) and tert-butyl-4-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine-1-carboxylate (Example 30, step 4).

Stage 6: tert-Butyl-4-[2-chloro-4-[2-[(1RS)-1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl]-7-fluoro-3-oxoisoindolin-5-yl]phenyl]piperidine-1-carboxylate

The title compound was obtained as a yellow solid, MS: m/e = 691.5 (M+H ⁺ ), using chemical transformations similar to those described in Example 3, step 2, starting from tert-butyl-4-[2-chloro-4-[2-[(1RS)-1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-ethoxy-2-oxoethyl] -7-fluoro-3-oxoisoindolin-5-yl]phenyl]piperidine-1-carboxylate (Example 30, step 5) and thiazole-2-amine.

Step 7: (2RS)-2-[6-[3-Chloro-4-(4-piperidyl)phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide

The title compound was obtained as a yellow solid, MS: m/e = 591.2 (M+H ⁺ ) using chemical transformations similar to those described in Example 3, step 3, starting from tert-butyl-4-[2-chloro-4-[2-[(1RS)-1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazole -2-ylamino)ethyl]-7-fluoro-3-oxoisoindolin-5-yl]phenyl]piperidine-1-carboxylate (Example 30, step 6).

Step 8: (2RS)-2-[6-[3-Chloro-4-(1-ethyl-4-piperidyl)phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide

The title compound was obtained as a light yellow solid, MS: m/e = 619.3 (M+H ⁺ ), using chemical transformations similar to those described in Example 4, step 4, starting from (2RS)-2-[6-[3-chloro-4-(4-piperidyl)phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1, 2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide (Example 30, step 7) and ethyl iodide.

Example 31

(2RS)-2-[6-[4-(1-Ethyl-4-piperidyl)phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide

The title compound was obtained as a light brown oil, MS: m/e = 603.4 (M+H ⁺ ) using chemical transformations similar to those described in Example 18, step 2 and Example 3, step 2, starting from ethyl-(2RS)-2-(6-bromo-4-fluoro-1-oxoisoindolin-2-yl)-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyr rolo[1,2-c]imidazol-1-yl]acetate (Example 17, step 9) and 1-ethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (Example 29, step 1).

Example 32

(2RS)-2-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[4-[(3R,4R)-1-ethyl-3-fluoro-4-piperidyl]phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide and (2RS)-2-(6,7-dihydro-5H- pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[4-[(3S,4S)-1-ethyl-3-fluoro-4-piperidyl]phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide

Stage 1: tert-Butyl-(3R,4R)-4-(4-bromophenyl)-3-hydroxypiperidine-1-carboxylate and tert-butyl-(3S,4S)-4-(4-bromophenyl)-3-hydroxypiperidine-1-carboxylate

tert-Butyl-4-(4-bromophenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (CAS 273727-44-9) (1.060 g, 3.13 mmol) was dissolved in 24 ml of THF and cooled to 0°C. Added dropwise at 0°C complex of borane and tetrahydrofuran, 1.0 M solution in THF (CAS 14044-65-6) (6.6 ml, 6.6 mmol, 2.11 eq.). After completion of the addition, the ice bath was removed and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was cooled to 0°C. Sodium hydroxide (6 M in water) (1.7 ml, 10.2 mmol, 3.25 eq.) was added and the reaction mixture was stirred at 0° C. for 10 minutes. Was added hydrogen peroxide, 35% wt. solution in water (977 mg, 0.88 ml, 10.1 mmol, 3.21 eq.), and the reaction mixture was stirred at 50° C. for 2 hours. The reaction mixture was cooled to room temperature and excess peroxide was quenched by adding Na ₂ S ₂ O ₃ solution (10% in water). The mixture was extracted with ethyl acetate and saturated NaHCO ₃ solution. The aqueous layer was extracted twice with ethyl acetate again. The organic layers were combined, dried over sodium sulfate, filtered and concentrated on Isolute® to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with an ethyl acetate:heptane gradient from 0:100 to 30:70. The desired products (894 mg, 76% yield, 95% purity) were obtained as an off-white solid, MS: m/e = 300.0/302.0 (M-tert-Bu+H ⁺ ).

Step 2: tert-Butyl-(3R,4R)-4-(4-bromophenyl)-3-fluoropiperidine-1-carboxylate and tert-butyl-(3S,4S)-4-(4-bromophenyl)-3-fluoropiperidine-1-carboxylate

A mixture of tert-butyl-(3R,4R)-4-(4-bromophenyl)-3-hydroxypiperidine-1-carboxylate and tert-butyl-(3S,4S)-4-(4-bromophenyl)-3-hydroxypiperidine-1-carboxylate (Example 32, step 1) (0.492 g, 1.31 mmol, eq.: 1; purity = 95%) was dissolved in 13 ml of dichloromethane and cooled to -76 °C. Bis(2-methoxyethyl)aminosulfur trifluoride (CAS 202289-38-1) (312 mg, 0.26 ml, 1.41 mmol, 1.07 eq.) was added dropwise at -76°C. The reaction mixture was allowed to slowly warm to room temperature and was stirred for 16 hours. The reaction mixture was quenched with saturated NaHCO ₃ solution and extracted three times with dichloromethane. The organic layers were combined, dried over sodium sulfate, filtered and concentrated on Isolute® to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with an ethyl acetate:heptane gradient from 0:100 to 20:80.

The desired products (300 mg, 61% yield, 95% purity) were obtained as a colorless oil, MS: m/e = 302.0/304.0 (M-tert-Bu+H ⁺ ).

Stage 3: tert-Butyl-(3R,4R)-3-fluoro-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine-1-carboxylate and tert-butyl-(3S,4S)-3-fluoro-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl)phenyl]piperidine-1-carboxylate

The title compounds were obtained as a mixture of trans compounds and as a yellowish white foam, MS: m/e = 350.0 (M-tert-Bu+H ⁺ ), using chemical transformations similar to those described in Example 19, step 2, starting from tert-butyl-(3R,4R)-4-(4-bromophenyl)-3-fluoropiperidine-1-carboxylate and tert-butyl-(3S,4S )-4-(4-bromophenyl)-3-fluoropiperidine-1-carboxylate (Example 32, step 2).

Step 4: tert-Butyl-(3R,4R)-4-[4-[2-[(1RS)-1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-ethoxy-2-oxoethyl]-7-fluoro-3-oxoisoindodin-5-yl]phenyl]-3-fluoropiperidine-1-carboxylate and tert-butyl-(3S ,4S)-4-[4-[2-[(1RS)-1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-ethoxy-2-oxoethyl]-7-fluoro-3-oxoisoindolin-5-yl]phenyl]-3-fluoropiperidine-1-carboxylate

Target compounds were obtained as a mixture and as a brown foam, MS: m/e=621.4 (M+H⁺), using chemical transformations similar to those described in Example 18, step 2, starting from ethyl-(2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-6-iodo-1-oxoisoindolin-2-yl)acetate (Example 18, step 1) and tert-butyl-(3R,4R)-3-fluoro -4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine-1-carboxylate and tert-butyl-(3S,4S)-3-fluoro-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine-1-carboxylate (Example 32, step 3).

Step 5: tert-Butyl-(3R,4R)-4-[4-[2-[(1RS)-1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl]-7-fluoro-3-oxoisoindolin-5-yl]phenyl]-3-fluoropiperidine-1-carboxylate and tert-Butyl-(3S,4S)-4-[4-[2-[(1RS)-1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl]-7-fluoro-3-oxoisoindolin-5-yl]phenyl]-1-fluoropiperidine-1-carboxylate

The title compounds were obtained as a mixture and as a brown solid, MS: m/e = 675.4 (M+H⁺), using chemical transformations similar to those described in Example 3, step 2, starting from a mixture of tert-butyl-(3R,4R)-4-[4-[2-[(1RS)-1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-ethoxy-2-oxoethyl]-7-fluoro-3-oxoisoindolin-5-yl]phenyl]-3-fluoropy peridin-1-carboxylate and tert-butyl-(3S,4S)-4-[4-[2-[(1RS)-1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-ethoxy-2-oxoethyl]-7-fluoro-3-oxoisoindolin-5-yl]phenyl]-3-fluoropiperidine-1-carboxylate (Example 3 2, step 4) and thiazol-2-amine.

Step 6: (2RS)-2-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-b-[4-[(3R,4R)-3-fluoro-4-piperidyl]phenyl]-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide and (2RS)-2-(6,7-dihydro-5 N-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-6-[4-[(3R,4R)-3-fluoro-4-piperidyl]phenyl]--oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide

Target compounds were obtained as a mixture and as a brown foam, MS: m/e=575.3 (M+H⁺), using chemical transformations similar to those described in Example 3, step 3, starting from a mixture of tert-butyl-(3R,4R)-4-[4-[2-[(1RS)-1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl]-7-fluoro-3-oxoisoindoline-5- yl]phenyl]-3-fluoropiperidin-1-carboxylate and tert-butyl-(3S,4S)-4-[4-[2-[(1RS)-1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl]-7-fluoro-3-oxoisoindolin-5-yl]phenyl]-3- fluoropiperidine-1-carboxylate (Example 32, step 5).

Step 7: (2RS)-2-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[4-[(3R,4R)-1-ethyl-3-fluoro-4-piperidyl]phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide and (2RS)-2-(6,7- dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[4-[(3S,4S)-1-ethyl-3-fluoro-4-piperidyl]phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide

Target compounds were obtained as a mixture and as a yellowish white foam, MS: m/e = 603.4 (M+H⁺), using chemical transformations similar to those described in Example 4, step 4, starting from the mixture amide and (2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-6-[4-[(3R,4R)-3-fluoro-4-piperidyl]phenyl]-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide (Example 32, step 6) and ethyl iodide.

