SA08290386B1 - Pyrazinone DerivAtives and Processes for their Preparation - Google Patents

Abstract

Pyrazinone Derivatives and Processes for Their Preparation Abstract The present invention relates to pyrazinone derivatives of formula (I): (I) wherein R1, R2, R3, R4, R5, R6 and R7 are as specified herein; Processes for its preparation, and pharmaceutical formulas containing it and its use in treatment. .

Description

— 0*7 Pyrazinone DerivAtives and Processes for their Preparation FULL DESCRIPTION BACKGROUND The present invention relates to 8 of the present invention; Processes for its preparation and pharmaceutical formulations containing it and its use in treatment. The primary function of the lungs is to transform them into a fragile structure as a result of multiple exposure to the surrounding environment; including © pollutants; Microbes «allergens and carcinogens». host factors resulting from interactions of lifestyle choices and genotype; affect the response to that exposure. Damage or injury to the lungs can increase the wide range of diseases of the respiratory system (or respiratory diseases). A number of these diseases are of critical importance to public health. Respiratory diseases include Je diseases Ve Lung injury sala Acute respiratory distress syndrome Respiratory Distress Syndrome (ARDS) Occupational lung disease Occupational lung disease Lung cancer Tuberculosis tuberculosis; Fibrosis ¢ pneumoconiosis « emphysema ¢ pneumonia » chronic obstructive pulmonary disease (COPD) and asthma. NO Asthma is among the most common respiratory diseases. Asthma is generally defined as an inflammatory disorder of the airways where there are clinical symptoms of intermittent airway obstruction. It can be distinguished clinically by worsening wheezing and shortness of breath YAAY 0

rv — - and rabies 0 is a chronic disabling disorder that appears to be increasing in prevalence and severity. It has been verified that 716 children and 79 adults living in developed countries suffer from asthma, and therefore treatment must be directed at controlling symptoms so that a normal life can be practiced, and at the same time basics for treating the basic inflammation are provided. Underlying inflammation © . Expression 0 indicates a wide range of lung diseases that can interfere with normal breathing. Recent clinical evidence defines COPD as a condition characterized by obstruction of the airways that is not fully reversible. Airway strictures are usually advanced and associated with an abnormal inflammatory response of the lung to harmful particles and gases. The most important source that participates in the existence of these particles and gases; At least in the western world, tobacco is smoked. COPD patients present with a variety of symptoms (coal ey), including coughing; shortness of breath excess production of sputum; This oa se occurs through the function of a number of cellular compartments, including neutrophils s macrophages “epithelial cells 0 off”. The two most common cases covered by COPD are chronic bronchitis 1007/5008. Chronic bronchitis is a long-term inflammation of the bronchi that causes increased mucus production and other changes. The symptoms that appear on the patient are coughing and increased spitting up. Chronic bronchitis can lead to more frequent and serious infections of the respiratory tract, narrowing and obstruction of the bronchi, difficulty in breathing and disability. YAAY

— chronic lung disease which affects the alveoli and/or the ends of the smallest bronchi the lung loses its elasticity and thus those areas of the lungs become enlarged. This leads to difficulty breathing and can lead to insufficient transport of oxygen (J) into the blood. The predominant symptom is in patients with emphysema Quill (Bua). © Therapeutic agents used in the treatment of respiratory diseases contain corticosteroids58. Corticosteroids (J) Also known as glucocorticosteroids or glucocorticoids, they are potent anti-inflammatory agents. While the exact mechanism of their effect is not clear, the end result of corticosteroid treatment is a reduction in the number, activity, and movement of cells. 0 Inflammation in the submucosal bronchi leading to reduced airway responses Corticosteroids can also reduce bronchial lining separation Vascular permeability Mucus secretion While treatment with corticosteroids can lead to significant advantages the effectiveness of these agents Moreover, while steroids can lead to therapeutic effects, it is desirable to be able to use 0 steroids in low doses to reduce the risk of unwanted side effects which May accompany regular administration. Recent studies have also focused on the problem of acquisition of steroid resistance among patients with respiratory diseases. For example; It was found that cigarette smokers who suffer from asthma are unresponsive to inhaled corticosteroids. However, the variance in response between smokers and non-smokers reduces 0 from high-dose inhaled corticosteroids: (Tomilinson et al., Thorax 2005; 60: 282-287) YAAY.

Another class of therapeutic agent used in the treatment of respiratory diseases is bronchodilators. Bronchodilators 5 can be used to relieve symptoms of respiratory diseases by relaxing bronchial smooth muscles; reduce airway obstruction; © and reduce super lung injury and reduce shortness of breath. Bronchodilators in clinical use contain 20017 receptor antagonists muscarinic receptor antagonists methylxanthines Bronchodilators are indicated primarily for symptomatic relief and are not considered to alter the natural history of respiratory disease. “p38 ¢ serine/threonine kinase PA is a member of the mitogenic and stress-activated protein kinase 0 (SAPK/MAPK) family of enzymes and participates in the intercellular signaling cascade that involves a number of responses associated with inflammatory processes. Four isoforms of the enzyme (Ls kinase p38) are known and identified as p380380 p38y and p38p. Airway p38 is activated by stress cytokines (including smoke 1068660 infections) or Oxidative products (08) and pro-inflammatory cytokines (for example, IL-1 or TNF-a) are included in the induction of pro-inflammatory cytokines (TNF-). a 1Pla IL-6 and template metalloprotease by bacterial lipopolysaccharide (LPS) addition of 38M by phosphorylation of 0 and 7182 positioned in the activation loop is activated by a bispecific MAP pre-kinase; MK3 ¢ kinase (MKK) enzymes ) and 116166. In turn, p38 phosphorylates a number of Ye targets that include other kinases and transcription factors.

on reproduction; 8 is included in the stability control of Bae cytokines mRNA containing IL-8 5 IL-6 IL-3 TNF-a, thus; Despite this succession; The kinase p38 is believed to play an important role in controlling the translational response to induce pro-inflammatory genes and the subsequent release of inflammatory cytokines such as TNF-a from cells. This mechanism was brought into play by the © research on the effects of 38m6 enzyme inhibition on chronic inflammation and arthritis: 0. (Kumar et al, Nature Reviews Drug Discovery (2003) 2: 71 7-725) Specifically, m-38 inhibitors have been described as potential agents for the treatment of rheumatoid arthritis. In addition to the links between 8 activation and chronic inflammation and arthritis, there is also data demonstrating the implication of a role for 38 in the pathogenesis of diseases such as pathogenesis of airway diseases, specifically COPD and asthma. Ra. asthma that stress triggers (including smoking call “infections” or oxidative products cause inflammation within an Al medium 38m0 inhibitors indicated as IL-13 5 IL- 5 IL-4 JL-6 «TL-1o.» TNF-a LPS Jari of Egg Albumen-induced Airways : Haddadetal BrJ Pharmacol, 2001, 132(8), 1715; Underwood etal., Am J Physiol Lung cell 90 .281, 293 YAAY

- moreover; They significantly inhibit neutrophils and MMP-9 release in LPS, ozone gas, or cigarette smoking models. There is a large amount of clinical data demonstrating the potential benefits of kinase 8 inhibition, which can be related is Jb 0 (Lee etal.

Immunopharmacology, 2000, 47, 1 85-200) ¢ Therapeutic inhibition of M38 activation could therefore be important in regulating airway inflammation. Increased efficacy is expected when p38 kinase inhibitors are administered either locally into the lung (eg by inhalation and through the nose) or by systemic administration (eg by mouth, intravenous, and subcutaneous). subcuteanous delivery ). A particular feature of the present invention relates to pharmaceutical compositions which are formulated to permit the administration of the compounds 0 described herein topically into the lung. Advantages associated with transferring the drug to the elderly by inhalation include the presence of a large surface area of the lung, absorption de gall, rapid absorption of dc jal, rapid onset of effect; Avoid metabolism in the gut and first tract; Low dose and few side effects. Known inhibitors of the p38 kinase enzyme can be reviewed in: G.

J.

Hanson in Expert Opinions on Therapeutic Patents, 1997, 7, 729-733, J Hynes et al 1 Current Topics in Medicinal chemistry 2005, 5, 967-985, C Dominguez et al in Expert Opinions on Therapeutic Patents, 2005 , 15, 801-816. YAAY

As long as the general description of the invention, the present invention provides a compound with the formula (0: R * 3C BH “0 RY N R® Hb N ~ Rt Rr? 0 A

Where: ° AgA 1818 R25 select each separately from (CF3 «halo «alkoxy (C1-C6) «alkyl (C1-C6) (H)

¢CN

02172829 OH halo calkoxy (C1-C6) “alkyl (C1-C6) (H) selects separately from R45 R3 alkyl (C1-C6) where “CONRIOR11 5 heteroaryl heteroaryl aryl” CN CF3

said alkoxy (C1-CO)s mentioned; Each individually replaced by 1 ? or ¥ combinations

¢halo 5 S(O)pR55 021812813 “alkoxy (01-03) “OH select separately from 0

5m choose from 1 caryl heteroaryl (C3-C7) « heterocycloalkyl » heteroaryl

¢OR16 5 012816 0211816817 «S(O)pR16 «(CR14R15)mNRI6R17 «cycloalkyl

(C3-C7) «cycloalkyl (C3-C7) «alkoxy (C1-C6) «alkyl (C1-C6) (H choose from 6 alkyl (C1-C6) where taryl y heteroaryl is a heteroaryl aryl alkyl (C1-C6) cycloalkyl

