DESC:FIELD OF INVENTION
The present invention relates to novel compounds of general formula (1), their suitable pharmaceutically acceptable salts, their solvates, their hydrates, their stereoisomers, their polymorphs, their racemic mixtures, their optically active forms and their use in the treatment of inflammatory conditions such as psoriasis, asthma, psoriatic arthritis or rheumatoid arthritis. Further, the present invention relates to processes of preparing such compounds, novel intermediates involved in their synthesis.

BACKGROUND TO THE INVENTION
Interleukin 17 (IL 17) is a pro-inflammatory cytokine that contributes to the pathogenesis of several inflammatory diseases. The IL-17 family of cytokines consists of six isoforms (IL-17A-IL-17F) and five receptors, IL-17RA-E. IL-17A is the prototype and the best-studied member of IL-17 family, and it shares the highest sequence homology with IL-17F at 50%. IL-17A and IL-17F are known to form tightly associated homodimers, but IL-17A/F heterodimers have also been identified in vivo. IL-17RA is the prototype of IL-17R family and a shared receptor for at least IL-17A, IL-17C, IL-17E, IL-17F, and IL-17A/F signaling. IL-17RA pairs with other IL-17R members to form heterodimeric receptor complexes on the cell surface for differential IL-17 cytokine signaling. IL-17A and IL-17F signaling through the cell surface receptor complex consists of IL-17RA and IL-17RC. Both IL-17RA and IL-17RC consist of a large extracellular domain, a single-pass transmembrane helix, and an intracellular signaling motif referred to as the SEFIR domain that drives downstream signaling.
Antagonizing IL-17A/IL-17RA protein–protein interaction (PPI) was hypothesized to reduce over exaggerated inflammation in autoimmune diseases. There are several ways to block IL-17A signaling by targeting IL-17A proteins or receptors. Clinically, three monoclonal antibodies (mAbs) are already approved for different immunological diseases, secukinumab and ixekizumab target IL-17A while brodalumab targets IL- 17RA. Numerous clinical trials of anti-IL-17A and IL-17RA antibodies are currently in progress. IL-17A/IL-17RA directed biotherapeutics have achieved impressive successes in durable clinical treatment of psoriasis, asthma, psoriatic arthritis, and rheumatoid arthritis. However, IL17A has also major implications in central nervous system neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and glaucoma.
There have been three IL-17 inhibitors approved by USFDA which are monoclonal antibodies (mAbs). There is no drug approved which belongs to the small-molecule class. Some of the patents which disclose small-molecule IL-17 inhibitors are WO 2019138017, WO 2020127685, WO 2020120141, WO 2020182666, WO 2021239745, WO 2021055376, WO 2021250194, WO 2021239743, WO 2022091056, WO 2022007462 and WO 2023225664.
However, mAbs have limited applications due to non-oral administration, poor tissue penetration, lacking blood-brain barrier penetration, often long half-life times, high cost-of-good, and most importantly being applicable only to extracellular targets. For these reasons, the development of small-molecule modulators targeting IL- 17A/IL-17RA is an emerging area, which potentially could considerably widen current indication areas. Small molecules generally have a good tissue penetration with potentially higher efficacy and a tunable half-life time and are orally bioavailable facilitating patient treatment.

SUMMARY OF THE INVENTION
The invention provides compounds which are active to control IL17A mediated pathways and their use for the treatment of inflammatory diseases. The novel compounds are defined by the general formula (1) as given below. The compounds of the present invention are useful for human treatment or for veterinary treatment of animal. The compounds of this invention are therefore suitable for the treatment/mitigation/regulation or prophylaxis of inflammatory diseases.

PREFERRED EMBODIMENTS
The main objective of the present invention is to provide novel compounds of general formula (1), their suitable pharmaceutically acceptable salts, their solvates, their hydrates, their stereoisomers, novel intermediates involved in their synthesis, their polymorphs, their racemic mixtures and their optically active forms or their mixtures suitable for the treatment of inflammatory diseases.
In an embodiment is provided a process for the preparation of novel compounds of general formula (1), their suitable pharmaceutically acceptable salts, their solvates, their hydrates, their stereoisomers, novel intermediates involved in their synthesis, their polymorphs, their racemic mixtures and their optically active forms.
In another embodiment is provided pharmaceutical compositions comprising the novel compounds of general formula (1), their suitable pharmaceutically acceptable salts, their solvates, their hydrates, their stereoisomers, novel intermediates involved in their synthesis, their polymorphs, their racemic mixtures and their optically active forms having pharmaceutically acceptable carriers, solvents, diluents, binder, disintegrant, coating agent, filler, glidant, and/or other suitable excipients.
In a further another embodiment is provided the use of the novel compounds of the present invention for the treatment of inflammatory diseases, by administering a therapeutically effective & non-toxic amount of novel compounds of general formula (1) or their pharmaceutically acceptable salts, or their pharmaceutically acceptable compositions.
In yet another embodiment is provided a method of treating inflammatory diseases using novel compounds of general formula (1) or their pharmaceutically acceptable salts, or their pharmaceutically acceptable compositions.

DETAILED DESCRIPTION:
In a preferred embodiment, the groups referred to above may comprise of:
- the “alkyl” group used either alone or in combination with other radicals, denotes a linear or branched radical containing one to six carbons, selected from -CH, -CH2, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, amyl, t-amyl, n-pentyl, n-hexyl, and the like;
- the “cycloalkyl”, or “alicyclic” group used either alone or in combination with other radicals, is selected from a cyclic radical containing three to six carbons, more preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like;
- the “heterocyclylalkyl” group used either alone or in combination with other radicals, is selected from groups containing an heterocyclyl radical, as defined above, attached directly to an alkyl radical, as define above;
- the “haloalkyl” group is selected from an alkyl radical, as defined above, suitably substituted with one or more halogens; such as fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, mono or polyhalo substituted methyl, ethyl, propyl, butyl, pentyl or hexyl groups;
- "halo" or "halogen" by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom;
- the “aryl” or “aromatic” group used either alone or in combination with other radicals, is selected from a suitable aromatic system containing one, two or three rings wherein such rings may be attached together in a pendant manner or may be fused or spiro or parallel, more preferably the groups are selected from phenyl, naphthyl, tetrahydronaphthyl, indane, biphenyl, anthracene, spiro[5.5]undeca-1,3,7,9-tetraene, 1,1':4',1''-terphenyl and the like;
- the “heteroaryl” or “heteroaromatic” group used either alone or in combination with other radicals, is selected from suitable monocyclic, bicyclic or tricyclic aromatic heterocyclic radicals containing one or more hetero atoms selected from O, N or S, bicyclic or tricyclic ring may present as parallel, fused, spirocyclic or bridged ring system, more preferably the groups are selected from pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, isothiazolyl, imidazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, benzofuranyl, benzothienyl, indolinyl, indolyl, azaindolyl, azaindolinyl, pyrazolopyrimidinyl, azaquinazolinyl, pyridofuranyl, pyridothienyl, thienopyrimidyl, quinolinyl, pyrimidinyl, pyrazolyl, quinazolinyl, pyridazinyl, triazinyl, benzimidazolyl, benzotriazolyl, phthalazynil, naphthylidinyl, purinyl, carbazolyl, phenothiazinyl, phenoxazinyl, benzoxazolyl, benzothiazolyl and the like;
- the “carbocycle” group used either alone or in combination with other radicals, is selected from groups as described in “cycloalkyl” or “aryl” or “aromatic”;
- the term “cycloalkene” used anywhere in the specification indicates hydrocarbons containing a ring of carbon atoms and one or more double bonds in the cycle that do not form an aromatic ring, for example but not limited to cyclohexene, cyclopentene, cyclohexa-1,4-diene, cycloheptene;
- the term “cycloalkyne” used anywhere in the specification indicates hydrocarbons containing a ring of carbon atoms and one or more triple bonds in the cycle that do not form an aromatic ring, for example but not limited to cyclohexyne, cyclopentyne, cyclohexa-1,4-diyne, cycloheptyne;
- The “spirocyclic ring system” when there are two positions for substitution on the same atom, for example but not limited to spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro[5.5]undecanyl, 2-oxa- 7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl and 6-oxa-l-azaspiro[3.3]heptanyl;
- As used herein, the term "heterocycle" or "heterocyclic ring" or "heterocyclic system" is intended to mean a stable 4 to 20-membered heterocyclic ring which is saturated, partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms & also contains hetero atoms independently selected from the group consisting of N, O and S and including any monocyclic or bicyclic or tricyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. It inclueds heteroaryl and heteroaromatic ring also. The term heterocycle as used in the specification includes both aromatic and non-aromatic single or fused cyclic system containing at least one heteroatom selected from N, O and S. The nitrogen and sulfur hetero atoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. A skilled person is well aware of the terms "heterocycle" or "heterocyclic system" and the present invention encompasses all such variations, alterations of definitions which are within the scope of such a skilled person. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. In a further optional embodiment, nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these hetero atoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term "aromatic heterocyclic system" is intended to mean a stable bicyclic or 8 to 14 membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S. It is preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1. Also included are parallel rings, fused rings, bridged bicyclic heterocycles, Spiro-compounds containing, for example, the above heterocycles.
- As used herein, the term “fused rings” is intended to mean, one ring is a 4-7-membered monocyclic ring which is saturated, partially unsaturated, or unsaturated (aromatic) and comprises a 4-membered heterocycle, 5-membered heterocycle, 6-membered heterocycle, 7-membered heterocycle, or a carbocycle, each fused to a second ring. The second ring is a 5 to 7 membered monocyclic ring which is saturated, partially unsaturated, or unsaturated (aromatic), and comprises a 4-membered heterocycle, 5-membered heterocycle, 6-membered heterocycle, 7-membered heterocycle or a carbocycle. It also includes two or three fused ring system.
- the “one or more suitable substituents” or “one or more substituents” used either one or more suitable substituents substituted on single carbon or it may be substituted on more than one carbon;
- the term "substituted," as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. Substitution selected from hydrogen, deuterium, hydroxy, cyano, halo, nitro, haloalkyl, oxo, (C1-C6)alkyl, (C3-C6)cycloalkyl, aminoalkyl, alkoxyalkyl, alkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, aralkyl, heterocyclylalkyl, alkylsulfonyloxy;
- the term “stereoisomers” used anywhere in the specification indicates that compounds of the present invention show (R) and (S) configuration;
- the term "polymorph" refers to the ability of the compound of the invention to exist in more than one form or crystal structure.
- Compounds of formula (1) may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The present invention is meant to comprehend all such isomeric forms of the compounds of formula (1), either as single species or mixtures thereof.
- Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.
- Some of the compounds described herein may exist with different points of attachment of hydrogen, referred to as tautomers. Such an example may be a ketone and its enol form known as keto-enol tautomers. The individual tautomers as well as mixture thereof are encompassed with compounds of formula (1).
Accordingly, the present invention relates to compounds of the novel compounds of general formula (1),