Example 33

(2RS)-2-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[4-(1-ethyl-4-piperidyl)-3-fluorophenyl]-4-fluoro-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide

Stage 1: tert-Butyl-4-(4-bromo-2-fluorophenyl)-4-hydroxypiperidine-1-carboxylate

4-Bromo-2-fluoro-1-iodobenzene (CAS 105931-73-5) (5 g, 16.6 mmol, 1.1 eq.) was dissolved in 80 ml THF and n-butyllithium (1.6 M solution in a mixture of hexane isomers) (10.4 ml, 16.6 mmol, 1.1 eq.) was added dropwise at -76° S. The reaction mixture was stirred at -76°C for 1 hour. A solution of tert-butyl 4-oxopiperidine-1-carboxylate (CAS 79099-07-3) (3 g, 15.1 mmol) dissolved in 40 ml THF was added dropwise at -76°C. After completion of the addition, the reaction mixture was stirred without a cooling bath for 2 hours. The reaction mixture was extracted with ethyl acetate and saturated NaHCO ₃ solution. The aqueous layer was back extracted with ethyl acetate. The organic layers were washed with water and saturated aqueous sodium chloride. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with a gradient of heptane:ethyl acetate from 100:0 to 0:100 to give the desired tert-butyl 4-(4-bromo-2-fluorophenyl)-4-hydroxypiperidine-1-carboxylate (5.3 g, 94% yield) as a white solid, MS: m/e = 272.1/274 ,1 (M-BOC+H ⁺ ).

Step 2: 4-(4-Bromo-2-fluorophenyl)-1,2,3,6-tetrahydropyridine

tert-Butyl 4-(4-bromo-2-fluorophenyl)-4-hydroxypiperidine-1-carboxylate (Example 33, step 1) (5.3 g, 14.2 mmol) was dissolved in 55 ml of trifluoroacetic acid and triethylsilane (CAS 617-86-7) (4.12 g, 5.65 ml, 35.4 mmol, 2 .5 equiv.). The reaction mixture was stirred at 60°C for 3 hours. The reaction mixture was concentrated to dryness and then extracted with ethyl acetate and saturated NaHCO ₃ solution. The aqueous layer was back extracted with ethyl acetate. The organic layers were washed with water. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness. The desired 4-(4-bromo-2-fluorophenyl)-1,2,3,6-tetrahydropyridine (4.5 g, quant.) was obtained as a yellow oil, MS: m/e=255.9/257.9 (M+H ⁺ ).

Stage 3: 4-(4-Bromo-2-fluorophenyl)- 1-ethyl-3,6-dihydro-2H-pyridine

4-(4-Bromo-2-fluorophenyl)-1,2,3,6-tetrahydropyridine (Example 33, step 2) (1.80 g, 5.62 mmol, purity = 80%) was dissolved in 20 ml of acetonitrile. Hunig's base (3.63 g, 4.91 ml, 28.1 mmol, 5 eq.) and ethyl iodide (1.14 g, 591 μl, 7.31 mmol, 1.3 eq.) were added at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was extracted with ethyl acetate and saturated NaHCO ₃ solution. The aqueous layer was back extracted with ethyl acetate. The organic layers were washed with water and saturated aqueous sodium chloride. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with a dichloromethane:methanol gradient from 100:0 to 85:15 to give the desired 4-(4-bromo-2-fluorophenyl)-1-ethyl-3,6-dihydro-2H-pyridine (0.71 g, 44% yield) as a yellow oil, MS: m/e = 283.9/285.9 (M+H ⁺ ).

Step 4: 4-(4-Bromo-2-fluorophenyl)-1-ethylpiperidine

The title compound was obtained as a yellow oil, MS: m/e = 286.0/288.0 (M+H ⁺ ), using chemical transformations similar to those described in Example 26, step 2, starting from 4-(4-bromo-2-fluorophenyl)-1-ethyl-3,6-dihydro-2H-pyridine (Example 33, step 3).

Step 5: Ethyl-(2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[4-(1-ethyl-4-piperidyl)-3-fluorophenyl]-4-fluoro-1-oxoisoindolin-2-yl]acetate

Ethyl (2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl]acetate (Example 27, step 1) (100 mg, 0.213 mmol) and 4 -(4-bromo-2-fluorophenyl)-1-ethylpiperidine (Example 33, step 4) (85 mg, 0.298 mmol, 1.4 eq) was dissolved in 2.0 ml THF. Cesium carbonate (2 M in water) (0.32 ml, 0.639 mmol, 3.0 eq.) and PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (16 mg, 0.021 mmol, 0.1 eq.) were added and the reaction mixture was stirred at 50°C for 1 hour. The reaction mixture was cooled to room temperature and then extracted with ethyl acetate and water. The aqueous layer was back extracted with ethyl acetate. The organic layers were washed with saturated aqueous sodium chloride. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with a methanol:ethyl acetate gradient from 0:100 to 10:90. The desired ethyl (2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[4-(1-ethyl-4-piperidyl)-3-fluorophenyl]-4-fluoro-1-oxoisoindolin-2-yl]acetate (43 mg, 37% yield) was obtained as a brown oil, MS: m/e=549.4 (M+H ⁺ ).

Step 6: (2RS)-2-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[4-(1-ethyl-4-piperidyl)-3-fluorophenyl]-4-fluoro-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide

The title compound was obtained as a white solid, MS: m/e = 603.6 (M+H ⁺ ) using chemical transformations similar to those described in Example 3, step 2, starting from ethyl-(2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[4-(1-ethyl-4-piperidyl)-3-fluorophenyl]-4 -fluoro-1-oxoisoindolin-2-yl]acetate (Example 33, step 5) and thiazol-2-amine.

Example 34

(2RS)-2-[6-[4-[1-(2,2-Difluoroethyl)-4-piperidyl]phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide

The title compound was obtained as a light yellow solid, MS: m/e = 621.3 (M+H ⁺ ), using chemical transformations similar to those described in Example 4, step 4, starting from (2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-1-oxo-6-[4-(4-piperidyl)phenyl]iso indolin-2-yl]-N-thiazol-2-ylacetamide hydrochloride

(Example 16, step 2) and 2,2-difluoroethyltrifluoromethanesulfonate.

Example 35

(2RS)-2-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-6-[4-[1-(2-methoxyethyl)-4-piperidyl]phenyl]-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide

The title compound was obtained as a light yellow solid, MS: m/e = 615.3 (M+H ⁺ ) using chemical reactions similar to those described in Example 4, step 4, starting from (2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-1-oxo-6-[4-(4-piperidyl)phenyl]isoind olin-2-yl]-N-thiazol-2-ylacetamide hydrochloride

(Example 16, step 2) and 1-bromo-2-methoxyethane.

Example 36

((2RS)-2-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-6-[4-[1-(2-fluoroethyl)-4-piperidyl]phenyl]-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide

The title compound was obtained as a light yellow solid, MS: m/e = 603.2 (M+H ⁺ ) using chemical reactions similar to those described in Example 4, step 4, starting from (2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-1-oxo-6-[4-(4-piperidyl)phenyl]isoind olin-2-yl]-N-thiazol-2-ylacetamide hydrochloride

(Example 16, step 2) and 2-fluoroethyl-4-methylbenzenesulfonate.

Example 37

(2RS)-2-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[3-ethyl-4-(1-ethyl-4-piperidyl)phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide

Stage 1: tert-Butyl-4-(4-bromo-2-ethylphenyl)-3,6-dihydro-2H-pyridine-1-carboxylate

The title compound was obtained as a light yellow oil, MS: m/e = 310.0/312.0 (M-tert-Bu+H ⁺ ), using chemical transformations similar to those described in Example 26, step 1, starting from 4-bromo-2-ethyl-1-iodobenzene (CAS 175278-30-5) and tert-butyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (CAS 286961-14-6).

Stage 2: tert-Butyl-4-(4-bromo-2-ethylphenyl)piperidine-1-carboxylate

tert-Butyl 4-(4-bromo-2-ethylphenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (Example 37, step 1) (1.29 g, 3.35 mmol, purity = 95%) was dissolved in 7.0 ml of ethyl acetate and 14 ml of methanol. The flask was alternately evacuated three times and refilled with argon. Platinum (IV) oxide (285 mg, 1 mmol, 0.3 eq., purity=80%) was added carefully. The flask was evacuated, purged with argon, evacuated and filled with hydrogen. The reaction mixture was stirred under argon (balloon) at room temperature for 16 hours. The reaction mixture was filtered and the filtrate was concentrated on Isolute® to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with an ethyl acetate:heptane gradient from 0:100 to 10:90. The desired tert-butyl 4-(4-bromo-2-ethylphenyl)piperidine-1-carboxylate (445 mg, 33% yield, purity = 90%) was obtained as an off-white solid, MS: m/e = 312.0/314.0 (M-tert-Bu+H ⁺ ).

Stage 3: tert-Butyl-4-[2-ethyl-4-(4.4,5.5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine-1-carboxylate

The title compound was obtained as a yellowish white foam, MS: m/e = 360.2 (M-tert-Bu+H ⁺ ), using chemical transformations similar to those described in Example 19, step 2, starting from tert-butyl 4-(4-bromo-2-ethylphenyl)piperidine-1-carboxylate (Example 37, step 2).

Stage 4: tert-Butyl-4-[4-[2-[(1RS)-1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-ethoxy-2-oxoethyl]-7-fluoro-3-oxoisoindolin-5-yl]-2-ethylphenyl]piperidine-1-carboxylate

The title compound was obtained as a light brown foam, MS: m/e = 631.4 (M+H ⁺ ), using chemical transformations similar to those described in Example 18, step 2, starting from ethyl-(2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-6-iodo-1-oxoisoindolin-2-yl) acetate (Example 18, step 1) and tert-butyl-4-[2-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine-1-carboxylate (Example 37, step 3).

Stage 5: tert-Butyl-4-[4-[2-[(1RS)-1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-ylamino)ethyl]-7-fluoro-3-oxoisoindolin-5-yl]-2-ethylphenyl]piperidine-1-carboxylate

The title compound was obtained as a brown solid, MS: m/e = 685.4 (M+H ⁺ ), using chemical transformations similar to those described in Example 3, step 2, starting from tert-butyl-4-[4-[2-[(1RS)-1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-ethoxy-2-oxoethyl]-7- fluoro-3-oxoisoindolin-5-yl]-2-ethylphenyl]piperidine-1-carboxylate (Example 37, step 4) and thiazole-2-amine.