6 mentioned may have an optional substitution of halo or (OH YAAY

7 choose from cycloalkyl (C3-C7) “alkoxy (C1-C6) alkyl (C1-C6) H and taryl or 6 and 07 with a SY nitrogen atom attached to it forming a ring with ; into atoms; and optionally contain another atom of inhomogeneity selected from 010818 8 and 0; R8 and 29 choose each of the 11 “cycloalkyl (C3-C6) “alkoxy (C1-C6)” alkyl (C1-C6) © or R95 R8 with the nitrogen atom to which they bond to form a ring with 4 to 1 atoms; and optionally contain another atom of inhomogeneity selected from 01819 8 and 0; R155 4 choose from H f (01-06) “alkyl or 4 and 2015 with the carbon atom they bond to form a ¢ (C=0) carbonyl group R22 R23 2 cycloalkyl (C3- C7) Whereas, the 0” X74 cycloalkyl (C3-C7)” aryl 1 chosen from the 6 aryl mentioned could have an optional substitution of the 0 heterocycloalkyl heteroaryl group thereof; Aryl heterocyclic “alkyl (C1-C6) H choose from 7 mentioned can have an alkyl (C1-C6) optional substitution where “cycloalkyl and (03-07)” cycloalkyl ( C3-C10) “alkoxy (C1-C6) individually selected groups of ¥ SY b NR20R21 5 heteroaryl heterocycloalkyl cheterocycloalkyl heterocycloalkyl “<NR29R30” OH “alkoxy (C1-C6) alkyl (C1) -C6) 11 choose from R22 05? Or ?1 mentioned could have an optional substitution of an alkyl (C1-C6) where caryl ? Or? sharpness of

YAAY

11 for 3 choose from 11 and talkkyl (C1-C6) or R235 R22 with a carbon atom to which they have a cycloalkyl (C3-C7) oss or the ¢theterocycloalkyl ring X is bonded OR combination ((CR24R25)n © 1024 and 225 select each from 01 “OH” alkoxy (C1-C6) “alkyl (C1-C6)

heterocycloalkyl and 11239140; Or 4 5 R25 with the carbon atom to which they bond to form a theterocycloalkyl ring Z is the aryl or cheteroaryl ring, where the aryl ring or the heterocyclic aryl is replaced by tR27 4 R26

<halo «aryl —O »aryl «OH »alkoxy (C1-C6) «alkyl (C1-C6) 11 sine 6 01 heterocyclic”; alkyl cheteroaryl —O heteroaryl < heterocycloalkyl —O < heterocycloalkyl ( C1- or alkyl (C1-C6) wherein “CONR34R35 3 NR34R35 “S(O)pR34” cycloalkyl —O mentioned may have an optional substitution by 1-7 or ¥ groups selecting each alkoxy (C6) ¢ {NR34R35 or heterocycloalkyl «OH separately from

R27 0 choose from 11 halo and (01-06) calkyl wherein said alkyl (C1-C6) is optionally substituted by YO) or ¥ groups; or 826 R275 together form a Cus cmethylenedioxy group that bonds with the adjacent carbon atom to the aryl ring or the heterocyclic aryl;

‎YAAY

11 - - Each occurrence of 228 selects separately from “CH2CF3 halo <NR29R30 CONR31R32 “COOR42” OR36 “alkoxy (C1-C6) and 0211337838 ??; R305 R29 separately selects from 1 SO2R41 “cycloalkyl (C3-C7) “alkyl (C1-C6) and 0(841); Cus that the said alkyl (C1-C6) has an optionally substituted with “OH 11856857 © or ¢theterocycloalkyl R32 5 1 each selected separately from “cycloalkyl (C3-C7). alkyl (C1-C6) ¢H or R325 R31 with a nitrogen atom attached to it forming a ring with ; into atoms; optionally containing a heteroatom of (NR23 5 and 0; R355 R34) separately selected from 11 cycloalkyl “cycloalkyl (C3-C7) calkyl (C1-C6) 0 bound to © 5 calkyl C(O)O(C1-C6) wherein said alkyl (C1-C6) is optionally substituted with C(O)OH «NR58RS59 »alkoxy (C1-C6) <halo «OH and <heterocycloalkyl or R355 R34 with a nitrogen atom to which they bond forming a ring with from 1 to 6 atoms chosen from alkyl (C1-C6) ¢H and cheterocycloalkyl where the alkyl (C1-C6 ) mentioned may have an optionally substituted ¢theterocycloalkyl group (R42 s R41 “R40 R39” R38¢ 237233 “R21 “R20” R19 (R18 (R13 “R12” R11 R10) 0 separately selected from H And talkyl (C1-C6) m in zero or 1 n is 1 or a ¢ YAAY

AY - — for each occurrence of p select each from zero 1 or ?; The cycloalkyl is a non-aromatic carbon ring; optionally combined with an “aryl group” where the said cycloalkyl ring optionally contains; when possible on up to two double links; and where; unless otherwise stated; Said © cycloalkyl can be optionally substituted with 1 or 7 substituent groups selecting separately from ¢{NR43R44 5 halo “CF3” CN “OH” alkoxy (01-06) “alkyl (C1) -C6) The heterocycloalkyl is a non-aromatic mono- or dicyclic ring with 4 atoms bonded to © or oN optionally fused to an aryl or heteroaryl group where the heterocycloalkyl ring contains: 1 0 or ?0845 atom or one N atom; or one N atom one NR45; or one saad N 11845 atom and 8(0(0) or © atom; or SO) Baal 4 N atom or 0 atom or 1 Yo atom 5; or a single 0 atom; YAAY

1# “or ? double bond and have an optional substitution 1 and optionally include; Where possible; calkoxy (C1-C6) “alkyl (C1-C6) substitution one or two separately selected from de sana bivalent -0011201120- substitution group (where NR46R47 and halo “CF3 «CN «OH - in the ring); And the terminal carbon substitution group is attached to the same oxygen atom carbon atoms The terminal Luis atom is attached to carbon The Cus atoms (Cus) valence CHINHCH2- © mentioned can be alkyl (C1-C6 ) where caryls stetrahydro-1,1-dioxido-3-thienyl ring); and where each OH or an alkoxy (C1-C6) aryl can be substituted with a group (which In turn, it can have an alkoxy substitution (C1-C6) an aryl optional substitution of thalo s CF3 «OH «alkyl group (C1-C6) ¢(NR34R35) with a carbon atom; where; unless otherwise stated; “OH (01-06) mole (C1-C6) has an atom of 1 or 7 atom 1 atom; contains 01 heterocyclic aromatic ring with 5; 6 9 or aryl the 0 and optionally one 00850 atom or one 10850 atom and one 8 atom or ©; one 8 atom or one oN heterocycle substituting one aryl where, unless otherwise noted, can be 0 calkoxy (01) -06 “alkyl (C1-C6) optional B1B7 or ¥ substitution groups selected from ¢{NR51R52 5 CF3 “CN tweezers” OH “aryl 5 alkyl (C1-C6) C(0)O “alkyl ( C1-C6) C(O) alkyl (C1-C6) H choose from 5 (C1-C3) mentioned has an optional substitution with a selection of alkyl (C1-C6) wherein

YAAY

1 - LB “and the suspension” OH is a heterocycloalkyl salt and (NR29R30) and since the alkyl (C1-C6) C (O)O mentioned has an optional substitution taryl ic gana 0 choose from alkyl (C1-C6) H and 0(0) (C1-C6) N Whereas said alkyl (C1-C6) can be optionally substituted by a selection of “OH” alkoxy (C1-C3) ¢NR53R54 5 cycloalkyl (03-06) <halo ©

R59 R58 “R57” R56 “R55” (R54 “(R53) (R52 “R51” R49 “(R48 “R47”) (R46 “R44” R43 talkyl (C1-C6) and H choose separately from Said alkyl (C1-C6) Cua calkyl (C1-C6) can separately select from 11 and 8 ¢OH 3 alkoxy (C1-C3) can be optionally substituted with a selection of

0 or a pharmaceutically acceptable salt thereof. In another respect the present invention provides a prodrug of the compound of formula (I) as specified herein or a pharmaceutically acceptable salt thereof; in another respect the present invention provides 18 oxide of the compound of formula (I) as specified herein or a pharmaceutically acceptable salt thereof .

VO It must be recognized that some of the compounds of the present invention can exist in eg liquefied Adie forms; into undissolved images. It must be understood that the present invention includes all such dissolved images.

‎YAAY

15 — — The invention also includes the following embodiments and combinations thereof: in an embodiment; The present invention provides a compound with the formula (1) where Rla RI and 82 are selected separately from CF3 s halo “alkyl (C1-C4) < H < H. In the form of AT the present invention provides US jo of which the formula is ) 1) where RI 1818 and 82 are selected separately from F «alkyl (C1-C4) (H and 01). In the La Al embodiment the present invention provides a compound of formula (1) where 181 and 18 are selected separately From FH and © and R2 chooses from (C1-C4) the collateral “Cls F.” In another embodiment clad, the present invention provides a compound of formula (I) where 81 Rlas is H and selects R2 from a selection of F “alkyl (C1-C4) and 0.01 and in another embodiment also the present invention provides a compound of formula (1) Cus 181 and 1818 is 11 and 12 is - methyl The present invention provides a compound of formula (I) where Ria RI and 82 are selected separately from 1 F alkyl (C1-C4) and in another embodiment also; the present invention provides a compound of formula (1) Where 81 Rlas each selects Yo separately from Fg H and selects R2 from Fsalkyl (C1-C4). In another embodiment as well, the present invention provides a compound of formula (I) where Rlag RI is H and chooses R2 from Fy alkyl (C1-C4) YAAY

- 101 -

Also in another embodiment the present invention provides a compound of formula Cus (I) 1818 is 11 RIS is F 22 is alkyl (C1-C4) and in another embodiment as well; The present invention US jo provides him with formula (I) where Rla is RIS H is 1 and 12 is .methyl

© in an embodiment; The present invention provides a compound of formula (1) Cus 1818 is 11. In one embodiment, the present invention provides a compound of formula (I) where Ria is 11, 81, and 82 selected separately from the 11 halo “alkyl ( C1-C4) and CF3. In another embodiment, the present invention provides a compound of formula (I) where Rla is R25 RI H selected separately from F alkyl (C1-C4) ( H

0 In another embodiment, the present invention provides a compound of formula (I) where 1818 is [1 and 81 is chosen from 11 and 22 is chosen from Fs alkyl (C1-C4) and in the AT form the present invention provides a compound of formula (I) where Rla is 11 RI is H R2 chosen from Fs alkyl (C1-C4) and in another embodiment; The present invention provides a compound of formula (I) where Rla is 11 181 and H is

.methyl and 02 are 0 where 83 and 84 separately select (I) in an embodiment; The present invention provides a compound having the formula where “CONRIORI1 5 aryl” CN “Cl” Cl “Br” alkoxy (C1-C4) calkyl (C1-C4) 11 of

‎YAAY

11 “_

The said alkyl (C1-C4) and the said (0©1-04) alkoxy have each of them separately; replacing

Optional b) 0 7 or ? Separately select combinations of 111,812,813 are contorted.