Wherein
R1 is independently selected from hydrogen, deuterium and -F;
R2 and R3 are independently selected from hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, C4-C7 heterocycloalkyl, C5-C6 heteroaryl, aryl, bicyclic, spirocyclic ring system; alternatively, R2 and R3 may combine together to form 3-8 membered cycloalkyl ring, 3-8 membered heterocyclic ring, aryl, bicyclic or spirocyclic ring system; wherein, C1-C6 alkyl, C3-C7 cycloalkyl, C4-C7 heterocycloalkyl, C5-C6 heteroaryl, aryl, bicyclic, spirocyclic ring system is substituted or unsubstituted with one or more substituents independently selected from halogen, haloalkyl, C1-C6 alkyl, C3-C6 cycloalkyl, -OR5, -SR5, -N(R5)2, -C(O)R5, -C(O)OR5, -OC(O) R5, -OC(O)N(R5)2, -C(O)N(R5)2, -N(R5)C(O) R5, -N(R5)C(O)O R5, -N(R5)C(O)N(R5)2, -N(R5)S(O)2(R5), -S(O)R5, -S(O)2R5, -S(O)2N(R5)2, -S(=O)(=NR5)R5, -NO2, =O and -CN;
C is independently selected from aryl, heterocyclic ring;
R4 is independently selected from
hydrogen, halogen, -OR5, -SR5, -N(R5)2, -C(O)R5, -C(O)OR5, -OC(O)R5, -OC(O)N(R5)2, -C(O)N(R5)2, -N(R5)C(O)R5, -N(R5)C(O)OR5, -N(R5)C(O)N(R5)2, -N(R5)S(O)2(R5), -S(O)R5, -S(O)2R5, -S(O)2N(R5)2, -S(=O)(=NR5)R5, -NO2, =O and -CN; C1-C6 alkyl, C4-C6 heterocycloalkyl, C3-C10 carbocycle each of which is optionally substituted with one or more substituents independently selected from halogen, -OR5, -SR5, -N(R5)2, -C(O)R5, -C(O)OR5, -OC(O)R5, -OC(O)N(R5)2, -C(O)N(R5)2, -N(R5)C(O)R5, -N(R5)C(O)OR5, -N(R5)C(O)N(R5)2, -N(R5)S(O)2(R5), -S(O) R5, -S(O)2R5, -S(O)2N(R5)2, -S(=O)(=NR5)R5, -NO2, =O and -CN;
n is selected from 0,1,2,3;
A is selected from 5 to 6 membered heteroaryl, 9 or 10 membered bicyclic heteroaryl, phenyl, each of them are optionally substituted with one or more substituents independently selected from (i), (ii), (iii) and (iv);
(i) halogen, deuterium, -OR5, -SR5, -N(R5)2, -C(O)R5, -C(O)OR5, -OC(O)R5, -OC(O)N(R5)2, -C(O)N(R5)2, -N(R5)C(O)R5, -N(R5)C(O)OR5, -N(R5)C(O)N(R5)2, -N(R5)S(O)2(R5), -S(O)R5, -S(O)2R5, -S(O)2N(R5)2, -S(=O)(=NR5)R5, -NO2, =O and -CN;
(ii) C1-C10 alkyl, optionally substituted with one or more substituents independently selected from: C1-C6 alkyl, halogen, deuterium, C3-C10 carbocycle, 3-10 membered heterocycle, -OR5, -SR5, -N(R5)2, -C(O)R5, -C(O)OR5, -OC(O)R5, -OC(O)N(R5)2, -C(O)N(R5)2, -N(R5)C(O) R5, -N(R5)C(O)OR5, -N(R5)C(O)N(R5)2, -N(R5)S(O)2(R5), -S(O)R5, -S(O)2R5, -S(O)2N(R5)2, -S(=O)(=NR5)R5, -NO2, =,O and -CN;
(iii) 3-8 membered cycloalkyl ring, 3-10 membered heterocycle, bicyclic, spirocyclic optionally substituted with one or more substituents independently selected from halogen, deuterium, -OR5, -SR5, -N(R5)2, -C(O)R5, -C(O)OR5, -OC(O)R5, -OC(O)N(R5)2, -C(O)N(R5)2, -N(R5)C(O)R5, -N(R5)C(O)OR5, -N(R5)C(O)N(R5)2, -N(R5)S(O)2(R5), -S(O)R5, -S(O)2R5, -S(O)2N(R5)2, -S(=O)(=NR5)R5, -NO2, =,O and -CN; and C1-C6 alkyl optionally substituted with one or more substituents independently selected from: halogen, deuterium, -OR5, -SR5, -N(R5)2, -C(O)R5, -C(O)OR5, -OC(O)R5, -OC(O)N(R5)2, -C(O)N(R5)2, -N(R5)C(O) R5, -N(R5)C(O)O R5, -N(R5)C(O)N(R5)2, -N(R5)S(O)2(R5), -S(O)R5, -S(O)2 R5, -S(O)2N(R5)2, -S(=O)(=NR5)R5, -NO2, =O and -CN;
(iv) ;
Y is selected from O, -CO, -N, C1-C6 alkyl or absent;
Z1 selected from ;
Z2 is independently selected from , hydrogen, C1-C6-alkyl or absent;
--- of Z1 and Z2 is a bond which may be present or absent;
Z1 and Z2 combine together to form 4-7 membered cycloalkene, 4-7 membered cycloalkyne ring;
when --- is present, E2 and E3 are absent;
E1, E2 and E3 are selected from hydrogen, C1-C6 alkyl, -OC1-C6 alkyl, C1-C6 haloalkyl, -NC1-C6 alkyl;
E1 and E3 may combine together to form 4-7 membered cycloalkyl, 4-7 membered heterocyclic ring.

B is selected from (i), (ii);
(i) 5-10 membered heteroaryl ring, 5-10 membered heterocyclic ring, 3-7 membered cycloalkyl ring, each of them are optionally substituted with C1-C6 alkyl, C3-C7 cycloalkyl, C4-C7 heterocyclic, bicyclic, spirocyclic ring, halogen, deuterium, -OR5, -SR5, -N(R5)2, -C(O)R5, -C(O)OR5, -OC(O)R5, -OC(O)N(R5)2, -C(O)N(R5)2, -N(R5)C(O)R5, -N(R5)C(O)O R5, -N(R5)C(O)N(R5)2, -N(R5)S(O)2(R5), -S(O) R5, -S(O)2R5, -S(O)2N(R5)2, -S(=O)(=NR5)R5, -NO2, =O and –CN, -P(O)CR5; wherein, if 5-10 membered heteroaryl ring contain nitrogen in ring then nitrogen may further attached to –O;
(ii)
;
R6 and R7 are each independently selected from (a), (b), (c) and (d);
(a) Hydrogen;
(b) halogen, -OR10, -SR10, -N(R10)2, -C(O)R10, -C(O)NH2, -C(O)-O-C1-6-alkyl, -OC(O)R10, -OC(O)N(R10)2, -N(R10)C(O)R10, -N(R10)C(O)OR10, -N(R10)C(O)N(R10)2, -N(R10)S(O)2(R10), -S(O)R10, -S(O)2R10, -S(O)2N(R10)2, -S(=O)(=NR10)R10, -NO2, - CN;
(c) C1-C6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR10, -SR10, -N(R10)2, -C(O)R10, -C(O)NH2, -C(O)-O-C1-6-alkyl, -OC(O)R10, -OC(O)N(R10)2, -N(R10)C(O)R10, -N(R10)C(O)OR10, -N(R10)C(O)N(R10)2, -N(R10)S(O)2(R10), -S(O)R10, -S(O)2R10, -S(O)2N(R10)2, -S(=O)(=NR10)R10, -NO2, - CN;
(d) C3-10 carbocycle and 3- to 10-membered heterocycle any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR10, -SR10, -N(R10)2, -C(O)R10, -C(O)NH2, -C(O)-O-C1-6-alkyl, - OC(O)R10, -OC(O)N(R10)2, -N(R10)C(O)R10, -N(R10)C(O)OR10, -N(R10)C(O)N(R10)2, -N(R10)S(O)2(R10), -S(O) R10, -S(O)2R10, -S(O)2N(R10)2, -S(=O)(=NR10)R10, -NO2, - CN;
R6 and R7 can come together to form a 3-8 membered cycloalkyl ring, 4-to 12-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR10, -SR10, -N(R10)2, -C(O)R10, -C(O)NH2, -C(O)-O-C1-6-alkyl, - OC(O)R10, -OC(O)N(R10)2, -N(R10)C(O)R10, -N(R10)C(O)O R10, - N(R10)C(O)N(R10)2, -N(R10)S(O)2(R10), -S(O) R10, -S(O)2 R10, -S(O)2N(R10)2, -S(=O)(=NR10)R10, -NO2, - CN; C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR10, -SR10, -N(R10)2, -C(O)R10, -C(O)NH2, -C(O)-O-C1-6-alkyl, - OC(O)R10, -OC(O)N(R10)2, -N(R10)C(O)R10, -N(R10)C(O)O R10, - N(R10)C(O)N(R10)2, -N(R10)S(O)2(R10), -S(O) R10, -S(O)2 R10, -S(O)2N(R10)2, -S(=O)(=NR10)R10, -NO2, - CN;
R5 and R10 are independently selected at each occurrence from (I), (II) and (III);
(I) hydrogen;
(II) C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OH, -OC1-C6 alkyl, -OC1-C6 haloalkyl -NH2, -NO2, =O, -CN, C3-10 carbocycle and 3- to 10-membered heterocycle, wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents selected from: halogen, -OH, C1-C6 haloalkyl, -OC1-C6 alkyl, -OC1-C6haloalkyl -NH2, -NO2, =O, and -CN;
(III) C3-10 carbocycle and 3-10 membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-C6 haloalkyl, -OC1-C6 alkyl, -OC1-C6 haloalkyl -NH2, -NO2, =O, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -OC1-C6 alkyl, -OC1-C6 haloalkyl -NH2, -NO2, =O, and –CN;
R8 and R9 are each independently selected from (a), (b), (c);
(a) Hydrogen;
(b) C1-C6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR10, -SR10, -N(R10)2, -C(O)R10, -C(O)NH2, -C(O)-O-C1-6-alkyl, -OC(O)R10, -OC(O)N(R10)2, -N(R10)C(O)R10, -N(R10)C(O)OR10, -N(R10)C(O)N(R10)2, -N(R10)S(O)2(R10), -S(O)R10, -S(O)2R10, -S(O)2N(R10)2, -S(=O)(=NR10)R10, -NO2, - CN; C3-10 carbocycle and 3- to 10-membered heterocycle any of which is optionally substituted with one or more substituents independently selected from halogen, -OR10, -SR10, -N(R10)2, -C(O)R10, -C(O)NH2, -C(O)-O-C1-6-alkyl, - OC(O)R10, -OC(O)N(R10)2, -N(R10)C(O)R10, -N(R10)C(O)O R10, - N(R10)C(O)N(R10)2, -N(R10)S(O)2(R10), -S(O) R10, -S(O)2 R10, -S(O)2N(R10)2, -S(=O)(=NR10)R10, -NO2, - CN;
(c) C3-10 carbocycle and 3- to 10-membered heterocycle any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR10, -SR10, -N(R10)2, -C(O)R10, -C(O)NH2, -C(O)-O-C1-6-alkyl, - OC(O)R10, -OC(O)N(R10)2, -N(R10)C(O)R10, -N(R10)C(O)O R10, - N(R10)C(O)N(R10)2, -N(R10)S(O)2(R10), -S(O) R10, -S(O)2 R10, -S(O)2N(R10)2, -S(=O)(=NR10)R10, -NO2, - CN; C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR10, -SR10, -N(R10)2, -C(O)R10, -C(O)NH2, -C(O)-O-C1-6-alkyl, - OC(O)R10, -OC(O)N(R10)2, -N(R10)C(O)R10, -N(R10)C(O)O R10, - N(R10)C(O)N(R10)2, -N(R10)S(O)2(R10), -S(O) R10, -S(O)2 R10, -S(O)2N(R10)2, -S(=O)(=NR10)R10, -NO2, - CN; or