Step 6: (2RS)-2-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[3-ethyl-4-(4-piperidyl)phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide

The title compound was obtained as a brown foam, MS: m/e = 585.3 (M+H ⁺ ), using chemical transformations similar to those described in Example 3, step 3, starting from tert-butyl-4-[4-[2-[(1RS)-1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-oxo-2-(thiazol-2-yl amino)ethyl]-7-fluoro-3-oxoisoindolin-5-yl]-2-ethylphenyl]piperidine-1-carboxylate (Example 37, step 5).

Step 7: (2RS)-2-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[3-ethyl-4-(1-ethyl-4-piperidyl)phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide

The title compound was obtained as a light brown foam, MS: m/e = 613.5 (M+H ⁺ ), using chemical reactions similar to those described in Example 4, step 4, starting from (2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[3-ethyl-4-(4-piperidyl)phenyl]-4-fluoro-1-oc soisoindolin-2-yl]-N-thiazol-2-ylacetamide (Example 37, step 6) and ethyl iodide.

Example 38

(2RS)-2-[6-[4-(4-Cyclopropylpiperazin-1-yl)-3-fluorophenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide

Stage 1: 1-Cyclopropyl-4-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine

The title compound was obtained as a yellow solid, MS: m/e = 347.3 (M+H ⁺ ), using chemical transformations similar to those described in Example 19, step 1 and step 2, starting from 4-bromo-2-fluoro-1-iodobenzene and 1-cyclopropylpiperazine dihydrochloride.

Step 2: (2RS)-2-[6-[4-(4-Cyclopropylpiperazin-1-yl)-3-fluorophenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide

The title compound was obtained as a yellow solid, MS: m/e = 613.3/615.3 (M+H ⁺ ), using chemical transformations similar to those described in Example 18, step 2 and Example 3, step 2, starting from ethyl-(2RS)-2-(6-bromo-4-fluoro-1-oxoisoindolin-2-yl)-2-[(6R)-6-fluoro-6,7-di hydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate (Example 17, step 9) and 1-cyclopropyl-4-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborlan-2-yl)phenyl]piperazine (Example 38, step 1).

Example 39

(2RS)-2-[6-[4-(4-Cyclopropylpiperazin-1-yl)-3-fluorophenyl]-4-chloro-1-oxoisoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide

Stage 1: 1-Cyclopropyl-4-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine

The title compound was obtained as a light brown solid, MS: m/e = m/e = 363.0/365.0 (M+H ⁺ ), using chemical transformations similar to those described in Example 19, step 1 and step 2 starting from 4-bromo-2-chloro-1-iodobenzene and 1-cyclopropylpiperazine dihydrochloride.

Step 2: (2RS)-2-[6-[4-(4-Cyclopropylpiperazin-1-yl)-3-fluorophenyl]-4-chloro-1-oxoisoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide

The title compound was obtained as a light brown solid, MS: m/e=650.4/652.3 (M+H⁺), using chemical transformations similar to those described in Example 18, step 2 and Example 3, step 2, starting from ethyl-(2RS)-2-(6-bromo-4-fluoro-1-oxoisoindolin-2-yl)-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate (Example 17, step 9) and 1-cyclopropyl-4-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborlan-2-yl)phenyl]piperazine (Example 39, step 1).

Example 40

(2RS)-2-[4-Chloro-6-[4-(4-cyclopropylpiperazin-1-yl)-3-fluorophenyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-acetamide

The title compound was obtained as a white solid, MS: m/e = 632.3/634.23 (M+H ⁺ ), using chemical transformations similar to those described in Example 18, step 2 and Example 3, step 2, starting from ethyl-(2RS)-2-(4-chloro-6-iodo-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-yl)acetate (Example 9, step 4) and 1-cyclopropyl-4-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine (Example 38, step 1).

Example 41

(2RS)-2-[6-[3-Chloro-4-[4-(2,2-difluoroethyl)piperazin-1-yl]phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide

Stage 1: 1-Cyclopropyl-4-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine

The title compound was obtained as a yellow solid, MS: m/e = 387.2/389.2 (M+H ⁺ ), using chemical transformations similar to those described in Example 19, step 1 and step 2, starting from 4-bromo-2-chloro-1-iodobenzene and 1-(2,2-difluoroethyl)piperazine.

Step 2: (2RS)-2-[6-[3-Chloro-4-[4-(2,2-difluoroethyl)piperazin-1-yl]phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide

The title compound was obtained as a brown solid, MS: m/e = 656.3/658.3 (M+H ⁺ ), using chemical transformations similar to those described in Example 18, step 2 and Example 3, step 2, starting from ethyl-(2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-6-d od-1-oxoisoindolin-2-yl)acetate (Example 18, step 1) and 1-cyclopropyl-4-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine (Example 41, step 1).

Example 42

(2RS)-2-[4-Fluoro-6-[4-(4-cyclopropylpiperazin-1-yl)-3-fluorophenyl]-1-oxoisoindolin-2-yl]-2-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-acetamide

The title compound was obtained as a light brown foam, MS: m/e = 616.4 (M+H ⁺ ), using chemical transformations similar to those described in Example 18, step 2 and Example 3, step 2, starting from ethyl-(2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-6-iodo-1-oxo isoindolin-2-yl)acetate (Example 18, step 1) and 1-cyclopropyl-4-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine (Example 38, step 1).

Example 43

(2RS)-2-[6-[2-(2-Chlorophenyl)ethynyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide

The title compound was obtained as a white solid, MS: m/e = 532.2/534.2 (M+H ⁺ ), using chemical transformations similar to those described in Example 1, step 9, starting from (2RS)-2-(6-bromo-4-fluoro-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl) -N-thiazol-2-ylacetamide (Example 1, step 8) and 1-chloro-2-ethynylbenzene.

Example 44

(2RS)-2-[6-[2-[4-[(4,4-Difluoro-1-piperidyl)methyl]phenyl]ethynyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide

The title compound was obtained as a white solid, MS: m/e = 631.3 (M+H ⁺ ), using chemical reactions similar to those described in Example 1, step 10, starting from (2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-6-[2-(4-formylphenyl)ethynyl]-1-oxoisoindo lin-2-yl]-N-thiazol-2-ylacetamide (Example 1, step 9) and 4,4-difluoropiperidine hydrochloride.

Example 45

(2RS)-2-(6,7-Dihydro-5H-pyrrolisin-1-yl)-2-[4-fluoro-6-(3-fluoro-4-morpholinophenyl)-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide

Step 1: (2RS)-2-(6,7-Dihydro-5H-pyrrolisin-1-yl)-2-[4-fluoro-6-(3-fluoro-4-morpholinophenyl)-1-oxoisoindolin-2-yl]acetonitrile

The title compound was obtained as a light brown oil, MS: m/e = 475.3 (M+H ⁺ ), using chemical transformations similar to those described in Example 18, step 2, starting from (2RS)-2-(6-bromo-4-fluoro-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolisin-1-yl)acetonitrile (Example 10, step 3) and (3-fluoro-4-morpholinophenyl)boronic acid (CAS 279262-09-8).

Step 2: (2RS)-2-(6,7-Dihydro-5H-pyrrolisin-1-yl)-2-[4-fluoro-6-(3-fluoro-4-morpholinophenyl)-1-oxoisoindolin-2-yl]acetate sodium

The title compound was obtained as a yellow solid, MS: m/e = 494.3 (M+H ⁺ ), using chemical transformations similar to those described in Example 10, step 4, starting from (2RS)-2-(6,7-dihydro-5H-pyrrolisin-1-yl)-2-[4-fluoro-6-(3-fluoro-4-morpholinophenyl)-1-oxoisoindolin-2-yl]acetonitrile la (Example 45, stage 1).

Step 3: (2RS)-2-(6,7-Dihydro-5H-pyrrolisin-1-yl)-2-[4-fluoro-6-(3-fluoro-4-morpholinophenyl)-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide

The title compound was obtained as a yellow foam, MC: m/e = 576.4 (M+H ⁺ ) using chemical transformations similar to those described in Example 1, step 8, starting from (2RS)-2-(6,7-dihydro-5H-pyrrolisin-1-yl)-2-[4-fluoro-6-(3-fluoro-4-morpholinophenyl)-1-oxoisoindolin-2-yl] sodium acetate ( Example 45, step 2) and thiazol-2-amine.

Example 46

(2RS)-2-[6-[3-Chloro-4-(4-cyclopropylpiperazin-1-yl)phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide

The title compound was obtained as a white solid, MS: m/e = 632.3/634.3 (M+H ⁺ ), using chemical transformations similar to those described in Example 18, step 2 and Example 3, step 2, starting from ethyl-(2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(4-fluoro-6-iodo- 1-oxoisoindolin-2-yl)acetate (Example 18, step 1) and 1-cyclopropyl-4-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine (Example 39, step 1).

Example 47

(2RS)-2-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-1-oxo-6-[2-[4-(trifluoromethyl)phenyl]ethynyl]isoindolin-2-yl]-N-thiazol-2-ylacetamide

The title compound was obtained as a light yellow solid, MS: m/e = 566.1 (M+H ⁺ ), using chemical transformations similar to those described in Example 1, step 9, starting from (2RS)-2-(6-bromo-4-fluoro-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N- thiazol-2-ylacetamide (Example 1, step 8) and 1-ethynyl-4-(trifluoromethyl)benzene

Example 48

(2RS)-2-(6,7-Dihydro-5H-pyrrolisin-1-yl)-2-[6-[4-(1-ethyl-4-piperidyl)phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide

The title compound was obtained as a light brown solid, MS: m/e = 584.5 (M+H ⁺ ), using chemical transformations similar to those described in Example 18, step 2, starting from (2RS)-2-(6-bromo-4-fluoro-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolisin-1-yl)-N-thiazol-2-ylacetate amide (Example 10, step 5) and 1-ethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (Example 29, step 1).