In another embodiment, Ae, the present invention, is a compound of formula (1) where R3 is H and 24 is chosen from

methyl wherein the “CONH2 4 phenyl “CN 1 Cl “ethoxy” methoxy “ethyl “methyl” H.NR12R13 dc ganas has an optional substitution ©

In another example; The present invention provides a compound of formula (I) where 183 and 1084 are 11.

in one of the models; The present invention provides a compound of formula (I) wherein RS is chosen from 1 rat; Ariel

heterocycloalkyl and NR16R17 “non-homotrophic heteroaryl”

In another example; The present invention provides a compound of formula (I) where 85 is chosen from a non-conjugate 0 aryl. heterocycloalkyl s NR16R17 < heteroaryl

In the “AT” form, the present invention provides a compound of formula (I), where RS is chosen from 11816817

-heterocycloalkyl f

In form AT the present invention provides a compound of formula (I) where RS is 11816817.

in one of the models; The present invention provides a compound of formula (I) where 186 R75 is selected separately © from 1.” cycloalkyl (C3-C6) 5 alkoxy (C1-C4) calkyl (C1-C4)

In the AT form, the present invention provides a compound of formula (1) where RE is 11 and 87 is chosen from

.cycloalkyl f (03-06) alkoxy (C1-C4) calkyl (C1-C4)

‎YAAY

- 18 and 87 choose from H is R6 where (I) and in another embodiment the present invention provides a compound having the formula cycloalkyl (C3-C6) and (OCH2CH3) ethoxy “(OCH3) methoxy is R75 H is R6 where (I) and in another embodiment the present invention provides a compound having the formula -cyclopropyl

RZ Edge : Ky? is R16 Cua (I) of the formula LS in one embodiment; The present invention provides © 2

A and in another embodiment; The present invention provides a compound of formula (1) where 1816 is , i

SRE for : has the form (1) where 1016 is US jo and in another form; The present invention provides 2c RZ < where 1816 is (I) The present invention provides a compound of formula “AT” and in the form of carbon and 823 with an atom of R22 or “alkyl (C1- C6) separately JS representing R235 R22 Cua .cycloalkyl (C3-C7) to which they bond forming ring 0 chosen from 11 and (01-06) R17 where (I) in one embodiment; The present invention provides a compound of the formula

H where 1817 is (I) The present invention provides a compound of the formula AT. and in Form (CI1-C6) 11 choose from R22 where (I) in one of the forms; The present invention provides a compound having the said formula in which the alkyl substitution (C1-C6) can be a primary Cus aryl and heterocycloalkyl R28 or ¥ group 1 optionally with Vo

YAAY

101 - - in one of the models; The present invention provides a compound of formula (I) wherein R22 is chosen from 11 and (6©-01) alkyl wherein said alkyl (C1-C6) can be optionally substituted by a single R28 group. In the Ae Al model of the present invention, it is a compound of formula (I), where R22 is chosen from (Cl- 3s H alkyl C6) branched; Whereas, the branched alkyl (C1-C6) has a single R28 group substitution. © In another embodiment, the present invention provides a compound of formula (I) where R22 is chosen from H isopropyl s; where no isopropyl is substituted with a single R28 group. In another embodiment, the present invention provides a compound of formula (I), where R22 is chosen from 11 and -01 (alkyl C6), and in another embodiment, the present invention provides a compound of formula (1), where R22 is H 0 In another embodiment, the present invention provides a compound of formula (I) where R22 is methyl in one embodiment; the present invention provides a compound of formula (D) where YR2 is 11. In an embodiment Another; the invention all provides a compound of formula R23 Cua (I) is alkyl (C1-C6) and in another embodiment the present invention provides a compound of formula (I) where R23 is methyl in In one embodiment, the present invention provides a compound of formula (1) where X is a bond. 1 YAAY

YY. — — — In another embodiment, the present invention provides a compound of formula (1), where R25 5 R24 is selected separately from 11 OH and (01-06) “alkyl.” In another embodiment, the present invention provides a compound of Formula (I) where R25 5 R24 is 11. In one embodiment, the present invention provides a compound of formula (I) where R26 is chosen from (11 01-06) aryl =O “OH” alkoxy ) 01-06( “© alkyl tweezers” <a “CONR34R35 3 NR34R35 “aryl alkyl (C1-C6) mentioned may have optional substitution) 0 YY Select groups separately from NR34R35 5. halo and in the “AT” form, the present invention provides a compound of formula (I) where R26 is chosen from 11 (Cl- NR34R35 aryl < halo “OH < alkoxy (01-06) alkyl C6) and .CF3 (Cl (H) is chosen from R26 wherein (I) the present invention provides a compound of formula AT and in the form of 0.F 4 Cl “OH” alkoxy (01-06) “alkyl C6)

H is R27 in one embodiment; The present invention provides a compound of formula (1) where R28 is selected in each occurrence of Cua (I) in an embodiment; the present invention provides a compound of formula NR29R30 5 CH2CF3. Each separately from R28 where in each occurrence of (I) the present invention provides a compound of formula aT and in the V0 model NR29R30 5 heterocycloalkyl is selected separately from -heterocycloalkyl is R28 Cus ( I) In another embodiment, the present invention provides a compound of the formula YAAY

71 - In one of the examples; The present invention provides a compound of formula (I) where 7 is an aryl ring substituted with R275 R26 and in the AT embodiment the present invention provides a compound of formula (I) where 7 is a phenyl ring substituted B R26 and 227. © in an embodiment; The invention Mall provides a compound of formula (I) where the cycloalkyl is non-

A congener is a non-aromatic monocyclic ring of 0 or +7 atoms bonded to © or 07 optionally fused to a caryl group where said heterocycloalkyl ring contains: one N atom; or one N atom and one NR45; or

S(O)pssaal gy Ns,” 0 or atom 0; It has an optional substitution on a carbon atom of b1 or ? Separately select substitution group of (C1-C6) for the “(C1-C6) alo” (C1-C6) precursor NR46R47 <halo “CF3” CN OH wah as the said alkyl (C1-C6) can have Substituted with an aryl' alkoxy (C1-C6) or Cua 5 OH each aryl group can be optionally substituted with an alkoxy (C1-C6) (which in turn can

0 to have an optional substitution with CF3 “OH” alkyl (C1-C6) “(NR34R35) and tweezers. In one embodiment, the present invention provides a compound of formula (1) Cua that the halo is chosen from Cl Fg

‎YAAY

YY _ — in an embodiment; The present invention provides a compound of formula (1) where halo is F in one embodiment; the present invention provides a compound of formula (1) where 8 is 1. in one embodiment; the invention provides Mall A compound of formula (I) where 8 is zero In one embodiment, the present invention provides a compound of formula (IA) or its pharmaceutically acceptable salt 26 Rr2R 4g H 0 ~~ N N H H r ?© o a where: 1 22 selects separately from ¢F g alkyl (C1-C4) < H 2 and 8223 selects separately from H and (01-06) alkyl OR R23 3 R22 with the carbon atom they bond to form a cycloalkyl (C3-C4) 0 826 is an alkoxy (C1-C6) which can be optionally substituted by 01834835 and R35 5 4 elect separately from 11 and (01-06) Gua alkyl that said alkyl (C1-C6) may have an optionally substituted with 011. In one embodiment, the present invention provides a compound of formula (IA) where 81 is chosen from 11 and 1. In one embodiment, the present invention provides a compound of formula RI Cua (IA) is 11. YAAY

YY _— — in an embodiment; The present invention provides a compound of formula (JA) where FA RI is in one embodiment; The present invention US jo provides for it the formula R2 Cua “(TA) is methyl in one embodiment; The present invention provides a compound of formula (0/8; where 181 is R25 F is .methyl©) in one embodiment; the present invention provides a compound of formula (8), where R235 is R22 with an Al carbon atom They are linked to form a cyclopropyl ring in one embodiment; the invention Mall provides a compound of formula (IA) wherein 822 and 823 each separately represent methyl i.e. ethyl in one embodiment; the present invention provides a compound thereof Formula (IA) where R26 is (C1-C6) alkoxy 0 substituted with R34 Cua (NR34R35) and 835 selects separately from 11 (C1-C4)s alkyl where The said alkyl (C1-C4) may have an optionally substituted with 011. In one embodiment, the present invention provides a compound of formula (TA) where 826 is chosen from: OCH2CH2NH2, - -OCH2CH2NHCH3, -OCH2CH2NHCH2CHS3, Vo -OCH2CH2NHCH(CH3)2, -OCH2CH2N(CH2CH3)2, YAAY

-OCH2CH2CH2NHCH3, -OCH2CH2CH2CH2NHCH3, -OCH2CH2NHCH2CH20H, -OCH2CH2N(CH3)CH2CH20H, -OCH2CH2NHCH(CH3)CH20H, © -OCH2CH2NHCH2CH2CH20H, and -OCH2CH2NHCH2CH(OH) CH3. Where the compound is selected from: (TA) in one of the embodiments; The present invention provides a compound of the formula

N-Cyclopropyl-4-methyl-3-[3-[[ 1-methyl-1-[2-[2- (methylamino)ethoxy]phenyl]ethyljJamino]-2-oxo0-1(2H)-pyrazinyl]-benzamide Ye

N-Cyclopropyl-4-methyl-3-[3-[[1-[2-[2- (methylamino)ethoxy]phenyl]cyclopropylJamino]-2-ox0-1(2H)-pyrazinyl]-benzamide

N-Cyclopropyl-3-fluoro-5-[3-[[1-[2-[2-[(2-hydroxyethyl)amino]ethoxy]phenyl]-1- methylethyl]amino]-2-oxo-1(2H) )-pyrazinyl]-4-methyl-benzamide,