R8 and R9 may combine together to form 3-8 membered cycloalkyl ring, 4-12 membered heterocyclic ring, aryl, bicyclic or spirocyclic ring system, wherein, 3-8 membered cycloalkyl ring, 4-12 membered heterocyclic ring, aryl, bicyclic and spirocyclic ring system is optionally substituted with one or more substituents independently selected from halogen, C1-C6 alkyl, -OR5, -SR5, -N(R5)2, -C(O)R5, -C(O)OR5, -OC(O)R5, -OC(O)N(R5)2, -C(O)N(R5)2, -N(R5)C(O)R5, -N(R5)C(O)OR5, -N(R5)C(O)N(R5)2, -N(R5)S(O)2(R5), -S(O) R5, -S(O)2R5, -S(O)2N(R5)2, -S(=O)(=NR5)R5, -NO2, =O and -CN; or
C1-C6 alkyl optionally substituted with one or more substituents independently selected from -OR5, -SR5, -N(R5)2, -C(O)R5, -C(O)OR5, -OC(O)R5, -OC(O)N(R5)2, -C(O)N(R5)2, -N(R5)C(O)R5, -N(R5)C(O)OR5, -N(R5)C(O)N(R5)2, -N(R5)S(O)2(R5), -S(O)R5, -S(O)2R5, -S(O)2N(R5)2, -S(=O)(=NR5)R5, -NO2, =O and -CN;
M is selected from CH or absent;
z independently selected from C, N;
R11 is independently selected from -NR10COR10, -NR10CON(R10)2, NR10.
Further preferred embodiments are those disclosed below:
R1 is independently selected from hydrogen and deuterium;
R2 and R3 are independently selected from C3-C7 cycloalkyl;
R2 and R3 may combine toghether to form 3-8 membered cycloalkyl ring;
R4 is independently selected from hydrogen and halogen;
n is selected from 0, 1, 2;
A is selected from 5 to 6 membered heteroaryl;
Y is selected from C1-C6 alkyl or absent;
B is selected from
(i) 5-10 membered heteroaryl ring;
(ii)
R6 and R7 are each independently selected from hydrogen, C1-C6 alkyl wherein alkyl is substituted with halogen;
R5 and R10 are independently selected at each occurrence from hydrogen, C1-C6 alkyl;
R8 and R9 are independently selected at each occurrence from hydrogen, C1-C6 alkyl wherein alkyl is substituted with halogen;
M is selected from CH or absent.
General Scheme 1: Synthesis of compounds of general formula (1)

Amine derivative [2] on reaction with dimethyl phosphine oxide in presence of Pd catalyst selected from Pd(OAc)2, Pd2dba3, Pd(PPh3)4 and ligand like Xantphos using base selected from K2CO3, Cs2CO3 or K3PO4 and like in solvent selected from dioxane, DMF, NMP and like to give intermediate [3]. Intermediate [3] on reaction with appropriate acid [4] using coupling reagent selected from DCC, EDAC, HATU, HBTU, T3P and like using base selected from TEA, DIEA, and like in a solvent selected from DCM, EDC, DMF give protected amine derivative [5]. Deprotection of protecting group (Pg) under condition selected from dioxane.HCl, TFA, Pd/C& H(2), resulted in amine compound [6]. Copuling of amine compound [6] with appropriate acid {A-COOH} using condition described about gave title compound [1].
Intermediate 2 and acid 4 were prepared as per the procedure reported in WO2023283453 and as per general method reported in Vogel text book of practical organic chemistry.
The pharmaceutically acceptable salts forming a part of this invention may be prepared by treating the compound of formula (1) with suitable acids in suitable solvents by processes known in the art.
The invention is further exemplified by the following examples below, which provides some of the several preferred embodiments of the present invention. These examples are provided merely as representative embodiments and should not be construed to limit the scope of the invention in any way.
Particularly useful compounds may be selected from
Sr No Structure Chemical name
1
N-((1S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide
2
N-((1S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-oxo-1-((2,2,2-trifluoroethyl) amino)propan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide
3
N-((1S)-2-((2-(dimethylphosphoryl)-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide
4
N-((1S)-1-cycloheptyl-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide
5
N-((1S)-2-((3-(dimethylphosphoryl)-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide
6
N-((1S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1-(penta-1,4-dien-3-yl)-1H-pyrazole-5-carboxamide
7
N-((1S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide
8
N-((1S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-3-methylisoxazole-4-carboxamide
9
N-((1S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1-(prop-2-yn-1-yl)-1H-pyrazole-5-carboxamide
10
N-((1S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide
11
N-((1S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1-(pent-1-en-4-yn-3-yl)-1H-pyrazole-5-carboxamide
12
1-(cyclopent-3-en-1-yl)-N-((1S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1H-pyrazole-5-carboxamide
13
1-allyl-N-((1S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1H-pyrazole-5-carboxamide
14
N-((S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-((R)-1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-3-methylisoxazole-4-carboxamide
15
ethyl 1-(5-(((1S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)carbamoyl)-1H-pyrazol-1-yl)cyclopropane-1-carboxylate
16
1-(5-(((1S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)carbamoyl)-1H-pyrazol-1-yl)cyclopropane-1-carboxylic acid.
17
N-((S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-((S)-1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-3-methylisoxazole-4-carboxamide
18
N-((1S)-1-cyclohexyl-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-2-oxoethyl)-3-methylisoxazole-4-carboxamide

General Scheme

Nitro derivative [7] upon reduction with reducting agent selected from Fe, SnCl2, Pd/C, Pd(OH)2 to give intermediate [8]. This intermediate [8] on reaction with pyrazole derivative [9] in presence of catalyst either PdCl2(ddpf) or PdCl2(PPh3)2 using aqueous base selected from K2CO3, Cs2CO3 or Na2CO3 and like in solvent selected from dioxane, DMF, NMP and like to give intermediate [10]. Intermediate [10] on reaction with appropriate acid [11] using coupling reagent selected from CDI, DCC, EDAC, HATU, HBTU, T3P and like using base selected from TEA, DIEA, Pyridine and like in a solvent selected from DCM, EDC, DMF, give protected amine derivative [12]. Deprotection of protecting group (Pg) under condition selected from dioxane.HCl, TFA, Pd/C& H(2), resulted in amine compound [13]. Coupling of amine compound [13] with appropriate acid {A-COOH} using condition described about resulted in compound [14]. Deprotection of protecting group (Pg) under condition selected from, TFA, NaOH gave title compound [1].
Particularly useful compounds may be selected from
19
(S)-N-(2-((4-(3,5-dimethyl-1H-pyrazol-4-yl)-3-(dimethylphosphoryl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide
20
(S)-N-(2-((4-(3,5-dimethyl-1H-pyrazol-4-yl)-2-(dimethylphosphoryl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide

In one of the embodiments, the present invention relates to compounds of the general formula (I),

R1, R2, R3, R4, n, A and B are as described above in the specification.
Any formula or compound described above in the specification having hydrogen anywhere in the structure can be deuterated.

Amine derivative [2] on reaction with dimethyl phosphine oxide in presence of Pd catalyst selected from Pd(OAc)2, Pd2dba3, Pd(PPh3)4 and ligand like Xantphos using base selected from K2CO3, Cs2CO3 or K3PO4 and like in solvent selected from dioxane, DMF, NMP and like to give intermediate [3]. Intermediate [3] on reaction with appropriate acid [15] using coupling reagent selected from DCC, EDAC, HATU, HBTU, T3P and like using base selected from TEA, DIEA, and like in a solvent selected from DCM, EDC, DMF give protected amine derivative [16]. Deprotection of protecting group (Pg) under condition selected from dioxane.HCl, TFA, Pd/C& H(2), resulted in amine compound [17]. Copuling of amine compound [17] with appropriate acid {A-COOH} using condition mentioned about gave title compound [1].

Particularly useful compounds may be selected from
21
N-(1-cyclohexyl-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-2-oxoethyl-1-d)-1-isopropyl-1H-pyrazole-5-carboxamide

Various Intermediates used in above scheme were prepared as per the procedure reported in (WO2021164746), and as per general method reported in Vogel text book of practical organic chemistry.
The pharmaceutically acceptable salts forming a part of this invention may be prepared by treating the compound of formula (1) with suitable acids in suitable solvents by processes known in the art.
The invention is further exemplified by the following examples below, which provides some of the several preferred embodiments of the present invention. These examples are provided merely as representative embodiments and should not be construed to limit the scope of the invention in any way.

List of Abbreviation
DMF: Dimethyl formamide
DCM: Dichloromethane
EDC: Dichloroethane
TFA: Trifluoro acetic acid
THF: Tetrahydrofurane
DIPEA: Disopropyl ethyl amine
EtOAc: Ethyl acetate
h: Hour(s)
rt: room temperature
min: Minute(s)
tRet: Retention time
HCl: Hydrochloric acid
RT: Room temperature [25-30 0C]
Cs2CO3: Cesium carbonate
K2CO3: Potassium carbonate
K3PO4: Potassium phosphate
TEA: Triethyl amine
Instrument details
Mass spectrum was recorded on LC-MS 2010-A Shimadzu.
NMR spectrum: Bruker Avanc 400 mHz
Suitable groups and substituents on the groups may be selected from those described anywhere in the specification.
The compounds of the present invention may be prepared using the methods described below, together with conventional techniques known to those skilled in the art of organic synthesis or variation thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to those described below, where all symbols are as defined earlier.

Amine intermediates
Sr No Amine analogue Chemical Name
A1
2-(4-amino-2-(dimethylphosphoryl)-5-fluorophenyl)-N-methyl-N-(2,2,2-trifluoroethyl)propanamide
A2
2-(4-amino-2-(dimethylphosphoryl)-5-fluorophenyl)-N-(2,2,2-trifluoroethyl)propanamide
A3
2-(4-amino-3-(dimethylphosphoryl)phenyl)-N-methyl-N-(2,2,2-trifluoroethyl)propanamide
A4
2-(4-amino-2-(dimethylphosphoryl)phenyl)-N-methyl-N-(2,2,2-trifluoroethyl)propanamide
A5
(R)-2-(4-amino-2-(dimethylphosphoryl)-5-fluorophenyl)-N-methyl-N-(2,2,2-trifluoroethyl)propanamide
A6
(S)-2-(4-amino-2-(dimethylphosphoryl)-5-fluorophenyl)-N-methyl-N-(2,2,2-trifluoroethyl)propanamide
A7
(5-amino-2-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl)dimethylphosphine oxide
A8
(2-amino-5-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl)dimethylphosphine oxide

Aminoacid intermediates

Sr No Aminoacid analogue Chemical Name
B1
(S)-2-amino-2-(4-methylcyclohexyl)acetic acid
B2
(S)-2-amino-2-cycloheptylacetic acid
B3
(S)-2-amino-2-cyclohexylacetic acid
B4
2-amino-2-cyclohexylacetic-2-d acid

Acid Intermediate

Sr No Acid Analogues Chemical Name
C1
1-isopropyl-1H-pyrazole-5-carboxylic acid
C2
1-(penta-1,4-dien-3-yl)-1H-pyrazole-5-carboxylic acid
C3
1-methyl-1H-pyrazole-5-carboxylic acid
C4
3-methylisoxazole-4-carboxylic acid
C5
1-(prop-2-yn-1-yl)-1H-pyrazole-5-carboxylic acid
C6
1-ethyl-1H-pyrazole-5-carboxylic acid
C7
1-(pent-1-en-4-yn-3-yl)-1H-pyrazole-5-carboxylic acid
C8
1-(cyclopent-3-en-1-yl)-1H-pyrazole-5-carboxylic acid
C9
1-allyl-1H-pyrazole-5-carboxylic acid
C10
1-(1-(ethoxycarbonyl)cyclopropyl)-1H-pyrazole-5-carboxylic acid
C11
1-(1-carboxycyclopropyl)-1H-pyrazole-5-carboxylic acid

Example 1: Preparation of N-((1S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide.