Example 49

(2RS)-2-[6-[3-Chloro-4-[4-(2-fluoroethyl)piperazin-1-yl]phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide

The title compound was obtained as a white solid, MS: m/e = 638.2/640.2 (M+H ⁺ ), using chemical transformations similar to those described in Example 4, step 4, starting from (2RS)-2-[6-(3-chloro-4-piperazin-1-ylphenyl)-4-fluoro-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide (Example 18, step 4) and 2-fluoroethyl-4-methylbenzenesulfonate.

Example 50

(2RS)-2-[6-[3-Ethyl-4-(1-ethyl-4-piperidyl)phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide

Stage 1: Ethyl-(2RS)-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-2-(4-fluoro-6-iodo-1-oxoisoindolin-2-yl)acetate

The title compound was obtained as a light yellow solid, MS: m/e = 488.0 (M+H ⁺ ), using chemical transformations similar to those described in Example 1, steps 5 and 6, starting from ethyl-(2RS)-2-amino-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate (Example 17 step 8) and using methyl 5-iodo-3-fluoro-2-methylbenzoate instead of 5-bromo-3-fluoro-2-methylbenzoate.

Stage 2: tert-Butyl-4-[4-[2-[(1RS)-2-ethoxy-1-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-2-oxoethyl]-7-fluoro-3-oxoisoindolin-5-yl]-2-ethylphenyl]piperidine-1-carboxylate

Ethyl (2RS)-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-2-(4-fluoro-6-iodo-1-oxoisoindolin-2-yl)acetate (Example 50, step 1) (200 mg, 0.41 mmol) and tert-butyl-4-[2-ethyl-4-(4,4,5 ,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine-1-carboxylate (Example 37, step 3) (233 mg, 0.534 mmol, 1.3 eq., purity = 95%) was dissolved in 3.0 ml of toluene. Cesium carbonate (401 mg, 1.23 mmol, 3 eq.), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (45 mg, 0.062 mmol, 0.15 eq.) and water (100 mg, 0.10 ml, 5.55 mmol, 13.5 eq.) were added and the reaction mixture was stirred at 6 5°C for 16 hours. The reaction mixture was cooled to room temperature and then extracted with ethyl acetate and water. The aqueous layer was back extracted with ethyl acetate. The organic layers were washed with water and saturated aqueous sodium chloride. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with a dichloromethane:methanol gradient from 100:0 to 95:5. The desired tert-butyl 4-[4-[2-[(1RS)-2-ethoxy-1-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-2-oxoethyl]-7-fluoro-3-oxoisoindolin-5-yl]-2-ethylphenyl]piperidine-1-carboxylate (232 mg, 78% yield, pure ma=90%) was obtained as a brown foam, MS: m/e=649.4 (M+H ⁺ ).

Stage 3: tert-Butyl-4-[2-ethyl-4-[7-fluoro-2-[(1RS)-1-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-2-oxo-2-(thiazol-2-ylamino)ethyl]-3-oxoisoindolin-5-yl]phenyl]piperidine-1-carboxy lat

The title compound was obtained as a brown solid, MS: m/e=703.6 (M+H ⁺ ), using chemical transformations similar to those described in Example 3, step 2, starting from tert-butyl-4-[4-[2-[(1RS)-2-ethoxy-1-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-2 -oxoethyl]-7-fluoro-3-oxoisoindolin-5-yl]-2-ethylphenyl]piperidine-1-carboxylate (Example 50, step 2) and thiazole-2-amine.

Step 4: (2RS)-2-[6-[3-Ethyl-4-(4-piperidyl)phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide

The title compound was obtained as a dark brown solid, MS: m/e=603.4 (M+H ⁺ ), using chemical transformations similar to those described in Example 3, step 3, starting from tert-butyl-4-[2-ethyl-4-[7-fluoro-2-[(1RS)-1-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-1- yl]-2-oxo-2-(thiazol-2-ylamino)ethyl]-3-oxoisoindolin-5-yl]phenyl]piperidine-1-carboxylate (Example 50, step 3).

Step 5: (2RS)-2-[6-[3-Ethyl-4-(1-ethyl-4-piperidyl)phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide

The title compound was obtained as a brown foam, MS: m/e=631.3 (M+H ⁺ ), using chemical transformations similar to those described in Example 4, step 4, starting from (2RS)-2-[6-[3-ethyl-4-(4-piperidyl)phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H- pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide (Example 50, step 4) and ethyl iodide.

Example 51

(2RS)-2-[7-Chloro-4-fluoro-6-(4-morpholinophenyl)-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide

The title compound was obtained as a white solid, MS: m/e=593.2/595.2 (M+H ⁺ ), using chemical transformations similar to those described in Example 18, step 2 and Example 3, step 2, starting from ethyl-(2RS)-2-(7-chloro-4-fluoro-6-iodo-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyr rolo[1,2-c]imidazol-1-yl)acetate (Example 13, step 6) and (4-morpholinophenyl)boronic acid.

Example 52

(2RS)-2-[4-Chloro-6-[3-ethyl-4-(1-ethyl-4-piperidyl)phenyl]-1-oxoisoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-l-yl]-N-thiazol-2-ylacetamide

Step 1: Ethyl-(2RS)-2-(4-chloro-6-iodo-1-oxoisoindolin-2-yl)-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate

The title compound was obtained as a light brown foam, MS: m/e = m/e = 504.0 (M+H ⁺ ), using chemical transformations similar to those described in Example 1, step 6, starting from ethyl-(2RS)-2-amino-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate (Example 17, step 8) and methyl 2-(bromomethyl)-3-chloro-5-iodobenzoate (Example 9, step 3).

Stage 2: tert-Butyl-4-[4-[7-chloro-2-[(1RS)-2-ethoxy-1-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-2-oxoethyl]-3-oxoisoindolin-5-yl]-2-ethylphenyl]piperidine-1-carboxylate

Ethyl (2RS)-2-(4-chloro-6-iodo-1-oxoisoindolin-2-yl)-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate (Example 52, step 1) (115 mg, 0.205 mmol, purity = 90%) and tert-butyl-4-[2-ethyl- 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine-1-carboxylate (Example 37, step 3) (126 mg, 0.288 mmol, 1.4 eq., purity = 95%) was dissolved in 2.5 ml of THF. Cesium carbonate (201 mg, 0.616 mmol, 3 eq.), PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (25 mg, 0.031 mmol, 0.15 eq.) and 0.50 ml of water were added and the reaction mixture was stirred at 65°C for 3 hours. The reaction mixture was cooled to room temperature and then extracted with ethyl acetate and water. The aqueous layer was back extracted with ethyl acetate. The organic layers were washed with water and saturated aqueous sodium chloride. The organic layers were combined, dried over sodium sulfate, filtered and concentrated on Isolute® to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with a dichloromethane:methanol gradient from 100:0 to 95:5. The desired tert-butyl 4-[4-[7-chloro-2-[(1RS)-2-ethoxy-1-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-2-oxoethyl]-3-oxoisoindolin-5-yl]-2-ethylphenyl]piperidine-1-carboxylate (132 mg, 87% yield, pure ma=90%) was obtained as a light brown oil, MS: m/e=665.4 (M+H ⁺ ).

Stage 3: tert-Butyl-4-[4-[7-chloro-2-[(1RS)-1-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-2-oxo-2-(thiazol-2-ylamino)ethyl]-3-oxoisoindolin-5-yl]-2-ethylphenyl]piperidine-1-carboxy lat

The title compound was obtained as a brown solid, MS: m/e=719.5 (M+H ⁺ ), using chemical transformations similar to those described in Example 3, step 2, starting from tert-butyl-4-[4-[7-chloro-2-[(1RS)-2-ethoxy-1-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-1- yl]-2-oxoethyl]-3-oxoisoindolin-5-yl]-2-ethylphenyl]piperidine-1-carboxylate (Example 52, step 2) and thiazole-2-amine.

Step 4: (2RS)-2-[4-Chloro-6-[3-ethyl-4-(4-piperidyl)phenyl]-1-oxoisoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1.2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide

The title compound was obtained as a brown solid, MS: m/e=619.4 (M+H ⁺ ), using chemical transformations similar to those described in Example 3, step 3, starting from tert-butyl-4-[4-[7-chloro-2-[(1RS)-1-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-2- oxo-2-(thiazol-2-ylamino)ethyl]-3-oxoisoindolin-5-yl]-2-ethylphenyl]piperidine-1-carboxylate (Example 52, step 3).

Step 5: (2RS)-2-[4-Chloro-6-[3-ethyl-4-(1-ethyl-4-piperidyl)phenyl]-1-oxoisoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide

The title compound was obtained as a brown foam, MS: m/e=647.5 (M+H ⁺ ), using chemical transformations similar to those described in Example 4, step 4, starting from (2RS)-2-[4-chloro-6-[3-ethyl-4-(4-piperidyl)phenyl]-1-oxoisoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H- pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide (Example 52, step 4) and ethyl iodide.

Example 53

(2RS)-2-[4-Chloro-6-[4-(1-ethyl-4-piperidyl)phenyl]-1-oxoisoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide

Stage 1: Ethyl-(2RS)-2-[4-chloro-6-[4-(1-ethyl-4-piperidyl)phenyl1-1-oxoisoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate

The title compound was obtained as a white foam, MS: m/e=565.3 (M+H ⁺ ) using chemical transformations similar to those described in Example 52, step 2, starting from ethyl-(2RS)-2-(4-chloro-6-iodo-1-oxoisoindolin-2-yl)-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole -1-yl]acetate (Example 52, step 1) and 1-ethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (Example 29, step 1).

Step 2: (2RS)-2-[4-Chloro-6-[4-(1-ethyl-4-piperidyl)phenyl]-1-oxoisoindolin-2-yl1-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide

The title compound was obtained as a white solid, MS: m/e=619.3 (M+H ⁺ ), using chemical transformations similar to those described in Example 3, step 2, starting from ethyl-(2RS)-2-[4-chloro-6-[4-(1-ethyl-4-piperidyl)phenyl]-1-oxoisoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5 N-pyrrolo[1,2-c]imidazol-1-yl]acetate (Example 53, step 1) and thiazol-2-amine.