N-Cyclopropyl-3-fluoro-5-[3-[[1-[2-[2-[[(2R)-2-hydroxypropyl Jamino]ethoxy]phenyl]- Ye 1-methylethyl]amino]-2-oxo -1(2H)-pyrazinyl]-4-methyl-benzamide

YAAY

© --

N-Cyclopropyl-3-fluoro-5-[3-[[1-[2-[2-[[(2S)-2-hydroxypropyl) adsorbed[Jethoxy]phenyl]-1- methylethyl]amino]-2- oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

N-Cyclopropyl-3-fluoro-4-methyl-5-[3-[[1-[2-[2- (methylamino)ethoxy]phenyl]cyclopropyl]amino}-2-oxo-1(2H)-pyrazinyl ]- benzamide

N-Cyclopropyl-3-fluoro-5-[3-[[1-[2-[2-[(2- © hydroxyethyl)amino]ethoxy]phenyl]cyclopropyl|amino]-2-oxo-1(2H)- pyrazinyl]-4- methyl-benzamide 3-[3-({1-[2-(2-Aminoethoxy)phenyl]-1-methylethyl } amino)-2-oxopyrazin-1(2H)-yl]-N- cyclopropyl -5-fluoro-4-methylbenzamide 3-[3-({1-[2-(2-Aminoethoxy)phenyl]cyclopropyl } amino)-2-oxopyrazin-1(2H)-yl]-N- Ve cyclopropyl-5 -fluoro-4-methylbenzamide and N-Cyclopropyl-3-fluoro-5-[3-{[1-(2-{2-[(2- hydroxyethyl)(methyl)amino]ethoxy} phenyl)cyclopropyl] amino}-2-oxopyrazin-1(2H)- yl]-4-methylbenzamide Yo in one embodiment; The present invention provides a compound with the formula (TA) where the compound is selected from: N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[2-(methylamino)ethoxy) [phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide YAAY

71 — N-Cyclopropyl-4-methyl-3-[3-[[1-[2-[2-(methylamino)ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H) -pyrazinyl]-benzamide N N-Cyclopropyl-3-fluoro-4-methyl-5-[3-[[1-[2-[2- (methylamino)ethoxy]phenyl]cyclopropylJamino]-2-oxo -1(2H)-pyrazinyl]-benzamide o and N-Cyclopropyl-3-fluoro-5-[3-[[ 1-[2-[2-[(2-hydroxyethyl)amino] ethoxy [phenyl]cyclopropyl[amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide in one embodiment; The present invention provides a compound of pharmaceutically acceptable formula (ID) or dale. 26 Rr®R m 0 : R N > 17 1 H H 0 x ) R' ya 0 R24 1 pick each from 11 ¢F g alkyl (C1 -C4) 6 is talkoxy (C1-C4) R23 3 2 separately select from 11 and talkkyl (C1-C6) or R23 5 R22 with the carbon atom they bond to form cycloalkyl (C3-C4) Vo 6 is (01-06) alkoxy which can be optionally substituted with 21434135 and YAAY

The mentioned can be alkyl (C1-C6) as alkyl (01-06) can be selected separately from 11 and R355 R34

OH to have an optional substitution by

Fy 11 select from RI where (ID) in one of the models; The present invention provides a compound of formula 11. is RI of a compound of formula (01; where Jal in one embodiment; the invention provides . is RI where (ID) in one embodiment; the present invention provides a compound of formula © in one embodiment; the present invention provides a compound of formula (0100); R2 Cua is methyl in one embodiment; the present invention provides a compound of formula “(ID) where R6 is methoxy in one embodiment; the present invention provides a compound of formula R23 35 R22 Cia “(ID) with a carbon atom to which they are bonded forming a cyclopropyl ring ye. In one embodiment the present invention provides a compound of formula R22 dua “(ID) and R23 each separately represent methyl or .ethyl in an embodiment; the present invention provides a compound of formula (ID) where R26 is (C1-C6 ) alkoxy is substituted with R355 R34 Cus (NR34R35) separately select from H and (01-04) Cu alkyl that said alkyl (C1-C4) can be optionally substituted with OH 5 in one embodiment; the present invention provides a compound of formula (ID) where R26 is - .OCH2CH2NHCH3 YAAY

— YA —

in one of the models; The present invention provides a compound with the formula (IA) where the compound is selected from: 3-Fluoro-N-methoxy-4-methyl-5-{3-[(1-methyl-1-{2-[2- (methylamino)ethoxy]phenyl}ethyl)amino]-2-oxopyrazin-1(2H)-yl } benzamide and N-Methoxy-4-methyl-3-{3-[(1-{2-[2- (methylamino)ethoxy[phenyl} cyclopropyl)amino]- 2-oxopyrazin-1(2H)-yl} benzamide ©

Or a pharmaceutically acceptable salt of that. in one of the models; The present invention provides a compound of formula (077; or its pharmaceutically acceptable salt. 34c 1_ AIEEE R N Ny TC H H CL I R' where: 810-00 and 22 choose each over sharpness of 11 alkyl (C1-C4) and 7; R6 is talkoxy (01-04) 0 cyclopropyl : R23 3 2 JS chooses apart from H and 3 talkkyl (C1-C6 ) or R23 5 R22 with the carbon atom they bond to form cycloalkyl (C3-C4) YAAY

R35 5 4 select each separately from 11 and an alkyl (C1-C6) where said alkyl (C1-C6) can have an optional substitution with 011. In an embodiment; The present invention provides a compound of formula (IE) where RI is chosen from FH in an embodiment; The present invention provides a compound of formula (IE) where RI is H© in [aa] models; The present invention provides a compound of formula (IE) where RI is . in one of the models; The present invention provides a compound of formula R2 Cus (IE) is methyl in one embodiment; The present invention provides a compound of formula (IE) where 166 is cyclopropyl in one embodiment; The present invention provides a compound of formula “(IE) in which R235 R22 with the carbon atom to which they are bonded forms a 0-cyclopropyl ring in one embodiment; The present invention provides a compound of formula (IE) in which 822 R235 each separately represents methyl ie .ethyl in an embodiment; The present invention provides a compound of formula (IA) in which R34 Cua and 1835 are selected separately from 11, alkyl (C1-C4) in an embodiment; The invention Mall provides a compound of formula (8); where 826 choose from: ‎N-Cyclopropyl-3-fluoro-5-[3-{[1-(2-{[(2R)-2-hydroxy-3- Vo ‎(methylamino)propyl]oxy} phenyl) - 1-methylethyl[Jamino}-2-oxopyrazin-1(2H)-yl]-4- methylbenzamide YAAY

- VY. _

N-Cyclopropyl-3-[3-{[1-(2-{[(2R)-3 -(ethylamino)-2-hydroxypropyl]oxy} phenyl)-1- methylethyl]amino}-2-oxopyrazin-1) 2H)-yl]-5 -fluoro-4-methylbenzamide and

N-Cyclopropyl-3-fluoro-5-[3-{[1-(2-{[(2S)-2-hydroxy-3- (methylamino)propyl]oxy}phenyl)-1-methylethylJamino }-2-oxopyrazin -1(2H)-yl]-4- methylbenzamide© or a pharmaceutically acceptable salt thereof.

N-methoxy-4-methyl-3-[3-[[(1R,2S)-2-methyl-3 -(4-morpholinyl)-1- phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl ]-benzamide;

N-methoxy-4-methyl-3-[2-0x0-3-[[(1R)-1 -phenylpropyl]Jamino]-1(2H)-pyrazinyl]-benzamide; Ye

N-methoxy-4-methyl-3-[3-[[(1R,2S)-2-methyl-1 -phenyl-3-(1-pyrrolidinyl)propylJamino]- 2-0x0-1(2H)-pyrazinyl] -benzamide;

N-cyclopropyl-4-methyl-3-[3-[[ 1-methyl-1-[2-[2- (methylamino)ethoxy]phenyl]ethylJamino]-2-oxo-1 (2H)-pyrazinyl]-benzamide ;

N-cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[3-1 (methylamino)propoxy]phenyl]ethylJamino]-2-oxo-1(2H)-pyrazinyl]- benzamide;

N-cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[2-(1- pyrrolidinyl)ethoxy|phenyl]ethyl]amino]-2-oxo-1(2H)- pyrazinyl]-benzamide;

YAAYX

1-

N-methoxy-4-methyl-3-[3-[(1-methyl-1 -phenylethyl)amino]-2-oxo-1 (2H)-pyrazinyl]-benzamide; 3-[3-[[(1R,2R)-3-hydroxy-2- methyl-1-phenylpropyljamino]- 2-ox0-1(2H)-pyrazinyl]-N- methoxy-4-methyl-benzamide;

N-cyclopropyl-4-methyl-3-[2-oxo- 3-[[(1R)-1-[2-[2-(1-© pyrrolidinyl)ethoxy]phenyl]propyl]amino]-1(2H) -pyrazinyl]-benzamide;

N-cyclopropyl-3-[3-[[(1R,2S)- 3-[(1,1- dimethylethyl)amino]-2 -methyl-1- phenylpropyl]amino]-2-oxo- 1(2H)- pyrazinyl] -4-methyl-benzamide;

N-methoxy-4-methyl-3-[3-[[(1R,2S) -2-methyl-3-(4-morpholinyl)-1-(1-naphthalenyl)propyl]amino]- 2-0x0-1 (2H)-pyrazinyl]-benzamidine; 01

N-cyclopropyl-3-[3-[[(1R,2S5)- 3-[[2-(dimethylamino)ethyl] amino]-2-methyl-1- phenylpropylJamino]-2-oxo-1(2H)-pyrazinyl ] -4-methyl-benzamide;

N-cyclopropyl-3-[3-[[(1R,25)-3-[4-(hydroxymethyl)-1 -piperidinyl]-2-methyl-1- phenylpropylJamino]-2-oxo-1(2H)-pyrazinyl ]-4-methyl-b enzamide;

N-methoxy-4-methyl-3-[3-[[(1R,2S) -2-methyl-1-(1-naphthalenyl)-3-(1- Yo pyrrolidinyl)propyljamino]-2-oxo- 1( 2H)-pyrazinyl]-benzamide;