Step1: 2-(4-Amino-2-(dimethylphosphoryl)-5-fluorophenyl)-N-methyl-N-(2,2,2-trifluoroethyl) propanamide.
In a 50 mL round bottom flask, 2-(4-amino-2-bromo-5-fluorophenyl)-N-methyl-N-(2,2,2-trifluoroethyl)propanamide (0.645 g, 1.806 mmol) was added followed by DMF (8 ml) at 28 °C to give a colorless solution. To this, dimethylphosphine oxide (0.155 g, 1.987 mmol) and K3PO4 (0.422 g, 1.987 mmol) was added at 28 °C. Purged the mixture with nitrogen gas. Then xantphos (0.104 g, 0.181 mmol) and Pd(OAc)2 (0.041 g, 0.181 mmol) was added in reaction mixture at 28 °C. The reaction mixture was stirred at 120 °C for 12 h. After completion of reaction, mixture was filtered through hyflow and washed with ethyl acetate and organic layer was evaporated under reduced pressure to afford desired compound as off white solid. The crude product was purified by combiflash chromatography using MeOH in DCM as mobile phase (Yield: 0.250 g, 39 %). ESI-MS: m/z [M+1] + 355.12.

Step II: ((1S)-2-((5-(Dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl) amino) -1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)carbamate.
Placed (2S)-2-((tert-butoxycarbonyl)amino)-2-(4-methylcyclohexyl)acetic acid (0.120 g, 0.441 mmol) in round bottom flask followed by DMF (2 mL) at 28 °C. To this, 2-(4-amino-2-(dimethylphosphoryl)-5-fluorophenyl)-N-methyl-N-(2,2,2-trifluoroethyl) propanamide (0.142 g, 0.401 mmol) was added at 28 °C. HATU (0.213 g, 0.561 mmol) and DIPEA (0.210 ml, 1.202 mmol) were added in stirred mixture at 28 °C. The reaction mixture was stirred at 28 °C for 1 h. After completion of reaction, mixture was quenched with water and aqueous layer was extracted with ethyl acetate. Organic layers were washed with water, brine solution. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford desired solid product. The crude product was purified by Combiflash chromatography using MeOH in DCM as mobile phase. (Yield: 0.12 g, 49 %). ESI-MS: 608.32 (M+H)+.

Step III: Dimethyl (5-((2S)-2-amino-2-(4-methylcyclohexyl)acetamido)-4-fluoro-2-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)phosphonate hydrochloride.
In a 50 ml round-bottomed flask, tert-butyl ((1S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)carbamate (100 mg, 0.165 mmol) was added followed by DCM (5 mL) at 28 °C. To this, dioxane HCl (1 mL, 0.165 mmol) was added in reaction mixture at 0 °C. The reaction mixture was stirred at 28 °C for 1h. After completion of reaction, organic volatiles were removed under reduced pressure to get desire solid product. (Yield: 0.09 g, 90 %). ESI-MS: 508.26 (M+H) +.

Step IV: N-((1S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl) amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide.
In a 50 mL round bottom flask, 2-(4-((S)-2-amino-2-((1r,4S)-4-methylcyclohexyl)acetamido)-2-(dimethylphosphoryl)-5-fluorophenyl)-N-methyl-N-(2,2,2-trifluoroethyl)propanamide hydrochloride (90 mg, 0.165 mmol) was added in DMF (2 ml) at 28 °C. To this, 1-isopropyl-1H-pyrazole-5-carboxylic acid (28.1 mg, 0.182 mmol), HATU (75 mg, 0.199 mmol) and DIPEA (0.087 ml, 0.496 mmol) were added. The reaction mixture was stirred at 28 °C for 1 h. After completion of reaction, mixture was quenched with water and aqueous layer was extracted with EtOAc. Organic layers were washed with water and brine solution. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford desired solid product. The crude product was purified by Combiflash chromatography using MeOH in DCM as mobile phase. (Yield: 0.04 g, 37 %). 1H NMR (DMSO- d6, 400 MHz) ? ppm: 10.09 (1H, s), 8.44 (1H, d, J = 8.0 Hz), 8.10 - 8.11 (1H, m), 7.50 (1H, s), 7.10 - 6.96 (1H, m), 6.95 (1H, s), 5.41 - 5.38 (1H, m), 4.58 - 4.54 (1H, m), 4.88 - 4.90 (1H, m), 4.10 - 4.02 (2H, m), 3.08 (3H, s), 1.83 - 1.64 (15H, m), 1.37 - 1.24 (10H, m), 0.89 - 0.85 (3H, m); ESI-MS: 644.28 [M+1] +.

Example 2: Preparation of N-((1S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-oxo-1-((2,2,2-trifluoroethyl) amino)propan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide.

N-((1S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-oxo-1-((2,2,2-trifluoroethyl) amino)propan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide prepared following the process as described in example 1 but using A2, B1, C1 as starting material. 1H NMR (DMSO d6) ? ppm: 10.11 (1H, s), 9.16 (1H, t, J = 6.4 Hz), 8.46 (1H, d, J = 8.4 Hz), 8.17 - 8.11 (1H, m), 8.10 (1H, s), 7.50 - 7.49 (1H, m), 7.34 - 7.31 (1H, m), 5.41 - 5.38 (1H, m), 4.66 - 4.54 (2H, m), 3.93 - 3.89 (1H, m), 3.80 - 3.75 (1H, m), 1.91 - 1.68 (12H, m), 1.40 - 1.30 (13H, m), 0.92 - 0.85 (3H, m). LC-MS: 630.4 [M+H]+.

Example 3: Preparation of N-((1S)-2-((2-(dimethylphosphoryl)-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide

N-((1S)-2-((2-(dimethylphosphoryl)-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide prepared following the process as described in example 1 but using A3, B1, C1 as starting material. 1H NMR (DMSO d6) d ppm: 12.60 (1H, br s), 8.57 (1H, d, J = 7.2 Hz), 8.37 - 8.34 (1H, m), 7.48 (1H, d, J = 2.0 Hz), 7.39 - 7.36 (2H, m), 6.97 (1H, t, J = 2.0 Hz), 5.33 (1H, t, J = 7.2 Hz), 4.31 (1H, d, J = 9.6 Hz), 4.16 - 4.08 (3H, m), 3.63 - 3.61 (1H, m), 3.32 - 3.13 (3H, m), 1.81 – 1.74 ( 4H, m), 1.71 - 1.67 (6H, m), 1.34 (8H, t, J = 6.0 Hz), 1.29 – 1.16 (3H, m), 0.86 - 0.84 (6H, m); ESI-MS: 626.4 [M+H]+

Example 4: Preparation of N-((1S)-1-cycloheptyl-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide.

N-((1S)-1-cycloheptyl-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide prepared following the process as described in example 1 but using A1, B2, C1 as starting material. 1H NMR (DMSO d6) d ppm: 10.11 (1H, s), 8.43 (1H, d, J = 8.4 Hz), 8.08 - 8.06 (1H, m), 7.49 (1H, d, J = 2.0 Hz), 7.13 - 7.10 (1H, m), 6.94 (1H, d, J = 2.0 Hz), 5.62 - 5.60 (1H, m), 5.40 - 5.37 (1H, m), 4.65 (1H, t, J = 8.4 Hz), 4.35 - 4.25 (1H, s), 4.10 - 4.00 (1H, m), 3.08 - 3.06 (2H, m), 2.91 (1H, s), 2.12 - 2.10 (1H, m), 1.83 - 1.75 (6H, m), 1.55 - 1.51 (4H, m), 1.38 - 1.34 (9H, m), 1.32 - 1.27 (6H, m), 0.87 - 0.86 (2H, m); ESI-MS: 644.4 [M+H]+.

Example 5: Preparation of N-((1S)-2-((3-(dimethylphosphoryl)-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide.

N-((1S)-2-((3-(dimethylphosphoryl)-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide prepared following the process as described in example 1 but using A4, B1, C1 as starting material. 1H NMR (DMSO d6) d ppm: 10.40 (1H, s), 8.53 – 8.50 (1H, m), 7.86 – 7.49 (1H, m), 7.18 – 7.16 (1H, s), 6.96 – 6.94 (1H, m), 5.50 – 5.49 (1H, m), 5.38 – 5.36 (1H, m), 4.32 – 4.31 (1H, m), 4.04 - 4.02 (2H, m), 3.09 – 2.89 (3H, m), 1.97 – 1.58 (10H, m), 1.34 – 1.25 (12H, m), 0.86 – 0.84 (6H, m); LC-MS: 626.0 [M+H]+

Example 6: Preparation of N-((1S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1-(penta-1,4-dien-3-yl)-1H-pyrazole-5-carboxamide.

N-((1S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1-(penta-1,4-dien-3-yl)-1H-pyrazole-5-carboxamide prepared following the process as described in example 1 but using A1, B1, C2 as starting material. 1H NMR (DMSO d6) d ppm: 10.23 (1H, s), 8.54 (1H, d, J = 6.8 Hz), 8.23 – 8.17 (1H, m), 7.51 (1H, s), 7.06 – 7.04 (2H, m), 6.32 – 6.31 (1H, m), 6.01 – 5.97 (1H, m), 5.85 – 5.83 (1H, m), 5.56 – 5.45 (1H, m), 5.13 – 5.10 (3H, m), 5.05 (1H, d, J = 8.0 Hz), 4.63 (1H, t, J = 6.8 Hz), 4.32 – 4.27 (1H, m), 4.10 – 4.07 (1H, m), 3.07 (2H, d, J = 8.0 Hz), 2.91 (1H, s), 1.82 – 1.67 (10H, m), 1.34 (3H, s), 1.33 – 1.31 (3H, m), 1.09 – 1.04 (1H, m), 0.86 – 0.84 (5H, m); ESI-MS: 668.3 [M+H]+

Example 7: Preparation of N-((1S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide.

N-((1S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide prepared following the process as described in example 1 but using A1, B1, C3 as starting material. 1H NMR (DMSO d6) d ppm: 1H NMR (DMSO d6) d ppm: 10.15 (1H, s), 8.48 (1H, d, J = 6.8 Hz), 8.12-8.05 (1H, m), 7.48-7.46 (1H, m), 7.46-7.44 (1H, m), 7.06 (1H, s), 5.62-5.56 (1H, m), 4.62-4.55 (1H, m), 4.35-4.25 (1H, m), 4.03 (3H, s), 3.07-3.05 (2H, m), 1.83-1.80 (3H, m), 1.75-1.71 (8H, m), 1.34-1.31 (3H, m), 1.26-1.22 (4H, m), 1.10-1.00 (1H, m), 0.88-0.85 (5H, m).; ESI-MS: 616.25 [M+H]+.