Example 54

(2RS)-2-[4-Chloro-6-[4-(1-cyclopropyl-4-piperidyl)phenyl]-1-oxoisoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide

Stage 1: tert-Butyl-4-[4-[7-chloro-2-[(1RS)-2-ethoxy-1-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-2-oxoethyl]-3-oxoisoindolin-5-yl]phenyl]piperidine-1-carboxylate

The title compound was obtained as a light brown foam, MS: m/e=637.3 (M+H ⁺ ), using chemical transformations similar to those described in Example 52, step 2, starting from ethyl-(2RS)-2-(4-chloro-6-iodo-1-oxoisoindolin-2-yl)-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c] imidazol-1-yl]acetate (Example 52, step 1) and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-1-carboxylate.

Stage 2: tert-Butyl-4-[4-[7-chloro-2-[(1RS)-1-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-2-oxo-2-(thiazol-2-ylamino)ethyl]-3-oxoisoindolin-5-yl]phenyl]piperidine-1-carboxylate

The title compound was obtained as a light brown foam, MS: m/e=691.3 (M+H ⁺ ), using chemical transformations similar to those described in Example 3, step 2, starting from tert-butyl-4-[4-[7-chloro-2-[(1RS)-2-ethoxy-1-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-1- yl]-2-oxoethyl]-3-oxoisoindolin-5-yl]phenyl]piperidine-1-carboxylate (Example 54, step 1) and thiazol-2-amine.

Step 3: (2RS)-2-[4-Chloro-1-oxo-6-[4-(4-piperidyl)phenyl]isoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide

The title compound was obtained as a white solid, MS: m/e=591.3 (M+H ⁺ ), using chemical transformations similar to those described in Example 3, step 3, starting from tert-butyl-4-[4-[7-chloro-2-[(1RS)-1-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-2-oxo -2-(thiazol-2-ylamino)ethyl]-3-oxoisoindolin-5-yl]phenyl]piperidine-1-carboxylate (Example 54, step 2).

Step 4: (2RS)-2-[4-Chloro-6-[4-(1-cyclopropyl-4-piperidyl)phenyl]-1-oxoisoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide

The title compound was obtained as a white solid, MS: m/e=631.3 (M+H ⁺ ), using chemical transformations similar to those described in Example 27, step 2, starting from (2RS)-2-[4-chloro-1-oxo-6-[4-(4-piperidyl)phenyl]isoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide (Example 54, step 3) and (1-ethoxycyclopropoxy)trimethylsilane.

Example 55

(2RS)-2-[4-Chloro-6-[4-[1-(2-fluoroethyl)-4-piperidyl]phenyl]-1-oxoisoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide

The title compound was obtained as a light brown solid, MS: m/e=637.3 (M+H ⁺ ), using chemical transformations similar to those described in Example 4, step 4, starting from (2RS)-2-[4-chloro-1-oxo-6-[4-(4-piperidyl)phenyl]isoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrole o[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide (Example 54, step 3) and 2-fluoroethyl-4-methylbenzenesulfonate.

Example 56

(2RS)-2-[4-Chloro-6-[4-[1-(2-cyanoethyl)-4-piperidyl]phenyl]-1-oxoisoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide

The title compound was obtained as a white solid, MS: m/e=644.3 (M+H ⁺ ), using chemical transformations similar to those described in Example 4, step 4, starting from (2RS)-2-[4-chloro-1-oxo-6-[4-(4-piperidyl)phenyl]isoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1 ,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide (Example 54, step 3) and 3-bromopropanenitrile.

Example 57

(2RS)-2-[4-Chloro-6-[3-ethyl-4-[1-(2-fluoroethyl)-4-piperidyl]phenyl]-1-oxoisoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide

The title compound was obtained as a white foam, MS: m/e=665.4 (M+H ⁺ ), using chemical transformations similar to those described in Example 4, step 4, starting from (2RS)-2-[4-chloro-6-[3-ethyl-4-(4-piperidyl)phenyl]-1-oxoisoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrole o[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide (Example 52, step 4) and 2-fluoroethyl-4-methylbenzenesulfonate.

Example 58

(2RS)-2-[4-Chloro-6-[4-[1-(2-fluoroethyl)-4-piperidyl]phenyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide

Step 1: 1-(2-Fluoroethyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine

The title compound was obtained as a dark red solid, MS: m/e=334.2 (M+H ⁺ ), using chemical transformations similar to those described in Example 4, step 4 and Example 19, step 2, starting from 4-(4-bromophenyl)piperidine and 2-fluoroethyl-4-methylbenzenesulfonate.

Step 2: (2RS)-2-[4-Chloro-6-[4-[1-(2-fluoroethyl)-4-piperidyl]phenyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide

The title compound was obtained as a light brown solid, MS: m/e=619.3 (M+H ⁺ ), using chemical transformations similar to those described in Example 52, step 2 and Example 3, step 2, starting from ethyl-(2RS)-2-(4-chloro-6-iodo-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c ]imidazol-1-yl)acetate (Example 9, step 4) and 1-(2-fluoroethyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine (Example 58, step 1).

Example 59

(2RS)-2-[4-Chloro-6-[4-[1-(2,2-difluoroethyl)-4-piperidyl]phenyl]-1-oxoisoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide

Stage 1: Ethyl-(2RS)-2-(4-chloro-6-bromo-1-oxoisoindolin-2-yl)-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate

The title compound was obtained as a yellow oil, MS: m/e = m/e = 474.0/476.0 (M+H ⁺ ), using chemical transformations similar to those described in Example 1, step 6, starting from ethyl-(2RS)-2-amino-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate (Example 17, step 8) and methyl 5-bromo-2-(bromomethyl)-3-chlorobenzoate (Example 6, step 1).

Step 2: 1-(2,2-Difluoroethyl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine

The title compound was obtained as a light brown solid, MS: m/e=352.2 (M+H ⁺ ), using chemical transformations similar to those described in Example 4, step 4 and Example 19, step 2, starting from 4-(4-bromophenyl)piperidine and 2,2-difluoroethyltrifluoromethanesulfonate.

Step 3: (2RS)-2-[4-Chloro-6-[4-[1-(2.2-difluoroethyl)-4-piperidyl]phenyl]-1-oxoisoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide

The title compound was obtained as a white solid, MS: m/e=655.2 (M+H ⁺ ), using chemical transformations similar to those described in Example 52, step 2 and Example 3, step 2, starting from ethyl-(2RS)-2-(4-chloro-6-bromo-1-oxoisoindolin-2-yl)-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo [1,2-c]imidazol-1-yl]acetate (Example 59, step 1) and 1-(2,2-difluoroethyl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (Example 59, step 2).

Example 60

(2RS)-2-[4,7-Dichloro-6-[4-(1-ethyl-4-piperidyl)phenyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide

Stage 1: Ethyl 5-amino-3-bromo-2-chloro-6-methylbenzoate

The title compound was obtained as a colorless oil, MS: m/e=293.7 (M+H ⁺ ), using chemical transformations similar to those described in Example 13, step 3, starting from 6-chloro-2-methyl-3-nitrobenzoic acid and NBS.

Stage 2: Ethyl 3-bromo-2,5-dichloro-6-methylbenzoate

Ethyl 5-amino-3-bromo-2-chloro-6-methylbenzoate (Example 60, step 1) (40 g, 136.7 mmol) was dissolved in 200 ml of dioxane and 40 ml of water. At 0-5° C., 200 ml HCl 30% in water and sodium nitrite (10.4 g, 150.4 mmol, 1.1 eq.) were added. The mixture was stirred for 1 hour and copper (I) chloride (14.9 g, 150.4 mmol, 1.1 eq.) was added. The mixture was stirred at 0-5°C for 1 hour. The reaction mixture was extracted with water and three times with ethyl acetate. The organic layers were dried over sodium sulfate and concentrated to dryness to give the desired product (35 g, 82% yield) as a colorless oil.

Step 3: Ethyl 5-bromo-2-(bromomethyl)-3,6-dichlorobenzoate

The title compound was obtained as a light green gum using chemical transformations similar to those described in Example 1, step 5, starting from ethyl 3-bromo-2,5-dichloro-6-methylbenzoate (Example 60, step 2).

Step 4: Ethyl-(2RS)-2-(6-bromo-4,7-dichloro-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate

The title compound was obtained as a gray solid, MS: m/e=472.0 (M+H ⁺ ), using chemical transformations similar to those described in Example 1, step 6, starting from ethyl-(2RS)-2-amino-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate (Example 1, step 3) and ethyl-5-bromo-2-( bromomethyl)-3,6-dichlorobenzoate (Example 60, step 3).

Step 5: Ethyl-(2RS)-2-[4,7-dichloro-6-[4-(1-ethyl-4-piperidyl)phenyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate

The title compound was obtained as a brown waxy substance, MS: m/e=581.3 (M+H ⁺ ), using chemical transformations similar to those described in Example 52, step 2, starting from ethyl-(2RS)-2-(6-bromo-4,7-dichloro-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-1 -yl)acetate (Example 60, step 5) and 1-ethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (Example 29, step 1).

Step 6: (2RS)-2-[4,7-Dichloro-6-[4-(1-ethyl-4-piperidyl)phenyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide

The title compound was obtained as a light yellow solid, MS: m/e=635.1 (M+H ⁺ ), using chemical transformations similar to those described in Example 3, step 2, starting from ethyl-(2RS)-2-[4,7-dichloro-6-[4-(1-ethyl-4-piperidyl)phenyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyr rolo[1,2-c]imidazol-1-yl)acetate (Example 60, step 5) and thiazol-2-amine.

Example 61

(2RS)-2-[4,7-Dichloro-6-[4-(1-ethyl-4-piperidyl)phenyl]-1-oxoisoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide

Stage 1: Ethyl-(2RS)-2-amino-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate hydrochloride

The title compound was obtained as a white solid using chemical transformations similar to those described in Example 1, step 4, starting from ethyl-(2RS)-2-amino-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate (Example 17, step 8).