N-cyclopropyl-3-[3-[[(1R,2S5)-3- [(2,2-dimethylpropyl)amino] -2-methyl-1- phenylpropylJamino]-2-oxo-1(2H)-pyrazinyl] -4-methyl-benzamide;

YAAY

—-YY-

N-cyclopropyl-3-[3-[[(1R 28)-3-[(1,1 -dimethylethyl)methylamino]-2 -methyl-1- phenylpropyl]amino}-2-oxo- 1(2H)-pyrazinyl ]-4 -methyl-benzamide;

N-cyclopropyl-3-[3-[[(1R ,29)-3-[(2R)-2- (methoxymethyl)-1 -pyrrolidinyl]-2-methyl-1- phenylpropyl]amino]-2-oxo- 1(2H)-pyrazinyl] -4-methyl-benzamide;

N-cyclopropyl-3-[3-[[(1R,2S)- 3-[(2S)-2-(methoxymethyl)-1-pyrro lidinyl]-2-methyl-1-©phenylpropyl]amino]-2- oxo- 1(2H)-pyrazinyl] -4-methyl-benzamide;

N-cyclopropyl-4-methyl-3- [3-[[(1R,2S)-2-methyl-3- (4-morpholinyl)-1- phenylpropyl]amino]-2-oxo- 1(2H)-pyrazinyl ]-benzamide;

N-cyclopropyl-4-methyl-3-[2-oxo- 3-[[(1R)-1-phenylpropyl] amino]-1(2H)-pyrazinyl]-benzamide; 001

N-cyclopropyl-3-[3-[[(1R,2S5)-3 -(4-hydroxy-1-piperidinyl)-2 -methyl-1- phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl ] -4-methyl-benzamide;

N-cyclopropyl-3-[3-[[(1R,25)-3- (diethylamino)-2-methyl-1 -phenylpropyl]amino]-2-oxo- 1(2H)-pyrazinyl] -4-methyl- benzamide;

N-cyclopropyl-3-[3-[[(1R,25)-3- [[2-(dimethylamino)ethyl] methylamino]-2-methyl-1- Yo phenylpropyl]amino]-2-oxo- 1(2H) )-pyrazinyl] -4-methyl-benzamide;

N-cyclopropyl-4-methyl-3-[3-( [(1R,2S)-2-methyl-1 -phenyl-3-(1- piperidinyl)propyl}amino]-2-oxo- 1(2H)- pyrazinyl]-benzamide;

YAAY

_YY0

N-cyclopropyl-4-methyl-3-[3- [[(1R,2S)-2-methyl-1-phenyl-3- (1- pyrrolidinyl)propyl]jamino] -2-0x0-1(2H)- pyrazinyl] -benzamide;

N-cyclopropyl-3-[3-[[(1R,25)-3 -(dimethylamino)-2-methyl-1 -phenylpropyl]amino]-2- oxo-1(2H)-pyrazinyl] -4-methyl- benzamide;

N-cyclopropyl-4-methyl-3-{3- [(1R,25)-2-methyl-3- (4-methyl-1-piperazinyl)-1- 2 phenylpropylJamino}-2-oxo- 1(2H) -pyrazinyl]-benzamide; 3-[3-[[(1R,2S)-3-(4-acetyl-1 -piperazinyl)-2-methyl-1 -phenylpropyl]amino}-2-oxo- 1(2H)- pyrazinyl]-N- cyclopropyl-4-methyl-benzamide;

N-cyclopropyl-3-[3-[[1 -(2-hydroxyphenyl)-1 -methylethylJamino]-2-oxo-1 (2H)- pyrazinyl]-4-methyl-benzamide; Ve

N-cyclopropyl-4-methyl-3-[3-[2-(3-methylphenyl)-1-pyrro lidinyl]-2-oxo-1(2H)-pyrazinyl]-benzamide;

N-cyclopropyl-3-[3-[2- (2-methoxyphenyl)-1 -pyrrolidinyl]-2-oxo-1(2H) -pyrazinyl]-4- methyl-benzamide;

N-cyclopropyl-4-methyl-3-[3-[[1-[2-[2- \o (methylamino)ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide ;

N-cyclopropyl-4-methyl-3-[3- [[1-[2-[2 -(ethylamino)ethoxy]phenyl] cyclopropyl]amino]- 2-ox0-1(2H)-pyrazinyl]-benzamide; and

YAAY

— Ys —

N-cyclopropyl-3-fluoro -4-methyl-5-[3-[[1-methyl-1-[2-[2- (methylamino)ethoxy]phenyl]ethyl]amino]-2-oxo- 1(2H) )-pyrazinyl]-benzamide,

N-Cyclopropyl-4-methyl-3-[3- [[(1R,2S)-2-methyl-3-(4 -methyl-1-piperidinyl)-1- phenylpropylJamino]-2-oxo- 1(2H) -pyrazinyl]-benzamide

N-Cyclopropyl-4-methyl-3-[3-[[(1R,2S)-2-methyl-3-[4-(1 -methylethyl)-1-piperazinyl]-1-©phenylpropyljamino]-2-oxo - 1(2H)-pyrazinyl] -benzamide

N-Cyclopropy!-4-methyl-3-[3- [[(1R,2S)-2-methyl-1 -phenyl-3-(1- piperazinyl)propyl]amino] -2-oxo-1(2H) -pyrazinyl]-benzamide

N-Cyclopropy!-3-[3-[[(1R,25)- 3-(hexahydro-4-methyl-1H-1,4- diazepin-1-yl)-2-methyl- 1-phenylpropy!]amino [-2-oxo- 1(2H)-pyrazinyl] -4-methyl-benzamide Ye

N-Cyclopropyl-3-[3-[[(1R ,25)-3-(4-fluoro-1 -piperidinyl) -2-methyl-1- phenylpropylJamino]-2-oxo-1(2H)-pyrazinyl] - 4-methyl-benzamide

N-Cyclopropyl-3-[3-[[(1R,2S5)-3- (4,4-difluoro-1-piperidinyl)-2-methyl-1- phenylpropyl]amino}-2-oxo-1 (2H) -pyrazinyl]-4 -methyl-benzamide

N-Cyclopropyl-3-[3-[[(1R,25)-3- [4-(dimethylamino)-1 -piperidinyl]-2-methyl-1- Yo phenylpropyl]amino}-2-oxo- 1(2H) )-pyrazinyl]-4-methyl-benzamide

N-Cyclopropyl-4-methyl-3-[3-[[(1R 25)-2-methyl-1-phenyl-3-[4- (trifluoromethyl)-1- piperidinyl]propyl] amino]-2-oxo- 1(2H)-pyrazinyl] -benzamide L

— Yo-

N-Cyclopropyl-4-methyl-3- [3-[[(1R,2S)-2-methyl-3-(3-0x0- 1-piperazinyl)-1- phenylpropyl]amino}-2-oxo- 1( 2H)-pyrazinyl]-benzamide

N-Cyclopropyl-3-[3-[[(1R,25)-3- (1,4-dioxa-8-azaspiro[4,5] dec-8-yl)-2-methyl-1- phenylpropyl]amino]- 2-oxo-1 (2H)-pyrazinyl]-4-methyl-benzamide

N-Cyclopropyl-4-methyl-3-[3-{ [(1R,2S)-2-methyl-3-[(3R)-3 -methyl-1-piperazinyl]-1- 2 phenylpropyl]amino}-2 -oxo- 1(2H)-pyrazinyl]-benzamide

N-Cyclopropyl-4-methyl-3-[3- [[(1R,25)-2-methyl-3-[(35)- 3-methyl-1-piperazinyl]-1- phenylpropyl]amino]-2- oxo-1(2H)-pyrazinyl]-benzamide

N-Cyclopropyl-4-methyl-3-[3- [[(1R,2S)-2-methyl-3-[(2 -methylpropyl)amino]-1- phenylpropyl]amino}-2-oxo- 1(2H) )-pyrazinyl]-benzamide Vo

N-Cyclopropyl-3-[3-[[(1R,2S5)-3- (cyclopropylamino)-2-methyl-1 -phenylpropyl]amino]-2- oxo-1(2H)-pyrazinyl] -4-methyl- benzamide

N-Cyclopropyl-4-methyl-3-[3-[[(1R 25)-2-methyl-3-[(2R)-2-methyl-1 -pyrrolidinyl]-1- phenylpropyl]amino]-2-oxo -1(2H)-pyrazinyl]-benzamide

N-Cyclopropyl-3-[3-[[(1R,2S5)-3- [(3S)-3-hydroxy-1 -piperidinyl]-2-methyl-1- Yo phenylpropylJamino]-2-oxo-1 (2H) )-pyrazinyl]-4-methyl-benzamide

N-Cyclopropyl-3-[3-[[(1R,25)-3- [(3R)-3-hydroxy-1 -piperidinyl]-2-methyl-1- phenylpropyljamino]-2-oxo- 1(2H) -pyrazinyl]-4-methyl-benzamide

—- 1 -

N-Cyclopropyl-4-methyl-3- [3-[[(1R,2S)-2-methyl-3- [(2R)-2-methyl-1 -piperazinyl]-1- phenylpropyl]amino}-2- oxo- 1(2H)-pyrazinyl]-benzamide

N-Cyclopropyl-3-[3-[[(1R 2.5)-3-(2,7-diazaspiro[3,5]non- 7-yl)-2-methyl-1- phenylpropyl]amino}]-2-oxo- 1(2H)-pyrazinyl] -4-methyl-benzamide

N-Cyclopropyl-4-methyl-3- [3-[[(1R,2S)-2-methyl-1 -phenyl-3-(4- 2 thiomorpholinyl)propyl]amino] -2-0x0-1(2H) -pyrazinyl]-benzamide

N-Cyclopropyl-3-[3-[[(1R,2S5)-3- [(35)-3-hydroxy-1 -pyrrolidinyl]-2-methyl-1- phenylpropyl]amino] -2-ox0-1( 2H)-pyrazinyl] -4-methyl-benzamide