Example 8: Preparation of N-((1S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-3-methylisoxazole-4-carboxamide.

N-((1S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-3-methylisoxazole-4-carboxamide prepared following the process as described in example 1 but using A1, B1, C4 as starting material. 1H NMR (DMSO d6) d ppm: 10.15 (1H, s), 9.45 (1H, d, J = 2.0 Hz), 8.44 (1H, d, J = 6.4 Hz), 8.10-8.00 (1H, m), 7.15-7.10 (1H, m), 5.65-5.58 (1H, m), 4.62-4.60 (1H, m), 4.35-4.25 (1H, m), 4.10-4.00 (1H, m), 3.08-3.06 (2H, m), 2.37 (3H, s), 1.83-1.75 (2H, m), 1.74-1.63 (9H, m), 1.35-1.32 (3H, m), 1.23 (3H, s), 1.15-1.05 (1H, m), 0.88-0.85 (5H, m); ESI-MS: 617.30 [M+H]+.

Example 9: Preparation of N-((1S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1-(prop-2-yn-1-yl)-1H-pyrazole-5-carboxamide.

N-((1S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1-(prop-2-yn-1-yl)-1H-pyrazole-5-carboxamide prepared following the process as described in example 1 but using A1, B1, C5 as starting material. 1H NMR (DMSO d6) d ppm: 10.19 (1H, s), 8.60 (1H, d, J = 6.4 Hz), 8.15-8.09 (1H, m), 7.56 (1H, s), 7.15-7.08 (2H, m), 5.62-5.61 (1H, m), 5.36 (2H, s), 4.63-4.60 (1H, m), 4.35-4.29 (1H, m), 4.10-4.03 (1H, m), 3.08-3.06 (2H, m), 2.91 (1H, s), 1.84-1.81 (3H, m), 1.75-1.69 (6H, m), 1.35-1.32 (3H, m), 1.28-1.24 (5H, m), 1.09-1.07 (1H, m), 0.88-0.86 (5H, m); ESI-MS: 640.3 [M+H]+.

Example 10: Preparation of N-((1S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide.

N-((1S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide prepared following the process as described in example 1 but using A1, B1, C6 as starting material. 1H NMR (DMSO d6) d ppm: 10.14 (1H, s), 8.49 (1H, d, J = 6.4 Hz), 8.15-8.08 (1H, m), 7.52 (1H, s), 7.14-7.08 (1H, m), 7.03 (1H, s), 5.62-5.61 (1H, m), 4.60-4.58 (1H, m), 4.52-4.45 (2H, m), 4.35-4.30 (1H, m), 4.10-4.00 (1H, m), 3.08-3.06 (2H, m), 2.91 (1H, s), 1.83-1.81 (3H, m), 1.75-1.64 (8H, m), 1.34-1.32 (4H, m), 1.30-1.23 (4H, m), 1.10-1.07 (1H, m), 0.91-0.86 (5H, m); ESI-MS: 630.30 [M+H]+.

Example 11: Preparation of N-((1S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1-(pent-1-en-4-yn-3-yl)-1H-pyrazole-5-carboxamide.

N-((1S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1-(pent-1-en-4-yn-3-yl)-1H-pyrazole-5-carboxamide prepared following the process as described in example 1 but using A1, B1, C7 as starting material. 1H NMR (DMSO d6) d ppm: 10.23 (1H, s), 8.56 (1H, d, J = 8.4 Hz), 8.17 – 8.15 (1H, m), 7.50 (1H, s), 7.06 – 7.05 (2H, m), 6.30 – 6.20 (1H, m), 5.70 – 5.67 (1H, m), 5.44 – 5.40 (1H, m), 5.16 (2H, br s), 4.59 (1H, t, J = 7.2 Hz), 4.32 – 4.07 (2H, m), 3.08 (2H, d, J = 8.0 Hz), 2.91 (1H, s), 1.83 – 1.67 (10H, m), 1.35 – 1.23 (8H, m), 0.86 – 0.83 (5H, m); ESI-MS: 666.4 [M+H]+

Example 12: Preparation of 1-(cyclopent-3-en-1-yl)-N-((1S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1H-pyrazole-5-carboxamide.

1-(cyclopent-3-en-1-yl)-N-((1S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1H-pyrazole-5-carboxamide prepared following the process as described in example 1 but using A1, B1, C8 as starting material. 1H NMR (DMSO d6) d ppm: 10.12 (1H, s), 8.51 (1H, d, J = 6.4 Hz), 8.20 – 8.18 (1H, m), 7.50 (1H, s), 7.06 – 7.05 (1H, m), 6.99 (1H, s), 5.89 – 5.85 (1H, m), 5.72 (2H, s), 5.57 – 5.55 (1H, m), 4.57 (1H, t, J = 6.8 Hz), 4.32 – 4.27 (1H, m), 4.1 – 4.07 (1H, m), 3.08 (2H, d, J = 8.4 Hz), 2.91 (1H, s), 2.77 – 2.64 (4H, m), 1.83 (2H, d, J = 10.4 Hz), 1.80 – 1.75 (8H, m), 1.40 (3H, s), 1.34 – 1.33 (3H, m), 1.09 – 1.04 (1H, m), 0.88 – 0.85 (5H, m); ESI-MS: 668.3 [M+H]+

Example 13: Preparation of 1-allyl-N-((1S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1H-pyrazole-5-carboxamide.

1-allyl-N-((1S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1H-pyrazole-5-carboxamide prepared following the process as described in example 1 but using A1, B1, C9 as starting material. 1H NMR (DMSO d6) d ppm: 10.25 (1H, s), 8.50 (1H, d, J = 8.4 Hz), 8.25 – 8.20 (1H, m), 7.52 – 7.51 (1H, m), 7.07 – 7.06 (2H, m), 5.95 – 5.90 (1H, m), 5.62 – 5.61 (1H, m), 5.09 – 5.08 (3H, m), 5.05 – 4.95 (1H, m), 4.55 – 4.51 (1H, m), 4.32 – 4.31 (1H, m), 4.10 – 4.01 (1H, m), 3.08 -2.91 (3H, m), 1.83 – 1.68 (7H, m), 1.35 - 1.23 (7H, m), 1.11 – 1.09 (2H, m), 0.87 – 0.85 (6H, m); ESI-MS: 642.2 [M+H]+.

Example 14: Preparation of N-((S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-((R)-1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-3-methylisoxazole-4-carboxamide.

N-((S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-((R)-1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-3-methylisoxazole-4-carboxamide prepared following the process as described in example 1 but A5, B1,C4 as starting material. 1H NMR (DMSO d6) d ppm: 10.20 (1H, s), 8.20 – 8.10 (1H, m), 8.00 (1H, s), 7.99 (1H, d, J = 2.0 Hz), 6.70 (1H, d, J = 2.4 Hz), 5.75 – 5.70 (1H, m), 4.60 – 4.59 (1H, m), 4.09 – 4.07 (2H, m), 3.07 – 2.91 (3H, m), 1.80 – 1.67 (7H, m), 1.34 – 1.31 (4H, m), 1.26 – 1.24 (4H, m), 1.26 – 1.24 (4H, m), 1.14 – 1.10 (4H, m), 0.85 – 0.84 (6H, m); ESI-MS: 617.20 [M+H]+.

Example 15: Preparation of ethyl 1-(5-(((1S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)carbamoyl)-1H-pyrazol-1-yl)cyclopropane-1-carboxylate.

ethyl 1-(5-(((1S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl) amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl) carbamoyl)-1H-pyrazol-1-yl)cyclopropane-1-carboxylate prepared following the process as described in example 1 but using A1, B1, C10 as starting material. 1H NMR (DMSO d6) d ppm: 10.20 (1H, s), 8.12 – 8.10 (1H, m), 8.01 (1H, s), 7.99 (1H, d, J = 2.4 Hz), 7.11 – 7.10 (1H, m), 6.70 (1H, d, J = 2.4 Hz), 5.06 – 5.05 (1H, m), 4.65 – 4.63 (1H, m), 4.11 - 4.07 (3H, m), 3.07 – 2.91 (3H, m), 1.91 – 1.67 (14H, m), 1.34 – 1.30 (3H, m), 1.26 – 1.24 (3H, m), 1.14 – 1.10 (4H, m), 0.89 – 0.84 (5H, m); ESI-MS: 714.3 [M+H]+.

Example 16: Preparation of 1-(5-(((1S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)carbamoyl)-1H-pyrazol-1-yl)cyclopropane-1-carboxylic acid.

1-(5-(((1S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)carbamoyl)-1H-pyrazol-1-yl)cyclopropane-1-carboxylic acid prepared following the process as described in example 1 but using A1, B1, C11 as starting material. 1H NMR (DMSO d6) d ppm: 13.10 (1H, s), 10.20 (1H, s), 8.12 – 8.10 (1H, m), 7.95 (1H, d, J = 2.0 Hz), 7.81 (1H, d, J = 9.2 Hz), 7.10 – 7.00 (1H, m), 6.67 (1H, d, J = 2.0 Hz), 5.64 – 5.63 (1H, m), 4.67 – 4.66 (1H, m), 4.10 - 4.06 (2H, m), 3.07 – 2.91 (3H, m), 1.84 – 1.65 (12H, m), 1.36 – 1.16 (8H, m), 0.92 – 0.84 (6H, m); ESI-MS: 686.0 [M+H]+.

Example 17: Preparation of N-((S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-((S)-1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-3-methylisoxazole-4-carboxamide.

N-((S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-((S)-1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-3-methylisoxazole-4-carboxamide prepared following the process as described in example 1 but using A6, B1, C4 as starting material. 1H NMR (DMSO d6) d ppm: 10.13 (1H, s), 9.44 (1H, s), 8.42 (1H, d, J = 8.0 Hz), 8.10 – 8.00 (1H, m), 7.11 – 7.07 (1H, m), 5.62 – 5.61 (1H, m), 4.62 – 4.61 (1H, m), 4.20 – 4.15 (1H, m), 4.00 - 3.99 (1H, m), 3.06 – 2.91 (3H, m), 1.83 – 1.63 (10H, m), 1.35 – 1.30 (7H, m), 1.27 – 1.23 (8H, m); ESI-MS: 617.2 [M+H]+.

Example 18: Preparation of N-((1S)-1-cyclohexyl-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-2-oxoethyl)-3-methylisoxazole-4-carboxamide.

N-((1S)-1-cyclohexyl-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-2-oxoethyl)-3-methylisoxazole-4-carboxamide prepared following the process as described in example 1 but using A1, B3, C4 as starting material. 1H NMR (DMSO d6) d ppm: 10.14 (1H, s), 9.45 (1H, s), 8.41 (1H, d, J = 8.4 Hz), 8.10 – 8.00 (1H, m), 7.11 – 7.00 (1H, m), 5.67 – 5.65 (1H, m), 4.64 – 4.63 (1H, m), 4.30 – 4.29 (1H, m), 4.04 – 4.02 (1H, m), 3.08 – 2.91 (3H, m), 1.76 – 1.63 (12H, m), 1.35 – 1.30 (3H, m), 1.26 – 1.21 (6H, m), 1.19 – 1.08 (2H, m); ESI-MS: 603.2 [M+H]+.

Example 19: Preparation of (S)-N-(2-((4-(3,5-dimethyl-1H-pyrazol-4-yl)-3-(dimethylphosphoryl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide.