Stage 2: Ethyl-(2RS)-2-(6-bromo-4,7-dichloro-1-oxoisoindolin-2-yl)-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate

The title compound was obtained as a yellowish white solid, MS: m/e = m/e = 492.1 (M+H ⁺ ), using chemical transformations similar to those described in Example 1, step 6, starting from ethyl-(2RS)-2-amino-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl] acetate hydrochloride ( Example 61, step 1) and ethyl 5-bromo-2-(bromomethyl)-3,6-dichlorobenzoate (Example 60, step 3).

Stage 3: Ethyl-(2RS)-2-[4,7-dichloro-6-[4-(1-ethyl-4-piperidyl)phenyl]-1-oxoisoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate

The title compound was obtained as a brown waxy substance, MS: m/e=599.3 (M+H ⁺ ), using chemical transformations similar to those described in Example 52, step 2, starting from ethyl-(2RS)-2-(6-bromo-4,7-dichloro-1-oxoisoindolin-2-yl)-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1, 2-c]imidazol-1-yl]acetate (Example 61, step 2) and 1-ethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (Example 29, step 1).

Step 4: (2RS)-2-[4,7-Dichloro-6-[4-(1-ethyl-4-piperidyl)phenyl]-1-oxoisoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide

The title compound was obtained as a brown solid, MS: m/e=655.2 (M+H ⁺ ), using chemical transformations similar to those described in Example 3, step 2, starting from ethyl-(2RS)-2-[4,7-dichloro-6-[4-(1-ethyl-4-piperidyl)phenyl]-1-oxoisoindolin-2-yl]-2-[(6R)-6-fluoro-6,7 -dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate (Example 61, step 3) and thiazol-2-amine.

Example 62

(2RS)-2-[4,7-Dichloro-6-[4-[1-(2-fluoroethyl)-4-piperidyl]phenyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide

Step 1: Ethyl-(2RS)-2-[4,7-dichloro-6-[4-[1-(2-fluoroethyl)-4-piperidyl]phenyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)acetate

The title compound was obtained as a yellowish white foam, MS: m/e=599.3 (M+H ⁺ ), using chemical transformations similar to those described in Example 52, step 2, starting from ethyl-(2RS)-2-(6-bromo-4,7-dichloro-1-oxoisoindolin-2-yl)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-1 -yl)acetate (Example 60, step 4) and 1-(2-fluoroethyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine (Example 58, step 1).

Step 2: (2RS)-2-[4,7-Dichloro-6-[4-[1-(2-fluoroethyl)-4-piperidyl]phenyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide

The title compound was obtained as a brown solid, MS: m/e=653.3 (M+H ⁺ ), using chemical transformations similar to those described in Example 3, step 2, starting from ethyl 5H-pyrrolo[1,2-c]imidazol-1-yl)acetate (Example 62, step 1) and thiazol-2-amine.

Example 63

(2RS)-2-[4,7-Dichloro-6-[4-[1-(2-fluoroethyl)-4-piperidyl]phenyl]-1-oxoisoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide

Step 1: Ethyl-(2RS)-2-[4,7-dichloro-6-[4-[1-(2-fluoroethyl)-4-piperidyl]phenyl]-1-oxoisoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate

The title compound was obtained as a light brown foam, MS: m/e=617.3 (M+H ⁺ ), using chemical transformations similar to those described in Example 52, step 2, starting from ethyl-(2RS)-2-(6-bromo-4,7-dichloro-1-oxoisoindolin-2-yl)-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2 -c]imidazol-1-yl]acetate (Example 61, step 2) and 1-(2-fluoroethyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine (Example 58, step 1).

Step 2: (2RS)-2-[4,7-Dichloro-6-[4-[1-(2-fluoroethyl)-4-piperidyl]phenyl]-1-oxoisoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide

The title compound was obtained as a yellowish white solid, MS: m/e=673.2 (M+H ⁺ ), using chemical transformations similar to those described in Example 3, step 2, starting from ethyl-(2RS)-2-[4,7-dichloro-6-[4-[1-(2-fluoroethyl)-4-piperidyl]phenyl]-1-oxoisoindolin-2-yl]-2-[(6R)- 6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate (Example 63, step 1) and thiazol-2-amine.

Example 64

(2RS)-2-[4,7-Dichloro-6-(4-morpholinophenyl)-1-oxoisoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-l-yl]-N-thiazol-2-ylacetamide

Step 1: Ethyl-(2RS)-2-[4,7-dichloro-6-(4-morpholinophenyl)-1-oxoisoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate

The title compound was obtained as a light brown foam, MS: m/e=573.3 (M+H ⁺ ), using chemical transformations similar to those described in Example 52, step 2, starting from ethyl-(2RS)-2-(6-bromo-4,7-dichloro-1-oxoisoindolin-2-yl)-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2 -c]imidazol-1-yl]acetate (Example 61, step 2) and (4-morpholinophenyl)boronic acid.

Step 2: (2RS)-2-[4,7-Dichloro-6-(4-morpholinophenyl)-1-oxoisoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide

The title compound was obtained as a brown solid, MS: m/e=627.3 (M+H ⁺ ), using chemical transformations similar to those described in Example 3, step 2, starting from ethyl-(2RS)-2-[4,7-dichloro-6-(4-morpholinophenyl)-1-oxoisoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrole o[1,2-c]imidazol-1-yl]acetate (Example 64, step 1) and thiazol-2-amine.

Example 65

(2RS)-2-[4-Chloro-6-[4-[(3R,4R)-1-ethyl-3-fluoro-4-piperidyl]phenyl]-1-oxoisoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide and (2RS)-2-[4 -chloro-6-[4-[(3S,4S)-1-ethyl-3-fluoro-4-piperidyl]phenyl]-1-oxoisoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide

Step 1: tert-Butyl-(3R,4R)-4-[4-[7-chloro-2-[(1RS)-2-ethoxy-1-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-2-oxoethyl]-3-oxoisoindolin-5-yl]phenyl]-3-fluoropiperidine-1-carboxy lat and tert-butyl-(3S,4S)-4-[4-[7-chloro-2-[(1RS)-2-ethoxy-1-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-2-oxoethyl]-3-oxoisoindolin-5-yl]phenyl]-3-fluoropiperidine-1-carboxylate

Target compounds were obtained as a mixture and as a brown foam, MS: m/e=655.4 (M+H⁺), using chemical transformations similar to those described in Example 52, step 2, starting from ethyl-(2RS)-2-(4-chloro-6-bromo-1-oxoisoindolin-2-yl)-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetate (Example 59, step 1) and a mixture of tert-butyl-( 3R,4R)-3-fluoro-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine-1-carboxylate, and tert-butyl-(3S,4S)-3-fluoro-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine-1-carbox ylate (Example 32, step 3).

Step 2: tert-Butyl-(3R,4R)-4-[4-[7-chloro-2-[(1RS)-1-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-2-oxo-2-(thiazol-2-ylamino)ethyl]-3-oxoisoindolin-5-yl]phenyl]-3-fluoropiper idine-1-carboxylate and tert-butyl-(3S,4S)-4-[4-[7-chloro-2-[(1RS)-1-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-2-oxo-2-(thiazol-2-ylamino)ethyl]-3-oxoisoindolin-5-yl]phenyl]-3- fluoropiperidine-1-carboxylate

Target compounds were obtained as a mixture and as a brown foam, MS: m/e=709.3 (M+H⁺), using chemical transformations similar to those described in Example 3, step 2, starting from a mixture of tert-butyl-(3R,4R)-4-[4-[7-chloro-2-[(1RS)-2-ethoxy-1-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-2-oxoethyl]-3-oxoisoindoline-5- yl]phenyl]-3-fluoropiperidine-1-carboxylate and tert-butyl-(3S,4S)-4-[4-[7-chloro-2-[(1RS)-2-ethoxy-1-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-2-oxoethyl]-3-oxoisoindolin-5-yl]phenyl]-3- fluoropiperidine-1-carboxylate (Example 65, step 1) and thiazole-2-amine.

Step 3: (2RS)-2-[4-Chloro-6-[4-[(3R,4R)-3-fluoro-4-piperidyl]phenyl]-1-oxoisoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide and (2RS)-2- [4-chloro-6-[4-[(3S,4S)-3-fluoro-4-piperidyl]phenyl]-1-oxoisoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide

Target compounds were obtained as a mixture and as a brown foam, MS: m/e=609.3 (M+H⁺), using chemical transformations similar to those described in Example 3, step 3, starting from a mixture of tert-butyl-(3R,4R)-4-[4-[7-chloro-2-[(1RS)-1-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-2-oxo-2-(thiazol-2-ylamino)ethyl]-3- oxoisoindolin-5-yl]phenyl]-3-fluoropiperidine-1-carboxylate and tert-butyl-(3S,4S)-4-[4-[7-chloro-2-[(1RS)-1-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-2-oxo-2-(thiazol-2-ylamino)ethyl]- 3-oxoisoindolin-5-yl]phenyl]-3-fluoropiperidine-1-carboxylate (Example 65, step 2).

Step 4: (2RS)-2-[4-Chloro-6-[4-[(3R,4R)-1-ethyl-3-fluoro-4-piperidyl]phenyl]-1-oxoisoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide and (2RS )-2-[4-chloro-6-[4-[(3S,4S)-1-ethyl-3-fluoro-4-piperidyl]phenyl]-1-oxoisoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide

Target compounds were obtained as a mixture and as a light brown foam, MS: m/e=637.5 (M+H⁺), using chemical transformations similar to those described in Example 4, step 4, starting from the mixture -thiazol-2-ylacetamide and (2RS)-2-[4-chloro-6-[4-[(3S,4S)-3-fluoro-4-piperidyl]phenyl]-1-oxoisoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide (Example 65, step 3) and ethyl iodide.