N-Cyclopropyl-4-methyl-3- [3-[[(1R,2S)-2-methyl-1 -phenyl-3-[4-(tetrahydro- 1,1-dioxido- 3-thienyl)-1- piperazinyl] propyl]amino]-2-oxo-1 (2H)-pyrazinyl]- benzamide Ve 1-[(2S,3R)-3-[[4-[5- [(cyclopropylamino)carbonyl] -2-methylphenyl] -3,4-dihydro- 3- oxopyrazinyl [Jamino]-2 -methyl-3-phenylpropyl]- 4 -piperidinecarboxamide

N-Cyclopropyl-3-[3-[[(1R ,28)-3-[(2-hydroxy-1,1 -dimethylethyl)amino]-2-methyl-1- phenylpropyl]amino}-2-oxo- 1 (2H)-pyrazinyl]-4-methyl-benzamide

N-Cyclopropyl-3-[3-[[(1R,2S)-3- [(3R,55)-3,5-dimethyl-1 -piperazinyl]-2-methyl-1- 'eo phenylpropyl]amino]- 2-oxo- 1(2H)-pyrazinyl]-4-methyl-benzamide

N-Cyclopropyl-4-methyl-3- [3-[[(1R,2S)-2-methyl-1 -phenyl-3-(4- piperidinylamino)propyl] amino]-2-oxo-1(2H)- pyrazinyl]- benzamide L

— VV-

N-Cyclopropyl-4-methyl-3-[3-[[(1R,2S)-2-methyl-3-(5 -methyl-2,5-diazabicyclo[2.2.1]hept-2-yD)-1 -phenylpropyl[amino]-2-oxo- 1(2H)-pyrazinyl]-benzamide

N-Cyclopropyl-3-[3-[[(1R,2S)- 3-(2,2-dimethyl-1-pyrrolidinyl) -2-methyl-1- phenylpropyl]amino]-2-oxo- 1(2H) -pyrazinyl]-4-methyl-benzamide©

N-Cyclopropyl-3-[3-[[1-[2- [2-(ethylamino)ethoxy] phenyl]-1-methyl ethyl]amino]-2-oxo- 1(2H)-pyrazinyl] -4-methyl -benzamide.

N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[2-(1- piperazinyl)ethoxy]phenyl] ethyl]amino]-2-oxo-1(2H)- pyrazinyl]-benzamide

N-Cyclopropyl-3-[3-[[1-[2- [2-(diethylamino)ethoxy]phenyl] -1-methylethyl]amino]-2- Vo oxo-1(2H)-pyrazinyl]-4-methyl - benzamide

N-Cyclopropyl-4-methyl-3-[3- [[1-methyl-1-[2-[2-(1- piperidinyl)ethoxy]phenyl] ethyl]amino]-2-oxo-1(2H)- pyrazinyl]-benzamide

N-Cyclopropyl-4-methyl-3-[3- [[1-methyl-1-[2-[2- (4-methyl-1- piperazinyl)ethoxy]phenyl] ethyl]amino]-2-oxo-1 (2H)-pyrazinyl]-benzamide 1

N-Cyclopropyl-4-methyl-3-[3- [[1-methyl-1-[2-[2-(4- morpholinyl)ethoxy]phenyl] ethyl]amino]-2-ox0-1(2H)- pyrazinyl]-benzamide

YAAY

— YA —

N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[4- (methylamino)butoxy]phenyl]ethylJamino}-2-oxo- 1(2H)-pyrazinyl] -benzamide

N-Cyclopropyl-4-methyl-3- [3-[[1-methyl-1-[2-[4- [(2,2,2- trifluoroethyl)amino]butoxy]phenyl]ethylJamino}-2-oxo- 1(2H)-pyrazinyl]-benzamide

N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[4-(4 -methyl-1- 2 piperazinyl)butoxy]phenyl]ethyl]amino]-2-oxo- 1(2H)-pyrazinyl]-benzamide

N-Cyclopropyl-4-methyl-3-[3- [[1-methyl-1-[2-[3-[(2,2,2- trifluoroethyl)amino]propoxy]phenyl]ethyl]amino]-2- oxo-1(2H)-pyrazinyl]-b enzamide

N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[3-(4 -methyl-1- piperazinyl)propoxylphenyl]ethyljamino]-2-oxo-1(2H)- pyrazinyl]-benzamide 01

N-Cyclopropyl-4-methyl-3-[3- [[1-methyl-1-[2-[1 -methyl-2-(4-methyl-1- piperazinyl)ethoxy]phenyl] ethyllamino]-2-oxo -1(2H)-pyrazinyl]-benzamide

N-Cyclopropyl-3-[3-[[1-[2-[2- [(2-methoxyethyl)amino] ethoxy]phenyl]-1- methylethyl]amino]-2-oxo-1(2H) -pyrazinyl] -4-methyl-benzamide

N-Cyclopropyl-3-[3-[[1-[2-[2- [(2-hydroxyethyl)amino] ethoxy]phenyl]-1- Yo methylethyl]amino]-2-oxo-1(2H)-pyrazinyl ]-4-methyl-benzamide

N-Cyclopropyl-4-methyl-3-[3- [[1-methyl-1-[2-[2-[(1 -methylethyl)amino] ethoxy]phenyl]ethyl]amino] -2-0x0-1( 2H)-pyrazinyl]-benzamide

YAAY

_vq—

N-Cyclopropyl-3-[3-[[1-[2-[2-[[(2S)-2-hydroxypropyl] amino]ethoxy]phenyl]-1- methylethyl]amino]-2-o0xo-1 (2H )-pyrazinyl] -4-methyl- 6-benzamide

N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-(4-piperidinylmethoxy)phenyl]ethyljamino}-2-oxo- 1(2H)-pyrazinyl]-benzamide

N-Cyclopropyl-4-methyl-3- [3-[[1-[2-(3-azetidiny] oxy)phenyl]-1-methylethyl] amino]-2- 2 oxo-1(2H)-pyrazinyl] - benzamide

N-Cyclopropyl-4-methyl-3-[3- [[1-methyl-1-[2-(3 -pyrrolidinyloxy)phenyl] ethyl]amino]- 2-0x0-1(2H)-pyrazinyl] -benzamide

N-Cyclopropyl-4-methyl-3-[3- [[1-methyl-1-[2-[2- (4-piperidinyl)ethoxy] phenyl]ethyljamino]-2-oxo- 1(2H)-pyrazinyl] -benzamide 01

N-Cyclopropyl-4-methyl-3-[3-[[1 -methyl-1-[2-(3-piperidinylmetho Xy) phenyl]ethyl]Jamino]-2-oxo- 1(2H)-pyrazinyl] -benzamide

N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-(4-piperidinyloxy)phenyl]ethyl] amino}]-2-ox0-1(2H)-pyrazinyl]-benzamide

N-Ethoxy-4-methyl-3-[3-[[1-methyl-1- [2-[2-(methylamino)ethoxy] phenyl]ethyljamino]- \e 2-0x0-1(2H)-pyrazinyl] -benzamide 4-Methyl-N-(1 -methylcyclopropyl)-3-[3-[[1 -methyl-1-[2-[2-(methylamino) ethoxy]phenyl]ethyl]amino]-2-oxo- 1 (2H)-pyrazinyl]-benzamide L

J

4-Methyl-3-[3-[[1-methyl-1-[2-[2-(methylamino) ethoxy]phenyl]ethyl]amino] -2-0xo0- 1(2H)-pyrazinyl]-benzamide

N-Cyclopropyl-3-[3-[[1-[2-[2-[[[(2S)-2-hydro xypropyl]amino] ethoxy]phenyl]cyclopropyl] amino}-2-oxo-1(2H)- pyrazinyl]-4-methyl-benzamide

N-Cyclopropyl-3-[3-[[1 -[2-[2-[(2- © methoxyethyl)amino]ethoxy] phenyl]cyclopropyl] amino]-2-oxo-1(2H)-pyrazinyl]-4 - methyl-benzamide

N-Cyclopropyl-3-[3-[[1-[2-[2-[4-(2-hydroxyethyl)-1-p piperazinyljethoxy]phenyl]cyclopropyl] amino]-2-oxo-1(2H)-pyrazinyl ]-4-methyl-benzamide

N-Cyclopropyl-3-[3-[[1-[2-[2- [(2-hydroxyethyl)amino] Ve ethoxy]phenyl]cyclopropyl] amino]-2-oxo-1(2H)-pyrazinyl] -4 -methyl-benzamide

N-Cyclopropyl-4-methyl-3-[3-[[1- [2-[2-[(1-methylethyl) amino] ethoxy] phenyl]cyclopropyl]amino]-2-oxo- 1(2H)-pyrazinyl ]-benzamide

N-Cyclopropyl-3-[3-[[1-{2-[2- (hexahydro-4-methyl-1H-1 ,4-diazepin-1- yl)ethoxy]phenyl] cyclopropyl}amino]-2-oxo - 1(2H)-pyrazinyl] -4-methyl-benzamide Yo

N-Cyclopropyl-3-[3-[[1-[2-[2- [(3R)-3-hydroxy-1-pyrroli dinyl]ethoxy] phenyl]cyclopropyl]amino]-2-0xo- 1(2H) -pyrazinyl] -4-methyl-benzamide L

N-Cyclopropyl-3-[3-[[1-[2- [2- (dimethylamino)ethoxy] phenyl]cyclopropyl] amino]-2- oxo-1(2H)-pyrazinyl] -4-methyl-benzamide

N-Cyclopropyl-4-methyl-3-[2-0ox0-3-[[1-[2-[2-(1- pyrrolidinyl)ethoxy]phenyl]cyclopropyl]amino]-1(2H)-pyrazinyl]-benzamide

N-Cyclopropyl-3-[3-[[1-[2-[2-[(29)-2- (hydroxymethyl)-1- 8 pyrrolidinyl]ethoxy]phenyl]cyclopropyl] amino]-2-oxo-1( 2H)-pyrazinyl] -4-methyl-benzamide

N-Cyclopropyl-4-methyl-3-[2-ox0-3-[[1-[2-[2-[(2,2 ,2- trifluoroethyl)amino]ethoxy]phenyl]cyclopropyl] amino]-1) 2H)-pyrazinyl]-b enzamide