Step I: (5-amino-2-bromophenyl)dimethylphosphine oxide

In a 50 mL single neck round bottom flask was added 2-bromo-5-nitrophenyl)dimethylphosphine oxide (1.0 g, 3.60 mmol) (Prepared according to procedure reported in WO2021164746), EtOH (30 ml) and Water (3.0 ml) at 25°C.
to give clear solution. To this Fe (1.004 g, 17.98 mmol) and NH4Cl (0.962 g, 17.98 mmol) was added at 25°C. Then the reaction mixture was stirred at 90 °C for 5 h. After completion of reaction, the reaction mixture was filtered through hyflow and diluted with water (20 mL) and the aqueous layer was extracted with EtOAc (20 mL X 3). All organic layers were combined and washed with water and brine solution. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford desired product, the crude material was purified by Combiflash chromatography using MeOH in DCM as mobile phase. (Yield: 0.330 g, 37 %). LC-MS: 249.9 [M+1] +.

Step II: (5-amino-2-(3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)dimethylphosphine oxide.
In a 10 mL single neck round bottom flask, (5-amino-2-bromophenyl)dimethylphosphine oxide (CAS No: 2287288-82-6) (30 mg, 0.121 mmol) and 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (42.6 mg, 0.121 mmol) was added in 1,4-dioxane (2.0 mL) and water (1.0 mL) at 25 °C to give clear solution. After that K2CO3 (50.1 mg, 0.363 mmol) and PdCl2(dppf) (13.27 mg, 0.018 mmol) were added in to a reaction mixture at 25 °C. Then the reaction mixture was stirred at 90 °C for 3 h. After completion of reaction, the reaction mixture was diluted with water (20 mL) and the aqueous layer was extracted with EtOAc (20 mL X 3). All organic layers were combined and washed with water and brine solution. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford desired product as thick oil, (Yield: 0.200 g, 42 %). LC-MS: 394.00 [M+1] +.

Step III: tert-butyl (S)-(2-((4-(3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-3-(dimethylphosphoryl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)carbamate.
In a 25 mL single neck round-bottomed flask, (5-amino-2-(3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)dimethylphosphine oxide (200 mg, 0.508 mmol) was added in Pyridine (8.0 ml) at 25 °C. Then EDC (585 mg, 3.05 mmol) and (S)-2-(4-methylcyclohexyl)-2-pivalamidoacetic acid (195 mg, 0.762 mmol) were added in to a reaction mixture at 25 °C. Then the reaction mixture was stirred at 25 °C for 16 h. After completion of reaction, the reaction mixture was quenched with water (50 ml) and aqueous layer was extracted with EtOAc (50 ml X 3). All organic layers were combined and washed with water and brine solution. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude product. The crude material was purified by Combiflash to afford desired product. (Yield: 0.170 g, 4529 %).

Step IV: (S)-2-amino-N-(4-(3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-3-(dimethylphosphoryl)phenyl)-2-(4-methylcyclohexyl)acetamide hydrochloride.
In a 50 ml round-bottomed flask, tert-butyl (S)-(2-((4-(3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-3-(dimethylphosphoryl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)carbamate (150 mg, 0.232 mmol) was added in DCM (5.0 ml) at 28 °C, followed by dioxane HCl (1 mL, 0.165 mmol) was added at 0 °C. The reaction mixture was stirred at 28 °C for 2h. After completion of reaction, organic volatiles were removed under reduced pressure to get desire solid product. (Yield: 0.1 g, 74 %). ESI-MS: 547.20 (M+H)+.
Step V: (S)-N-(2-((4-(3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-3-(dimethylphosphoryl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide.
In a 50 mL round bottom flask was added (S)-2-amino-N-(4-(3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-3-(dimethylphosphoryl)phenyl)-2-(4-methylcyclohexyl)acetamide hydrochloride (100 mg, 0.171 mmol) in DMF (2 ml) at 28 °C. To this, 1-isopropyl-1H-pyrazole-5-carboxylic acid (29.1 mg, 0.189 mmol), HATU (98 mg, 0.257 mmol) and DIPEA (0.090 ml, 0.514 mmol) were added. The reaction mixture was stirred at 28 °C for 1 h. After completion of reaction, reaction mixture was quenched in water and aqueous layer was extracted with EtOAc. Organic layers were washed with water and brine solution. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford desired solid product. The crude product was purified by combiflash chromatography using MeOH in DCM as mobile phase. (Yield: 0.05 g, 43 %). ESI-MS: 683.30 [M+1] +.

Step VI: (S)-N-(2-((4-(3, 5-dimethyl-1H-pyrazol-4-yl)-3-(dimethylphosphoryl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide.
In a 25 mL single neck round-bottomed flask, (S)-N-(2-((4-(3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-3-(dimethylphosphoryl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide (50 mg, 0.085 mmol) was added in DCM (10.0 ml) at 25 °C. To this, TFA (56.4 µl, 0.732 mmol) was added at 25 °C. The reaction mixture was stirred at 25 °C for 4 h. After completion of reaction, the reaction mixture was concentrated under reduced pressure, the residue was basified with Methanolic ammonia and concentrated under reduced pressure to afford desired crude product. The crude product was purified by combiflash chromatography using methanol in dichloromethane as mobile phase. (Yield: 25 mg, 59 %). 1H NMR (DMSO d6) d ppm: 12.38 (1H, s), 10.41 (1H, s), 8.51 (1H, d, J = 8.4 Hz), 7.92 (1H, d, J = 10.4 Hz), 7.81 (1H, s), 7.50 (1H, d, J = 1.6 Hz), 7.31 (1H, d, J = 9.6 Hz), 6.97 (1H, d, J = 1.6 Hz), 5.41 - 5.38 (1H, m), 4.39 - 4.35 (1H, m), 2.23 (6H, s), 1.90 - 1.80 (2H, m), 1.65 - 1.60 (6H, m), 1.57 - 1.55 (1H, m), 1.36 - 1.31 (7H, m), 1.20 - 1.17 (4H, m), 0.87 - 0.86 (5H, m); ESI-MS: 553.3 [M+H]+.

Example 20: Preparation of (S)-N-(2-((4-(3,5-dimethyl-1H-pyrazol-4-yl)-2-(dimethylphosphoryl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide.

(S)-N-(2-((4-(3,5-dimethyl-1H-pyrazol-4-yl)-2-(dimethylphosphoryl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide prepared following the process as described in example 19 but A3, B1, C1 as startnig material. 1H NMR (DMSO d6) d ppm: NA; ESI-MS: 553.4 [M+H] +

Example 21: Preparation of N-(1-cyclohexyl-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-2-oxoethyl-1-d)-1-isopropyl-1H-pyrazole-5-carboxamide.

Step I: 2-Amino-2-cyclohexylacetic-2-d acid
In a 10 mL single neck round-bottomed flask, 2-amino-2-cyclohexylacetic acid (100 mg, 0.636 mmol) was added in acetic-d3 acid-d (4.0 mL) or acetic acid-d (4.0 mL) at 25 °C. 2-hydroxybenzaldehyde (15.54 mg, 0.127 mmol) was added in reaction mixture at 25 °C. The reaction mixture was stirred at 100 °C for 2 h. After completion of reaction, the solution was concentrated under reduced pressure to dryness. The residue was treated with D2O (2.0 mL) and stirred for 15 min, then diluted with water (4.0 mL) the solution was concentrated under reduced pressure. MeOH (2.0 mL) was added in residue, solid material was filtered to get desired product. (Yield: 80 mg, 75 %). 1H NMR (D2O, 400 MHz) ? ppm: 0.55 – 0.55 (5H, m), 1.12 – 1.09 (2H, m), 1.21 (3H, bs), 1.45-1.42 (3H, m). ESI-MS: 159.3 [M+1] +.

Step: II 2-((tert-butoxycarbonyl) amino)-2-cyclohexylacetic-2-d acid.
In a 100 mL two neck round-bottomed flask, 2-amino-2-cyclohexylacetic-2-d acid (1.7 g, 10.74 mmol) was added in 1,4-dioxane (40 mL) and water (30 mL) at 5-10 °C. Sodium carbonate (5.69 g, 53.7 mmol) and BOC-anhydride (3.74 mL, 16.12 mmol) were added in reaction mixture at 0-5 °C, stirred at 25 °C for 16 h. After completion of reaction, the reaction mixture was quenched in water (50 mL), acidified by using dil.HCl (pH-6.0) and aq. layer was extracted with EtOAc. Organic layers were washed with water and brine solution. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford desired product. (2.4 g, 86%) ESI-MS: m/z [M+H] + 159.3.

Step III : Tert-butyl (1-cyclohexyl-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-2-oxoethyl-1-d)carbamate.
In a 10 mL single neck round-bottomed flask, 2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetic-2-d acid (123 mg, 0.474 mmol) was added in pyridine (2.0 mL) at 25°C. EDC.HCl (455 mg, 2.371 mmol) and 2-(4-amino-2-(dimethylphoscphoryl)-5-fluorophenyl)-N-methyl-N-(2,2,2-trifluoroethyl)propanamide (140 mg, 0.395 mmol) were added in reaction mixture at 25 °C and stirred for 16 h. After completion of reaction, the reaction mixture was quenched in water (20 mL) and aq. layer was extracted with EtOAc. Organic layers were washed with water and brine solution. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by combiflash chromatography using Methanol in DCM as mobile phase. (Yield: 100 mg, 43 %). ESI-MS: m/z [M+H] + 595.30

Step: IV: 2-(4-(2-amino-2-cyclohexylacetamido-2-d)-2-(dimethylphosphoryl)-5-fluorophenyl)-N-methyl-N-(2,2,2-trifluoroethyl)propanamide hydrochloride
In a 10 mL single neckround-bottomed flask, tert-butyl (1-cyclohexyl-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-2-oxoethyl-1-d)carbamate (100 mg, 0.168 mmol) was added in MeOH (5.0 mL) at 5-10 °C. 1,4-dioxane hydrochloride (0.561 ml, 1.682 mmol) was added at 5-10 °C. The reaction mixture was stirred at 25 °C for 1 h. After completion of reaction, the solution was concentrated under reduced pressure to dryness give desired product. (Yield: 80 mg, 90 %). ESI-MS: m/z [M+H] + 495.25.