Example 66

(2RS)-2-[(6R)-6-Fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-2-[4-fluoro-6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide

Step 1: [1-[(4-Ethynylphenyl)methyl]-4-piperidyl]methanol

The title compound was obtained as an orange viscous oil, MS: m/e=230.2 (M+H ⁺ ), using chemical transformations similar to those described in Example 1, step 10, starting from 4-ethynylbenzaldehyde and 4-piperidylmethanol.

Step 2: (2RS)-2-[(6R)-6-Fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-2-(4-fluoro-6-iodo-1-oxoisoindolin-2-yl)-N-thiazol-2-ylacetamide

The title compound was obtained as a light brown foam, MS: m/e=542.0 (M+H ⁺ ), using chemical transformations similar to those described in Example 3, step 2, starting from ethyl-(2RS)-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-2-(4-fluoro-6-iodo-1-oxoisoind olin-2-yl)acetate (Example 50, step 1) and thiazol-2-amine.

Step 3: (2RS)-2-[(6R)-6-Fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-2-[4-fluoro-6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide

The title compound was obtained as a yellowish white solid, MS: m/e=643.5 (M+H ⁺ ) using chemical reactions similar to those described in Example 1, step 9, starting from (2RS)-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-2-(4-fluoro-6-iodo-1-oxoisoindoline -2-yl)-N-thiazol-2-ylacetamide (Example 66, step 2) and [1-[(4-ethynylphenyl)methyl]-4-piperidyl]methanol (Example 66, step 1).

Example 67

(2RS)-2-[4-Chloro-6-[4-(1-ethyl-3,3-difluoro-4-piperidyl)phenyl]-1-oxoisoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide

Stage 1: tert-Butyl-4-(4-bromophenyl)-3-oxo-piperidine-1-carboxylate

tert-Butyl-4-(4-bromophenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (CAS 273727-44-9) (500 mg, 1.4 mmol) was combined with 15 ml of dichloromethane and cooled to 0°C. Dess-Martin periodinane (15% solution in dichloromethane) (5.95 g, 4.37 ml, 2.11 mmol, 1.5 eq.) was added at 0° C. and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into dichloromethane and extracted with water and saturated NaHCO ₃ solution. The aqueous layer was back extracted with dichloromethane. The organic layers were washed with Na ₂ S ₂ O ₃ solution. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with an ethyl acetate:heptane gradient from 0:100 to 50:50. The desired tert-butyl 4-(4-bromophenyl)-3-oxo-piperidine-1-carboxylate (450 mg, 72% yield, purity=80%) was obtained as a colorless oil, MS: m/e=300.0 (M-tert-Bu+H ⁺ ).

Stage 2: tert-Butyl-4-(4-bromophenyl)-3,3-difluoropiperidine-1-carboxylate

In a 100 ml plastic round bottom flask, a mixture of tert-butyl 4-(4-bromophenyl)-3-oxopiperidine-1-carboxylate (Example 67, step 1) (875 mg, 2.47 mmol), triethylamine trihydrofluoride (CAS 73602-61-6) (1.19 g, 1.21 ml, 7.41 mmol, 3 eq. c.) and XtalFluor-E® (CAS 63517-29-3) (1.13 g, 4.94 mmol, 2 eq.) in 40 ml dichloromethane was stirred at room temperature for 16 hours. The reaction mixture was quenched with saturated NaHCO ₃ solution, stirred for 10 min and then extracted twice with dichloromethane. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with an ethyl acetate:heptane gradient from 0:100 to 30:70. The desired tert-butyl 4-(4-bromophenyl)-3,3-difluoropiperidine-1-carboxylate (680 mg, 70% yield, purity=95%) was obtained as a colorless oil, MS: m/e=320.0 (M-tert-Bu+H ⁺ ).

Stage 3: tert-Butyl-3,3-difluoro-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine-1-carboxylate

The title compound was obtained as a colorless oil, MS: m/e=324.1 (M-tert-Bu+H ⁺ ), using chemical transformations similar to those described in Example 19, step 2, starting from tert-butyl-4-(4-bromophenyl)-3,3-difluoropiperidine-1-carboxylate (Example 67, step 2).

Stage 4: tert-Butyl-4-[4-[7-chloro-2-[(1RS)-2-ethoxy-1-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-2-oxoethyl]-3-oxoisoindolin-5-yl]phenyl]-3,3-difluoropiperidine-1-carboxylate

The title compound was obtained as a yellowish white foam, MS: m/e=673.3 (M+H ⁺ ), using chemical transformations similar to those described in Example 52, step 2, starting from ethyl ]imidazol-1-yl]acetate (Example 59, step 1) and tert-butyl-3,3-difluoro-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine-1-carboxylate (Example 67, step 3).

Step 5: tert-Butyl-4-[4-[7-chloro-2-[(1RS)-1-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-2-oxo-2-(thiazol-2-ylamino)ethyl]-3-oxoisoindolin-5-yl]phenyl]-3.3-difluoropiperidin-1- carboxylate

The title compound was obtained as a light brown foam, MS: m/e=727.3 (M+H ⁺ ), using chemical transformations similar to those described in Example 3, step 2, starting from tert-butyl-4-[4-[7-chloro-2-[(1RS)-2-ethoxy-1-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-1- yl]-2-oxoethyl]-3-oxoisoindolin-5-yl]phenyl]-3,3-difluoropiperidine-1-carboxylate (Example 67, step 4) and thiazol-2-amine.

Step 6: (2RS)-2-[4-Chloro-6-[4-(3,3-difluoro-4-piperidyl)phenyl]-1-oxoisoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide

The title compound was obtained as a brown foam, MS: m/e=627.2 (M+H ⁺ ), using chemical transformations similar to those described in Example 3, step 3, starting from tert-butyl-4-[4-[7-chloro-2-[(1RS)-1-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-2-oc co-2-(thiazol-2-ylamino)ethyl]-3-oxoisoindolin-5-yl]phenyl]-3,3-fluoropiperidine-1-carboxylate (Example 67, step 5).

Step 7: (2RS)-2-[4-Chloro-6-[4-(1-ethyl-3.3-difluoro-4-piperidyl)phenyl]-1-oxoisoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide

The title compound was obtained as a yellowish white solid, MS: m/e=655.2 (M+H ⁺ ), using chemical transformations similar to those described in Example 1, step 10, starting from (2RS)-2-[4-chloro-6-[4-(3,3-difluoro-4-piperidyl)phenyl]-1-oxoisoindolin-2-yl]-2-[(6R)-6-fluoro-6.7 -dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide (Example 67, step 6) and acetaldehyde.

Example 68

(2RS)-2-[4-Chloro-6-[4-[1-(2-hydroxyethyl)-4-piperidyl]phenyl]-1-oxoisoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide

The title compound was obtained as a white solid, MS: m/e=635.4 (M+H ⁺ ), using chemical transformations similar to those described in Example 1, step 10, starting from (2RS)-2-[4-chloro-1-oxo-6-[4-(4-piperidyl)phenyl]isoindolin-2-yl]-2-[(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[ 1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide (Example 54, step 3) and 2-hydroxyacetaldehyde.

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¹⁶ CAS 457613-78-4

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²⁰ CAS 1430472-07-3

²¹ CAS 1702698-94-9

²² CAS 27628-46-2

²³ CAS 899821-27-3

Claims (147)