N-Cyclopropyl-3-[3-[[1 _[2-[2-(ethylmethylamino)ethoxy]phenyl]eyclopropyljamino]-2- 01 oxo-1(2H)-pyrazinyl] -4-methyl-benzamide

N-Cyclopropyl-3-[3-[[1-[2-[2- [(3-hydroxy-2 ,2-dimethylpropyl)amino] ethoxy]phenyl]cyclopropylJamino] -2-oxo-1(2H)-pyrazinyl ]-4-methyl-benzamide

N-Cyclopropyl-4-methyl-3-[2-oxo- 3-[[1-[2-[2-(1- piperazinyl)ethoxy]phenyl]cyclopropyl]amino]-1(2H)-pyrazinyl]-benzamide Yo

N-Cyclopropyl-3-[3-[[1-[2-[2- (3,3-difluoro-1-pyrro lidinyl)ethoxy] phenyl]cyclopropyl]amino] -2-ox0-1(2H)-pyrazinyl ] -4-methyl-benzamide Agha

—~ty-

N-Cyclopropyl-3-[3-[[1-[2- [2-[(2-fluoroethyl)amino Jethoxy]phenyljcyclopro pyl]amino]- 2-ox0-1(2H)-pyrazinyl] -4-methyl- benzamide

N-Cyclopropyl-4-methyl-3- 3-[[1-[2-[2-[(1 -methylpropyl)amino] ethoxy]phenyl]cyclopropyl] amino]-2-oxo-1(2H)-pyrazinyl] -benzamide

N-Cyclopropyl-4-methyl-3- [3-[[1-[2-[2-[(2R)-2 -methyl-1- 5 pyrrolidinyl]ethoxy]phenyl]cyclopropyl] amino]-2-oxo- 1(2H)-pyrazinyl]-benzamide 3-[3-[[1-[2-[2- (cyclobutylamino)ethoxy] phenyl]cyclopropyl] amino]-2-oxo-1(2H)- pyrazinyl]-N- Cyclopropyl-4-methyl-benzamide

N-Cyclopropyl-3-[3-[[1-[2-[2-[[(1R)-2-hydroxy-1- methylethyl}amino] ethoxy]phenyl]cyclopropyl] amino]-2-oxo-1 ( 2H)-pyrazinyl] -4-methyl-benzamide 01

N-Cyclopropyl-3-[3-[[1-[2-[2- [(3-hydroxypropyl)amino ] ethoxy]phenyl] cyclopropylJamino]-2-oxo- 1(2H)-pyrazinyl] -4-methyl- benzamide 3-[3-[[1-[2-(2- aminoethoxy)phenyl]cyclopropyl] amino]-2-oxo-1(2H)-pyrazinyl]-N- cyclopropyl-4-methyl-b enzamide

N-Cyclopropyl-3-[3-[[1-[2- [2-(ethylamino)ethoxy]phenyl] -1-methylethyl]amino]-2-oxo- Yo 1(2H)-pyrazinyl]-5 -fluoro -4-methyl-benzamide

N-Cyclopropyl-3-fluoro-5-[3- [[1-[2-[2-[2 -hydroxyethyl)amino] ethoxy]phenyl]-1- methylethyl]amino]-2-oxo-1(2H) -pyrazinyl]-4-methyl-b enzamide

YAAY

— $Y —

N-Cyclopropyl-3-fluoro -4-methyl-5-[3-[[1-methyl-1-[2-[2-[(1-methylethyl) amino] ethoxy]phenyl]ethyl]amino}-2- 0xo-1(2H)-pyrazinyl]-benamidine

N-Cyclopropyl-3-fluoro-5-[3-[[1-[2-[2-[(2- methoxyethyl)aminolethoxy] phenyl]-1- methylethyl]amino]-2-oxo-1(2H)- pyrazinyl]-4-methyl-benzamide

N-Cyclopropyl-3-fluoro-5-[3-[[1-[2-[2-[[(2R)-2-hydroxypropyl]amino] ethoxy]phenyl]-1-©methylethyl]amino]-2- oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

N-Cyclopropy!l-3-fluoro-5-3- [[1-[2-[2-[(2-hydroxy-2 -methylpropyl)amino} ethoxy]phenyl] -1 -methylethyl]amino]-2- oxo-1(2H)-pyrazinyl}-4-methyl-benzamide

N-Cyclopropyl-3-fluoro-5-[3- [[1-[2-[2-[[(25)-2 -hydroxypropyl]amino] ethoxy]phenyl]-1- methylethyl]amino]-2-oxo -1 (2H)-pyrazinyl] -4-methyl-benzamide 01

N-Cyclopropyl-3-fluoro-4 -methyl-5-[3-{[1-[2-[2 -(methylamino)ethoxy] phenyl] cyclopropyl]amino]-2-oxo- 1(2H)-pyrazinyl] - benzamide

N-Cyclopropyl-3-fluoro-5-[3-[[1- [2-[2-[(2- hydroxyethyl)amino] ethoxy]phenyl]cyclopropyl] amino]-2-oxo-1(2H)-pyrazinyl [-4- methyl-benzamide yo

N-Cyclopropyl-3-fluoro-5-[3-[[1- 2-[2-[(2 -methoxyethyl)amino]ethoxy] phenyl]cyclopropyl]amino] -2-ox0-1(2H)-pyrazinyl] -4-methyl-benzamide

YAAY

_ss—

N-Cyclopropyl-3-[3-[[1-[2-[2 -(ethylamino)ethoxy] phenyl]cyclopropyl] amino]-2-0Xo- 1(2H)-pyrazinyl}-5 -fluoro-4-methyl -benzamide

N-Cyclopropyl-3-fluoro-5- [3-[[1-[2-[2-[[(25)-2 -hydroxypropyl]amino] ethoxy] phenyl]cyclopropyl] amino]-2-oxo-1( 2H)-pyrazinyl]-4-methyl-benzamide

N-Cyclopropyl-3-fluoro -4-methyl-5-[3-[[1-[2-[2-[(1 -methylethyl)amino] 5 ethoxy]phenyl]cyclopropyl] amino]-2-oxo-1 (2H)-pyrazinyl]-benzamide

N-Cyclopropyl-3-fluoro-5- [3-[[1-[2-[2-[[(2R)-2- hydroxypropyl]amino] ethoxy]phenyl]cyclopropyl] amino]-2-oxo-1( 2H)-pyrazinyl] -4- methyl-benzamide

N-Cyclopropyl-3-[3-[[1-[2- [2-(ethylamino)ethoxy] phenyl]-1-methyl ethylJamino]-2-oxo- 1(2H)-pyrazinyl] -4-methyl-benzamide

N-Cyclopropyl-3-[3-[[1-ethyl-1- [2-[2-(ethylamino)ethoxy] phenyl]propyl}amino]-2-oxo- 1(2H)-pyrazinyl]-4-methyl - benzamide Yo

N-Cyclopropyl-4-methyl-3-[3- ]]1-]2-2 -(methylamino)ethoxy] phenyl]cyclobutyl]amino]- 2-0x0-1(2H)-pyrazinyl]-benzamide

N-Cyclopropyl-3-[3-[[1-[2- [2-(ethylamino)ethoxy] phenyl]cyclobutyl] amino|-2-0xo- 1(2H)-pyrazinyl] -4-methyl-benzamide ,

— fo ——

N-Cyclopropyl-3-[3-[[1-[2-[2-[(2-hydroxyethyl) amino]ethoxy] phenylicycl obutyl] amino]-2-oxo-1(2H)-pyrazinyl] -4-methyl - benzamide

N-Cyclopropyl-4-methyl- 3-[3-[[1-[2-[2-[(1 -methylethyl)amino] ethoxy]phenyl]cyclobutyl] amino]-2-oxo-1(2H)-pyrazinyl ]- benzamide

N-Cyclopropyl-3-[3-[[(1R,2R)- 3-hydroxy-1- (2-methylphenyl)-2 -methylpropyl]amino]-2-©oxo-1(2H)-pyrazinyl]-4 -methyl-benzamide

N-Cyclopropyl-3-[3-[[(1R ,2R)-3-hydroxy-1-(3 -methylphenyl) -2-methylpropyljamino]-2- oxo-1(2H)-pyrazinyl] -4-methyl- benzamide

N-Cyclopropyl-3-[3-[[(1R,2R)- 3-hydroxy-1-(2 -methoxyphenyl)-2-methylpropyl] amino}]- 2-ox0-1(2H)-pyrazinyl]-4 -methyl-benzamide Ve

N-Cyclopropyl-3-[3-[[(1R,25)-1- (2-methylphenyl)-2-methyl-3 -(1- pyrrolidinyl)propyljamino] -2-ox0-1(2H)-pyrazinyl] -4-methyl-benzamide

N-Cyclopropyl-3-[3-[[(1R,25)-1 -(3-methylphenyl)-2-methyl-3- (1- pyrrolidinyl)propyl]amino]-2-0xo- 1(2H)- pyrazinyl]-4-methyl-benzamide

N-Cyclopropyl-3-[3-[[(1R,2S)- 1-(2-methoxyphenyl) -2-methyl-3-(1- 1 pyrrolidinyl)propyl] amino]-2-oxo-1(2H) -pyrazinyl] -4-methyl-benzamide

N-Cyclopropyl-3-[3-[[1-[5 -fluoro-2- [2-(methylamino)ethoxy]phenyl] cyclopropyljamino]-2-oxo- 1(2H)-pyrazinyl] -4-methyl-benzamide b

491 =

N-Cyclopropyl-3-[3-[[1-[5- fluoro-2-[2-[(2-hydroxyethyl)amino) ethoxy] phenyl]cyclopropyl] amino]-2-oxo-1(2H)-pyrazinyl ]-4-methyl-benzamide

N-Cyclopropyl-3-[3-[[1-[2- [2-(ethylamino)ethoxy]-5- fluorophenyl]cyclopropyljamino 1- 2-0x0-1(2H)-pyrazinyl] -4-methyl- benzamide

N-Cyclopropyl-3-fluoro-5- {3-[(1-{5-fluoro-2-[2- (methylamino)ethoxy]phenyl } © cyclopropyl)amino] -2-oxopyrazin-1(2H)-yl } -4-methylbenzamide