Step: V: N-(1-cyclohexyl-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-2-oxoethyl-1-d)-1-isopropyl-1H-pyrazole-5-carboxamide
In a 10 mL single neck round-bottomed flask, 1-isopropyl-1H-pyrazole-5-carboxylic acid (25.6 mg, 0.166 mmol) was added in DMF (2.0 mL) at 0-5 °C. DIPEA (0.079 ml, 0.452 mmol) and HATU (86 mg, 0.226 mmol) was added in reaction mixture at 0-5 °C, stirred for 15 min. 2-(4-(2-amino-2-cyclohexylacetamido-2-d-2-d)-2-(dimethylphosphoryl)-5-fluorophenyl)-N-methyl-N-(2,2,2-trifluoroethyl)propanamide hydrochloride (80 mg, 0.151 mmol) was added in reaction mixture and stirred at 25 °C for 1 h. After completion of reaction, the reaction mixture was quenched in water (20 mL) and aq. layer was extracted with EtOAc. Organic layers were washed with water and brine solution. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by combiflash chromatography using Methanol in DCM as mobile phase. (Yield: 45 mg, 48 %). 1H NMR (DMSO- d6, 500 MHz) ? ppm: 10.20 (1H, br s), 8.45 (1H, s), 8.20 - 8.00 (1H, m), 7.50 (1H, s), 7.15 - 7.00 (1H, m), 6.95 (1H, s), 5.62 - 5.60 (1H, m), 5.43 - 5.37 (1H, m), 4.35 - 4.05 (2H, m), 3.07 - 3.05 (2H, m), 1.86 - 1.78 (2H, m), 1.75 - 1.69 (6H, m), 1.65 - 1.50 (2H, m), 1.37 - 1.32 (9H, m), 1.29 - 1.23 (5H, m), 1.18 - 1.14 (3H, m). ESI-MS: 631.30 [M+H] +

Invitro study protocol:
To evaluate potential inhibitor of IL- 17A, Human IL-17A/IL-17RA HTRF binding kit (Cisbio, cat no : 64BDIL17PEG) was used, which measures interaction between IL-17A and it's receptor, IL-17RA. In presence of an IL-17A inhibitor, this interaction is perturbed. NCEs were routinely screened using this kit according to the manufacturer's protocol. Briefly, 4 uL of Tag1-IL17A and 2uL of increasing concentration of 10X (with a final 1% DMSO concentration) compound (1nM to 10 uM) were pre-incubated for 1 hr at room temperature in low volume white 384 well plate. After that, 4 uL of Tag2-IL17RA were added in each well. Finally 10 uL of premix of detection reagent, which contains 1X each of anti-Tag1 EU cryptate (donor) and anti-Tag2 XL665 antibody (acceptor), were added in each well and plate was incubated in dark for 24 hrs at room temperature. Next day, plate was read in Hidex multimode reader with an excitation wave length of 330 nm and dual emissions wave length of 665 and 620 nm.
% inhibition of binding interaction of compounds was calculated from the HTRF ratio, with respect to vehicle, which represents 100% binding. For IC50 determination, % inhibition of binding interaction were fed in Graph Pad prism using a four parameter non linear regression analysis.

Biological Activity
The exemplified compounds belonging to Formula I demonstrated potent IL17A inhibitory potency.
Comp Id IC(50) nM Comp Id IC(50) nM
1 182 10 214
4 208 11 100
5 250 12 63
6 68 13 237
8 227 17 135
9 160

When tested in the above assay, compounds with accompanying examples no 2, 3, 7, 14, 15, 16, 18, 19,20,21 exhibit IC50 values > 500 nM.
The novel compounds of general formula (1), their suitable pharmaceutically acceptable salts, their solvates, their hydrates, their stereoisomers, their polymorphs, their racemic mixtures and their optically active forms or their mixtures of the present invention can be formulated into suitable pharmaceutically acceptable compositions by combining with suitable excipients by techniques and processes and concentrations as are well known.
The novel compounds of general formula (1), their suitable pharmaceutically acceptable salts, their solvates, their hydrates, their stereoisomers, their polymorphs, their racemic mixtures and their optically active forms or their mixtures of the present invention are useful as a medicament for the inflammatory conditions such as psoriasis, asthma, psoriatic arthritis or rheumatoid arthritis and suitable for humans and other warm-blooded animals, and may be administered either by oral, topical or parenteral administration.
The quantity of the active component, that is, The novel compounds of general formula (1), their suitable pharmaceutically acceptable salts, their solvates, their hydrates, their stereoisomers, their polymorphs, their racemic mixtures and their optically active forms or their mixtures of the present invention and unit dosage form thereof may be varied or adjusted widely depending upon several factors such as the particular application method, the potency of the particular compound and the desired concentration.

Use of the novel compounds of general formula (1), their suitable pharmaceutically acceptable salts, their solvates, their hydrates, their stereoisomers, their polymorphs, their racemic mixtures and their optically active forms or their mixtures of the present invention for the treatment of inflammatory conditions such as psoriasis, asthma, psoriatic arthritis or rheumatoid arthritis.

A method of treatment of inflammatory conditions such as psoriasis, asthma, psoriatic arthritis or rheumatoid arthritis by administering to a subject in need thereof a therapeutically effective amount of the novel compounds of general formula (1), their suitable pharmaceutically acceptable salts, their solvates, their hydrates, their stereoisomers, their polymorphs, their racemic mixtures and their optically active forms or their mixtures of the present invention.

The invention relates to IL-17 inhibitor for inflammatory conditions, such as psoriasis, asthma, psoriatic arthritis or rheumatoid arthritis.
,CLAIMS:We claim:
1. A novel compounds of general formula (1), their suitable pharmaceutically acceptable salts, their solvates, their hydrates, their stereoisomers, their polymorphs, their racemic mixtures and their optically active forms or their mixtures,

Wherein,
R1 is selected from hydrogen, deuterium and -F;
R2 and R3 are selected from hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, C4-C7 heterocycloalkyl, C5-C6 heteroaryl, aryl, bicyclic, spirocyclic ring system; alternatively, R2 and R3 may combine together to form 3-8 membered cycloalkyl ring, 3-8 membered heterocyclic ring, aryl, bicyclic or spirocyclic ring system; wherein, C1-C6 alkyl, C3-C7 cycloalkyl, C4-C7 heterocycloalkyl, C5-C6 heteroaryl, aryl, bicyclic, spirocyclic ring system is substituted or unsubstituted with one or more substituents independently selected from halogen, haloalkyl, C1-C6 alkyl, C3-C6 cycloalkyl, -OR5, -SR5, -N(R5)2, -C(O)R5, -C(O)OR5, -OC(O) R5, -OC(O)N(R5)2, -C(O)N(R5)2, -N(R5)C(O) R5, -N(R5)C(O)O R5, -N(R5)C(O)N(R5)2, -N(R5)S(O)2(R5), -S(O)R5, -S(O)2R5, -S(O)2N(R5)2, -S(=O)(=NR5)R5, -NO2, =O and -CN;
C is selected form aryl, heterocyclic ring;
R4 is selected from
hydrogen, halogen, -OR5, -SR5, -N(R5)2, -C(O)R5, -C(O)OR5, -OC(O)R5, -OC(O)N(R5)2, -C(O)N(R5)2, -N(R5)C(O)R5, -N(R5)C(O)OR5, -N(R5)C(O)N(R5)2, -N(R5)S(O)2(R5), -S(O)R5, -S(O)2R5, -S(O)2N(R5)2, -S(=O)(=NR5)R5, -NO2, =O and -CN; C1-C6 alkyl, C4-C6 heterocycloalkyl, C3-C10 carbocycle each of which is optionally substituted with one or more substituents independently selected from halogen, -OR5, -SR5, -N(R5)2, -C(O)R5, -C(O)OR5, -OC(O)R5, -OC(O)N(R5)2, -C(O)N(R5)2, -N(R5)C(O)R5, -N(R5)C(O)OR5, -N(R5)C(O)N(R5)2, -N(R5)S(O)2(R5), -S(O) R5, -S(O)2R5, -S(O)2N(R5)2, -S(=O)(=NR5)R5, -NO2, =O and -CN;
n is selected from 0,1,2,3;
A is selected from 5 to 6 membered heteroaryl, 9 or 10 membered bicyclic heteroaryl, phenyl, each of them are substituted or unsubstituted with one or more substituents selected from (i), (ii), (iii) and (iv);
(i) halogen, deuterium, -OR5, -SR5, -N(R5)2, -C(O)R5, -C(O)OR5, -OC(O)R5, -OC(O)N(R5)2, -C(O)N(R5)2, -N(R5)C(O)R5, -N(R5)C(O)OR5, -N(R5)C(O)N(R5)2, -N(R5)S(O)2(R5), -S(O)R5, -S(O)2R5, -S(O)2N(R5)2, -S(=O)(=NR5)R5, -NO2, =O and -CN;
(ii) C1-C10 alkyl, substituted or unsubstituted with one or more substituents selected from: C1-C6 alkyl, halogen, deuterium, C3-C10 carbocycle, 3-10 membered heterocycle, -OR5, -SR5, -N(R5)2, -C(O)R5, -C(O)OR5, -OC(O)R5, -OC(O)N(R5)2, -C(O)N(R5)2, -N(R5)C(O) R5, -N(R5)C(O)OR5, -N(R5)C(O)N(R5)2, -N(R5)S(O)2(R5), -S(O)R5, -S(O)2R5, -S(O)2N(R5)2, -S(=O)(=NR5)R5, -NO2, =,O and -CN;
(iii) 3-8 membered cycloalkyl ring, 3-10 membered heterocycle, bicyclic, spirocyclic substituted or unsubstituted with one or more substituents selected from halogen, deuterium, -OR5, -SR5, -N(R5)2, -C(O)R5, -C(O)OR5, -OC(O)R5, -OC(O)N(R5)2, -C(O)N(R5)2, -N(R5)C(O)R5, -N(R5)C(O)OR5, -N(R5)C(O)N(R5)2, -N(R5)S(O)2(R5), -S(O)R5, -S(O)2R5, -S(O)2N(R5)2, -S(=O)(=NR5)R5, -NO2, =,O and -CN; and C1-C6 alkyl substituted or unsubstituted with one or more substituents selected from: halogen, deuterium, -OR5, -SR5, -N(R5)2, -C(O)R5, -C(O)OR5, -OC(O)R5, -OC(O)N(R5)2, -C(O)N(R5)2, -N(R5)C(O) R5, -N(R5)C(O)O R5, -N(R5)C(O)N(R5)2, -N(R5)S(O)2(R5), -S(O)R5, -S(O)2 R5, -S(O)2N(R5)2, -S(=O)(=NR5)R5, -NO2, =O and -CN;
(iv) ;
Y is selected from O, -CO, -N, C1-C6 alkyl or absent;
Z1 is selected from ;
Z2 is selected from , hydrogen, C1-C6-alkyl or absent;
--- of Z1 and Z2 is a bond which is present or absent;
Z1 and Z2 combine together to form 4-7 membered cycloalkene, 4-7 membered cyloalkyne ring;
when --- is present, E2 and E3 are absent;
E1, E2 and E3 are selected from hydrogen, C1-C6 alkyl, -OC1-C6 alkyl, C1-C6 haloalkyl, -NC1-C6 alkyl;
E1 and E3 may combine to form 4-7 membered cycloalkyl, 4-7 membered heterocyclic ring;
B is selected from (i), (ii);
(i) 5-10 membered heteroaryl ring, 5-10 membered heterocyclic ring, 3-7 membered cycloalkyl ring, each of them are substituted or unsubstituted with C1-C6 alkyl, C3-C7 cycloalkyl, C4-C7 heterocyclic, bicyclic, spirocyclic ring, halogen, deuterium, -OR5, -SR5, -N(R5)2, -C(O)R5, -C(O)OR5, -OC(O)R5, -OC(O)N(R5)2, -C(O)N(R5)2, -N(R5)C(O)R5, -N(R5)C(O)O R5, -N(R5)C(O)N(R5)2, -N(R5)S(O)2(R5), -S(O) R5, -S(O)2R5, -S(O)2N(R5)2, -S(=O)(=NR5)R5, -NO2, =O and –CN, -P(O)CR5; wherein, if 5-10 membered heteroaryl ring contain nitrogen in ring then nitrogen may further attached to –O;
(ii)
;
R6 and R7 are each independently selected from (a), (b), (c) and (d);
(c) Hydrogen;
(d) halogen, -OR10, -SR10, -N(R10)2, -C(O)R10, -C(O)NH2, -C(O)-O-C1-6-alkyl, -OC(O)R10, -OC(O)N(R10)2, -N(R10)C(O)R10, -N(R10)C(O)OR10, -N(R10)C(O)N(R10)2, -N(R10)S(O)2(R10), -S(O)R10, -S(O)2R10, -S(O)2N(R10)2, -S(=O)(=NR10)R10, -NO2, - CN;
(c) C1-C6 alkyl substituted or unsubstituted with one or more substituents selected from: halogen, -OR10, -SR10, -N(R10)2, -C(O)R10, -C(O)NH2, -C(O)-O-C1-6-alkyl, -OC(O)R10, -OC(O)N(R10)2, -N(R10)C(O)R10, -N(R10)C(O)OR10, -N(R10)C(O)N(R10)2, -N(R10)S(O)2(R10), -S(O)R10, -S(O)2R10, -S(O)2N(R10)2, -S(=O)(=NR10)R10, -NO2, - CN;
(d) C3-10 carbocycle and 3- to 10-membered heterocycle any of which is substituted or unsubstituted with one or more substituents independently selected from: halogen, -OR10, -SR10, -N(R10)2, -C(O)R10, -C(O)NH2, -C(O)-O-C1-6-alkyl, - OC(O)R10, -OC(O)N(R10)2, -N(R10)C(O)R10, -N(R10)C(O)OR10, -N(R10)C(O)N(R10)2, -N(R10)S(O)2(R10), -S(O) R10, -S(O)2R10, -S(O)2N(R10)2, -S(=O)(=NR10)R10, -NO2, - CN;
R6 and R7 can come together to form a 3-8 membered cycloalkyl ring, 4-to 12-membered heterocycle substituted or unsubstituted with one or more substituents independently selected from: halogen, -OR10, -SR10, -N(R10)2, -C(O)R10, -C(O)NH2, -C(O)-O-C1-6-alkyl, - OC(O)R10, -OC(O)N(R10)2, -N(R10)C(O)R10, -N(R10)C(O)O R10, - N(R10)C(O)N(R10)2, -N(R10)S(O)2(R10), -S(O) R10, -S(O)2 R10, -S(O)2N(R10)2, -S(=O)(=NR10)R10, -NO2, - CN; C1-6 alkyl substituted or unsubstituted with one or more substituents independently selected from halogen, -OR10, -SR10, -N(R10)2, -C(O)R10, -C(O)NH2, -C(O)-O-C1-6-alkyl, - OC(O)R10, -OC(O)N(R10)2, -N(R10)C(O)R10, -N(R10)C(O)O R10, - N(R10)C(O)N(R10)2, -N(R10)S(O)2(R10), -S(O) R10, -S(O)2 R10, -S(O)2N(R10)2, -S(=O)(=NR10)R10, -NO2, - CN;
R5 and R10 are selected at each occurrence from (I), (II) and (III);
(I) hydrogen;
(II) C1-6 alkyl substituted or unsubstituted with one or more substituents independently selected from: halogen, -OH, -OC1-C6 alkyl, -OC1-C6 haloalkyl -NH2, -NO2, =O, -CN, C3-10 carbocycle and 3- to 10-membered heterocycle, wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are substituted or unsubstituted with one or more substituents selected from: halogen, -OH, C1-C6 haloalkyl, -OC1-C6 alkyl, -OC1-C6haloalkyl -NH2, -NO2, =O, and -CN;
(III) C3-10 carbocycle and 3-10 membered heterocycle, each of which is substituted or unsubstituted with one or more substituents independently selected from: halogen, -OH, C1-C6 haloalkyl, -OC1-C6 alkyl, -OC1-C6 haloalkyl -NH2, -NO2, =O, -CN; and C1-6 alkyl substituted or unsubstituted with one or more substituents independently selected from halogen, -OH, -OC1-C6 alkyl, -OC1-C6 haloalkyl -NH2, -NO2, =O, and –CN;
R8 and R9 are each selected from (a), (b), (c);
(a) Hydrogen;
(b) C1-C6 alkyl substituted or unsubstituted with one or more substituents independently selected from: halogen, -OR10, -SR10, -N(R10)2, -C(O)R10, -C(O)NH2, -C(O)-O-C1-6-alkyl, -OC(O)R10, -OC(O)N(R10)2, -N(R10)C(O)R10, -N(R10)C(O)OR10, -N(R10)C(O)N(R10)2, -N(R10)S(O)2(R10), -S(O)R10, -S(O)2R10, -S(O)2N(R10)2, -S(=O)(=NR10)R10, -NO2, - CN; C3-10 carbocycle and 3- to 10-membered heterocycle any of which is substituted or unsubstituted with one or more substituents independently selected from halogen, -OR10, -SR10, -N(R10)2, -C(O)R10, -C(O)NH2, -C(O)-O-C1-6-alkyl, - OC(O)R10, -OC(O)N(R10)2, -N(R10)C(O)R10, -N(R10)C(O)O R10, - N(R10)C(O)N(R10)2, -N(R10)S(O)2(R10), -S(O) R10, -S(O)2 R10, -S(O)2N(R10)2, -S(=O)(=NR10)R10, -NO2, - CN;
(c) C3-10 carbocycle and 3- to 10-membered heterocycle any of which is substituted or unsubstituted with one or more substituents independently selected from: halogen, -OR10, -SR10, -N(R10)2, -C(O)R10, -C(O)NH2, -C(O)-O-C1-6-alkyl, - OC(O)R10, -OC(O)N(R10)2, -N(R10)C(O)R10, -N(R10)C(O)O R10, - N(R10)C(O)N(R10)2, -N(R10)S(O)2(R10), -S(O) R10, -S(O)2 R10, -S(O)2N(R10)2, -S(=O)(=NR10)R10, -NO2, - CN; C1-6 alkyl substituted or unsubstituted with one or more substituents independently selected from halogen, -OR10, -SR10, -N(R10)2, -C(O)R10, -C(O)NH2, -C(O)-O-C1-6-alkyl, - OC(O)R10, -OC(O)N(R10)2, -N(R10)C(O)R10, -N(R10)C(O)O R10, - N(R10)C(O)N(R10)2, -N(R10)S(O)2(R10), -S(O) R10, -S(O)2 R10, -S(O)2N(R10)2, -S(=O)(=NR10)R10, -NO2, - CN; or