1. Compound of formula I where L is absent or represents -(C≡C)-, A represents B is phenyl or pyridyl, C is thiazolyl, Y is N or CH, each R ¹ is independently halogen, each R ² is independently selected from the group consisting of i) -(CH ₂ ) _k -N(R ⁴ ,R ⁵ ), ii) halogen, iii) halo-C _1-6 -alkyl, iv) C _1-6 alkyl optionally substituted with OH; R ⁴ and R ⁵ together with the N atom to which they are attached form a heterocyclyl, wherein the heterocyclyl is piperazinyl, piperidinyl or morpholino and is optionally substituted with one to three R ⁶ ; each R ⁶ is independently selected from the group consisting of i) -OH, ii) halogen, iii) C _3-8 -cycloalkyl, iv) halo-C _1-6 -alkyl and v) C _1-6 alkyl; each R ⁷ is independently selected from the group consisting of i) H and ii) halogen, R ⁸ is H, each R ⁹ is independently selected from the group consisting of i) H and ii) halogen, k is 0, 1 or 2, n is 0, 1, 2, 3, or 4; m is 0, 1 or 2; p is 0, or a pharmaceutically acceptable salt thereof. 2. The compound of formula I or its pharmaceutically acceptable salt according to claim 1, where L is absent or is -(C≡C)-, A represents B is phenyl or pyridyl, C is thiazolyl, Y is N or CH, each R ² is independently selected from the group consisting of i) -(CH ₂ ) _k -N(R ⁴ ,R ⁵ ), ii) halo-C _1-6 -alkyl and iii) C _1-6 alkyl optionally substituted with OH; R ⁴ and R ⁵ together with the N atom to which they are attached form a heterocyclyl, wherein the heterocyclyl is piperazinyl, piperidinyl or morpholino and is optionally substituted with one to three R ⁶ ; each R ⁶ is independently selected from the group consisting of i) -OH, ii) halogen, iii) C _3-8 -cycloalkyl, iv) halo-C _1-6 -alkyl and v) C _1-6 alkyl; R ⁷ is H or halogen; R ⁸ is H; R ⁹ is halo; k is 0 or 1; n is 0; m is 1; r is 0. 3. The compound of formula I or its pharmaceutically acceptable salt according to claim 1, where A represents where Y is N or CH and each R ^a , R ^b , R ^c or R ^d is independently halogen, in particular where A is 6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl or 6,7-dihydro-5H-pyrrolisin-1-yl. 4. The compound of formula I or its pharmaceutically acceptable salt according to any one of paragraphs. 1-3, where B represents phenyl. 5. The compound of formula I or its pharmaceutically acceptable salt according to any one of paragraphs. 1-4, where B is pyridinyl. 6. The compound of formula I or its pharmaceutically acceptable salt according to any one of paragraphs. 1-5 where n is 0. 7. The compound of formula I or its pharmaceutically acceptable salt according to any one of paragraphs. 1-6 where m is 1. 8. The compound of formula I or its pharmaceutically acceptable salt according to any one of paragraphs. 1-7 where p is 0. 9. The compound of formula I or its pharmaceutically acceptable salt according to any one of paragraphs. 1-8, where R ² is -(CH ₂ ) _k -N(R ⁴ ,R ⁵ ), k is 0 or 1 and R ⁴ and R ⁵ together with the N atom to which they are attached form a heterocyclyl, wherein the heterocyclyl is piperazinyl, piperidinyl or morpholino and is optionally substituted with R ⁶ . 10. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: (2RS)-2-(6,7-dihydro-5H-pyrrolisin-1-yl)-2-[4-fluoro-6-[2-[4-[(4-hydroxy-1-piperidyl)methyl]phenyl]ethynyl]-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide, (2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-6-[2-[4-[(4-methylpiperazin-1-yl)methyl]phenyl]ethynyl]-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide, (2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-6-[2-[4-[(4-hydroxy-1-piperidyl)methyl]phenyl]ethynyl]-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide, (2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-1-oxo-6-(4-piperazin-1-ylphenyl)isoindolin-2-yl]-N-thiazol-2-ylacetamide, (2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-6-[4-(4-hydroxy-1-piperidyl)phenyl]-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide, (2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-6-[2-[4-(hydroxymethyl)phenyl]ethynyl]-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide, (2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-1-oxo-6-[2-[4-(1-piperidylmethyl)phenyl]ethynyl]isoindolin-2-yl]-N-thiazol-2-ylacetamide, (2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[4-(4-ethylpiperazin-1-yl)phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide, (2RS)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[6-(4-ethylpiperazin-1-yl)-3-pyridyl]-4-fluoro-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide, (2RS)-2-[4-chloro-6-[2-[4-[(4-hydroxy-1-piperidyl)methyl]phenyl]ethynyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide, (2RS)-2-[4-chloro-6-[4-(4-ethylpiperazin-1-yl)phenyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide, (2RS)-2-[4-chloro-6-[4-(4-hydroxy-1-piperidyl)phenyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide, (2RS)-2-[4-chloro-6-[6-(4-hydroxy-1-piperidyl)-3-pyridyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide and (2RS)-2-[7-chloro-4-fluoro-6-[2-[4-[(4-hydroxy-1-piperidyl)methyl]phenyl]ethynyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide. 11. A compound or a pharmaceutically acceptable salt thereof, where the compound is selected from the group consisting of: 2-[4-chloro-1-oxo-6-[2-[4-(1-piperidylmethyl)phenyl]ethynyl]isoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[4-(1-ethyl-4-piperidyl)phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide; 2-[4-fluoro-6-[2-[4-[(4-hydroxy-1-piperidyl)methyl]phenyl]ethynyl]-1-oxoisoindolin-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide; 2-[6-[3-chloro-4-(4-ethylpiperazin-1-yl)phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide; 2-[6-[3-chloro-4-[rac-(3R)-3-methylpiperazin-1-yl]phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide; 2-[6-[3-chloro-4-[rac-(3R)-4-ethyl-3-methylpiperazin-1-yl]phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide; 2-[4-chloro-6-[4-[(1-ethyl-4-piperidyl)oxy]phenyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide; 2-[6-(3-chloro-4-morpholinophenyl)-4-fluoro-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide; 2-[6-[3-chloro-4-(4-ethylpiperazin-1-yl)phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide; 2-[6-(3-chloro-4-morpholinophenyl)-4-fluoro-1-oxoisoindolin-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide; 2-[6-[3-chloro-4-[rac-(3R)-4-ethyl-3-methylpiperazin-1-yl]phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide; 2-[6-[4-(1-ethyl-4-piperidyl)-3-fluorophenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide; 2-[6-[4-(1-cyclopropyl-4-piperidyl)phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide; 2-[4-chloro-6-[4-(1-cyclopropyl-4-piperidyl)phenyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide; 2-[4-chloro-6-[4-(1-ethyl-4-piperidyl)phenyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide; 2-[6-[3-chloro-4-(1-ethyl-4-piperidyl)phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide; 2-[6-[4-(1-ethyl-4-piperidyl)phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-1-oxo-6-[4-[rac-(3R,4R)-1-ethyl-3-fluoro-4-piperidyl]phenyl]isoindolin-2-yl]-N-thiazol-2-ylacetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[4-(1-ethyl-4-piperidyl)-3-fluorophenyl]-4-fluoro-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide; 2-[6-[4-[1-(2,2-difluoroethyl)-4-piperidyl]phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-6-[4-[1-(2-methoxyethyl)-4-piperidyl]phenyl]-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-6-[4-[1-(2-fluoroethyl)-4-piperidyl]phenyl]-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[3-ethyl-4-(1-ethyl-4-piperidyl)phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide; 2-[6-[4-(4-cyclopropylpiperazin-1-yl)-3-fluorophenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide; 2-[6-[3-chloro-4-(4-cyclopropylpiperazin-1-yl)phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide; 2-[4-chloro-6-[4-(4-cyclopropylpiperazin-1-yl)-3-fluorophenyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-acetamide; 2-[6-[3-chloro-4-[4-(2,2-difluoroethyl)piperazin-1-yl]phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide; 2-[6-[4-(4-cyclopropylpiperazin-1-yl)-3-fluorophenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide; 2-[6-[2-(2-chlorophenyl)ethynyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide; 2-[6-[2-[4-[(4,4-Difluoro-1-piperidyl)methyl]phenyl]ethynyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide; 2-(6,7-dihydro-5H-pyrrolisin-1-yl)-2-[4-fluoro-6-(3-fluoro-4-morpholinophenyl)-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide; 2-[6-[3-chloro-4-(4-cyclopropylpiperazin-1-yl)phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[4-fluoro-1-oxo-6-[2-[4-(trifluoromethyl)phenyl]ethynyl]isoindolin-2-yl]-N-thiazol-2-ylacetamide; 2-(6,7-dihydro-5H-pyrrolisin-1-yl)-2-[6-[4-(1-ethyl-4-piperidyl)phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-N-thiazol-2-ylacetamide; 2-[6-[3-chloro-4-[4-(2-fluoroethyl)piperazin-1-yl]phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide; 2-[6-[3-ethyl-4-(1-ethyl-4-piperidyl)phenyl]-4-fluoro-1-oxoisoindolin-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide; 2-[7-chloro-4-fluoro-6-(4-morpholinophenyl)-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide; 2-[4-chloro-6-[3-ethyl-4-(1-ethyl-4-piperidyl)phenyl]-1-oxoisoindolin-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide; 2-[4-chloro-6-[4-(1-ethyl-4-piperidyl)phenyl]-1-oxoisoindolin-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide; 2-[4-chloro-6-[4-(1-cyclopropyl-4-piperidyl)phenyl]-1-oxoisoindolin-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide; 2-[4-chloro-6-[4-[1-(2-fluoroethyl)-4-piperidyl]phenyl]-1-oxoisoindolin-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide; 2-[4-chloro-6-[4-[1-(2-cyanoethyl)-4-piperidyl]phenyl]-1-oxoisoindolin-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide; 2-[4-chloro-6-[3-ethyl-4-[1-(2-fluoroethyl)-4-piperidyl]phenyl]-1-oxoisoindolin-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide; 2-[4-chloro-6-[4-[1-(2-fluoroethyl)-4-piperidyl]phenyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide; 2-[4-chloro-6-[4-[1-(2,2-difluoroethyl)-4-piperidyl]phenyl]-1-oxoisoindolin-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide; 2-[4,7-dichloro-6-[4-(1-ethyl-4-piperidyl)phenyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide; 2-[4,7-dichloro-6-[4-(1-ethyl-4-piperidyl)phenyl]-1-oxoisoindolin-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide; 2-[4,7-dichloro-6-[4-[1-(2-fluoroethyl)-4-piperidyl]phenyl]-1-oxoisoindolin-2-yl]-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-thiazol-2-ylacetamide; 2-[4,7-dichloro-6-[4-[1-(2-fluoroethyl)-4-piperidyl]phenyl]-1-oxoisoindolin-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide; 2-[4,7-dichloro-6-(4-morpholinophenyl)-1-oxoisoindolin-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide; 2-[4-chloro-1-oxo-6-[4-[rac-(3R,4R)-1-ethyl-3-fluoro-4-piperidyl]phenyl]isoindolin-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide; 2-[4-fluoro-6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-1-oxoisoindolin-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide; 2-[4-chloro-6-[4-(1-ethyl-3,3-difluoro-4-piperidyl)phenyl]-1-oxoisoindolin-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide; 2-[4-chloro-6-[4-[1-(2-hydroxyethyl)-4-piperidyl]phenyl]-1-oxoisoindolin-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide. 12. A compound or a pharmaceutically acceptable salt thereof, where the compound is selected from the group consisting of: 2-[4-chloro-6-[3-ethyl-4-[1-(2-fluoroethyl)-4-piperidyl]phenyl]-1-oxoisoindolin-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide; 2-[4-chloro-1-oxo-6-[4-[rac-(3R,4R)-1-ethyl-3-fluoro-4-piperidyl]phenyl]isoindolin-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-thiazol-2-ylacetamide. 13. The compound of formula I or its pharmaceutically acceptable salt according to any one of paragraphs. 1-11 for use in the therapeutic and/or prophylactic treatment of non-small cell lung cancer characterized by mutations that activate the epidermal growth factor receptor (EGFR). 14. The compound of formula I or its pharmaceutically acceptable salt according to any one of paragraphs. 1-11 for use in the manufacture of a medicament for the therapeutic and/or prophylactic treatment of non-small cell lung cancer characterized by EGFR activating mutations. 15. A pharmaceutical composition that inhibits EGFR mutant variants containing T790M/L858R, T790M/L858R/C797S, L858R or L858R/C797S, and the composition contains an effective amount of a compound according to any one of paragraphs. 1-11 and a pharmaceutically acceptable excipient.