R8 and R9 combined to form 3-8 membered cycloalkyl ring, 4-12 membered heterocyclic ring, aryl, bicyclic or spirocyclic ring system, wherein, 3-8 membered cycloalkyl ring, 4-12 membered heterocyclic ring, aryl, bicyclic and spirocyclic ring system is optionally substituted with one or more substituents independently selected from halogen, C1-C6 alkyl, -OR5, -SR5, -N(R5)2, -C(O)R5, -C(O)OR5, -OC(O)R5, -OC(O)N(R5)2, -C(O)N(R5)2, -N(R5)C(O)R5, -N(R5)C(O)OR5, -N(R5)C(O)N(R5)2, -N(R5)S(O)2(R5), -S(O) R5, -S(O)2R5, -S(O)2N(R5)2, -S(=O)(=NR5)R5, -NO2, =O and -CN; or
C1-C6 alkyl optionally substituted with one or more substituents independently selected from -OR5, -SR5, -N(R5)2, -C(O)R5, -C(O)OR5, -OC(O)R5, -OC(O)N(R5)2, -C(O)N(R5)2, -N(R5)C(O)R5, -N(R5)C(O)OR5, -N(R5)C(O)N(R5)2, -N(R5)S(O)2(R5), -S(O)R5, -S(O)2R5, -S(O)2N(R5)2, -S(=O)(=NR5)R5, -NO2, =O and -CN;
M is selected from CH or absent;
z independently selected from C, N;
R11 is independently selected from -NR10COR10, -NR10CON(R10)2, NR10.
2. The novel compounds of general formula (1) as claimed in claim 1,
wherein,
R1 is selected from hydrogen and deuterium;
R2 and R3 are selected from C3-C7 cycloalkyl;
R2 and R3 combine together to form 3-8 membered cycloalkyl ring;
R4 is selected from hydrogen and halogen;
n is selected from 0, 1, 2;
A is selected from 5 to 6 membered heteroaryl;
Y is selected from C1-C6 alkyl or absent;
B is selected from
(iii) 5-10 membered heteroaryl ring;
(iv)
R6 and R7 are each selected from hydrogen, C1-C6 alkyl wherein alkyl is substituted with halogen;
R5 and R10 are selected at each occurrence from hydrogen, C1-C6 alkyl;
R8 and R9 are selected at each occurrence from hydrogen, C1-C6 alkyl wherein alkyl is substituted with halogen;
M is selected from CH or absent.
3. Compounds of the formula (1) as claimed in claim 1:
N-((1S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide;
N-((1S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-oxo-1-((2,2,2-trifluoroethyl) amino)propan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide;
N-((1S)-2-((2-(dimethylphosphoryl)-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide;
N-((1S)-1-cycloheptyl-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide;
N-((1S)-2-((3-(dimethylphosphoryl)-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide;
N-((1S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1-(penta-1,4-dien-3-yl)-1H-pyrazole-5-carboxamide;
N-((1S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide;
N-((1S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-3-methylisoxazole-4-carboxamide;
N-((1S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1-(prop-2-yn-1-yl)-1H-pyrazole-5-carboxamide;
N-((1S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide;
N-((1S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1-(pent-1-en-4-yn-3-yl)-1H-pyrazole-5-carboxamide;
1-(cyclopent-3-en-1-yl)-N-((1S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1H-pyrazole-5-carboxamide;
1-allyl-N-((1S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1H-pyrazole-5-carboxamide;
N-((S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-((R)-1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-3-methylisoxazole-4-carboxamide;
ethyl 1-(5-(((1S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)carbamoyl)-1H-pyrazol-1-yl)cyclopropane-1-carboxylate;
1-(5-(((1S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)carbamoyl)-1H-pyrazol-1-yl)cyclopropane-1-carboxylic acid;
N-((S)-2-((5-(dimethylphosphoryl)-2-fluoro-4-((S)-1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-3-methylisoxazole-4-carboxamide;
N-((1S)-1-cyclohexyl-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-2-oxoethyl)-3-methylisoxazole-4-carboxamide;
(S)-N-(2-((4-(3,5-dimethyl-1H-pyrazol-4-yl)-3-(dimethylphosphoryl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide;
(S)-N-(2-((4-(3,5-dimethyl-1H-pyrazol-4-yl)-2-(dimethylphosphoryl)phenyl)amino)-1-(4-methylcyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide;
N-(1-cyclohexyl-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-2-oxoethyl-1-d)-1-isopropyl-1H-pyrazole-5-carboxamide.
4. Use of the novel compounds of general formula (1) as claimed in claim 1 for the treatment of inflammatory conditions such as psoriasis, asthma, psoriatic arthritis or rheumatoid arthritis.
5. Method of treating inflammatory conditions such as psoriasis, asthma, psoriatic arthritis or rheumatoid arthritis comprising administering to a subject in need thereof a therapeutically effective amount of the novel compounds of general formula (1) as claimed in claim 1 or its suitable pharmaceutical composition.
6. Use of the novel compounds of general formula (1) as claimed in claim 1 in the manufacture of medicament for the treatment of inflammatory conditions such as psoriasis, asthma, psoriatic arthritis or rheumatoid arthritis.