N-Cyclopropy!-3-fluoro-5-[3-{[1-(5-fluoro-2-{2-[(2 -hydroxyethyl)amino]ethoxy } phenyl)cyclopropyl] amino} -2-oxopyrazin-1 (2H)-yl]-4-methylbenzamide

N-Cyclopropyl-3-[3-({1-[3 -fluoro-2-(2-{[(2R)-2 -hydroxypropyl]amino} ethoxy)phenyl]cyclopropyl} amino)-2-oxopyrazin-1 ( 2H)-yl]-4 -methylbenzamide 3-[3-({1- [2-(2-Aminoethoxy)-3 -fluorophenyl]cyclopropyl} amino)-2-oxopyrazin-1(2H)- yl]-N- cyclopropyl-4-methylbenzamide

N-Cyclopropyl-3-[3-{[1-(3-fluoro -2-{2-[(2 ~hydroxyethyl)amino]ethoxy } phenyl)cyclopropyl]amino}-2-0 xopyrazin-1(2H)- yl]-4 -methylbenzamide 01

N-Cyclopropyl-3-{3-[(1-{2-[2-(ethylamino)ethoxy]-3 -fluorophenyl} cyclopropyl)amino]- 2-oxopyrazin-1(2H)-yl} -4-methylbenzamide

N-Cyclopropyl-3-{3-[(1-{3-fluoro-2-[2-(methylamino)ethoxy] phenyl} cyclopropyl)amino] -2-oxopyrazin-1(2H)-yl} -4-methylbenzamide the

N-Cyclopropyl-4-ethyl-3-[3-({1-[2-(2-{[(2S)-2-hydroxypropyl]Jamino} ethoxy)phenyl]-1- methylethyl }amino)-2-oxopyrazin -1(2H)-yl]benzamide

N-Cyclopropyl-4-ethyl-3-{3-[(1-{2-[2-(ethylamino)ethoxy] phenyl}-1- methylethyl)amino] -2-oxopyrazin-1(2H)-yl} benzamide

N-Cyclopropyl-3-[3-({1-[2-(2-{[(1R)-1-(hydroxymethyl)-2- °e methylpropyljamino} ethoxy)phenyl]cyclopropyl} amino)-2-oxopyrazin- 1(2H)-yl]-4- methylbenzamide

N-Cyclopropyl-3-[3-({1-[2-(2-{[2-hydroxy-1- (hydroxymethyl)ethylJamino }ethoxy)phenyl]cyclopropyl} amino)-2-oxopyrazin-1(2H)- yl]-4-methylbenzamide Veo

N-Cyclopropyl-3-[3-{[1-(2-{2-[(1,1-dioxidotetrahydrothi ophen-3- yl)amino]ethoxy} phenyl)cyclopropyl]amino} -2-oxopyrazin-1(2H) )-yl]-4-methylbenzamide

N-Cyclopropyl-3-{3-[(1-{2-[2-(5,6 -dihydroimidazo[1,2-a]pyrazin-7( 8H)- yl)ethoxy]phenyl} cyclopropyl)amino] - 2-oxopyrazin-1(2H)-yl} -4-methylbenzamide \o

N-Cyclopropyl-4-methyl-3-{3-[(1-{2-[2-(1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin- 5-yl)ethoxy[phenyl} cyclopropyl)amino]-2-oxopyrazin-1(2H)-yl}benzamide

YAAY

— tA —

N-Cyclopropyl-4-methyl-3-{2-ox0-3-[(1-{2-[2-(propylamino)ethoxy]phenyl} cyclopropyl)amino]pyrazin-1(2H)-yl}benzamide

N-Cyclopropyl-3-[3-({1-[2-({(2R)-2 -hydroxy-3-[(2-hydroxyethyl)amino] propyl} oxy)phenyl]cyclopropyl} amino)-2-oxopyrazin -1(2H)-yl] -4-methylbenzamide

N-Cyclopropyl-3-[3-{[1-(2-{[(2R)-3 -(ethylamino)-2- hydroxypropyl]oxy} phenyl)cyclopropyl]amino}-2 -oxopyrazin-1(2H)- yl]-4-methylbenzamide©

N-Cyclopropyl-3-[3-{[1-(2-{[(2R)-2 -hydroxy-3-(methylamino)propyl] oxy }phenyl)cyclopropyljamino} -2-oxopyrazin-1(2H)-yl ]-4 -methylbenzamide

N-Cyclopropyl-3-[3-({1-[2-({ (285)-2-hydroxy-3-[(2- hydroxyethyl)aminoJpropyl}oxy)phenyl] cyclopropyl} amino)-2-oxopyrazin-1 (2H)-yl]-4-methylbenzamide Ye

N-cyclopropyl-3-[3-{[1-(2-{[(2S)-3- (ethylamino)-2- hydroxypropyl]oxy} phenyl)cyclopropyl] amino }-2-oxopyrazin-1(2H)- yl]-4-methylbenzamide

N-Cyclopropyl-3-[3-{[1-(2-{[(2S)-2-hydroxy-3 -(methylamino)propyl] oxy} phenyl)cyclopropyl]amino}-2-oxopyrazin-1(2H) -yl]-4-methylbenzamide Very expensive

3-[3-{[1-(2-{[(2R)-2-Amino-3 -hydroxypropyl]oxy}phenyl)-1 -methylethyl]amino}-2- oxopyrazin-1(2H)-yl] - N-cyclopropyl-4-methylbenzamide

N-Cyclopropyl-3-[3-{[1-(2-{ [(2R)-2-(dimethylamino)-3 -hydroxypropyl]oxy}phenyl)-1- methylethyl]Jamino}-2-oxo pyrazin-1 (2H)-yl]-4-methylbenzamide

N-Cyclopropyl-3-fluoro-5-[3-{[1-(2-{[(2R)-2-hydroxy-3-© (methylamino)propyljoxy} phenyl)-1-methylethylJamino }-2-oxopyrazin- 1(2H)-yl]-4- methylbenzamide

N-Cyclopropyl-3-[3-{[1-(2-{[(2R)-3- (ethylamino)-2-hydroxypropyl]oxy }phenyl)-1- methylethyl]Jamino}-2-oxopyrazin-1) 2H)-yl]-5-fluoro-4-methylbenzamide

N-Cyclopropyl-3-[3-{[1-(2-{ [(25)-3-(ethylamino)-2 -hydroxypropyl]oxy}phenyl)- 1- 01 methylethyl]amino}-2-oxopyrazin-1 (2H)-yl]-5-fluoro-4-methylbenzamide

N-Cyclopropyl-3-fluoro-5-[3-{[1 -(2-{[(25)-2-hydroxy-3- (methylamino)propyl]oxy} phenyl)-1-methylethyl]amino}-2 -0xo0 pyrazin-1(2H)-yl]-4- methylbenzamide 3-[3-({1-[2-(2-Aminoethoxy)phenyl]-1 -methylethyl}amino)-2-oxopyrazin-1 (2H) -yl]-N- \o cyclopropyl-5-fluoro-4-methylb enzamide

N-(2-{2-[1-({4-[5- (Cyclopropylcarbamoyl)-3-fluoro-2 -methylphenyl]-3-0x0-3,4- dihydropyrazin-2-yl}amino)-1 - methylethyl]phenoxy}ethyl)glycine

YAAY

N-(2-{2-[1-({4-[5-(Cyclopropylcarbamoyl)-3 -fluoro-2-methylphenyl]-3-oxo-3,4- dihydropyrazin-2-yl} amino)-1- methylethyl] phenoxy } ethyl)-beta-alanine 3-[3-({1-[2- (2-Aminoethoxy)phenyl] cyclopropyl }amino)-2-oxopyrazin-1(2H)-y1]-N-cyclopropyl- 5-fluoro-4-methylbenzamide

N-Cyclopropyl-3-fluoro-5-[3- {[1-2-{2-[(2- © hydroxyethyl)(methyl) amino]ethoxy } phenyl)cyclo propyljamino}-2- oxopyrazin-1(2H) -yl]-4-methylbenzamide 3_Fluoro-N-methoxy-4-methyl-5-{3-[(1- methyl-1-{2-[2-(methyl amino)ethoxy]phenyl} ethyl)amino]-2 -oxopyrazin-1 (2H)-yl}benzamide

N-Methoxy-4-methyl-3-{3-[(1-{2-[2-(methylamino)etho xy]phenyl} cyclopropyl) amino]- 0 2-oxopyrazin-1(2H)-yl} benzamide

N-Cyclopropyl-3-fluoro -4-methyl-5-[3-{[1-methyl-1- 2-{[2- (methylamino)ethyl] sulfanyl} phenyl)ethyljamino} -2-oxopyrazin-1 (2H) )-yl]benzamide 3-{3-[(1-{2-[(2-Aminoethyl) sulfanyl]phenyl}-1-methylethyl) amino]-2-oxopyrazin- 1(2H)-yl}-N-cyclopropyl -5-fluoro-4-methylbenzamide \o

N-Cyclopropyl-3-fluoro -4-methyl-5-{3-[(1-methyl-1-{2-[3-(methylamino)propyl] phenyl} ethyl)amino] -2-oxopyrazin-1(2H) )-yl} benzamide

YAAY

N-Cyclopropyl-4-methyl-3-[3-(2-{2-[3-(methyl amino)propoxy]phenyl}pyrro lidin-1-y1)-2-oxopyrazin-1(2H)-yl]benzamide

N-Cyclopropyl-3-fluoro -4-methyl-5-[3-{[(1R,2S) -2-methyl-1-phenyl-3 -pyrrolidin-1- ylpropyl]amino}-2-0x opyrazin-1 (2H)-yl]benzamide

N-Cyclopropyl-3-fluoro-4 -methyl-5-[3-{[(1R,25)-2 -methyl-1-phenyl-3 -piperidin-1- ylpropyl]amino}-2 -oxopyrazin-1( 2H)-yl]benzamide 4-Chloro-N-cyclopropyl-3-[3-[(1 -methyl-1-{2-[2-(methyl amino)ethoxy]phenyl} ethyl)amino] -2-oxopyrazin- 1 (2H)-yl]benzamide 4-Chloro-N-cyclopropyl-3-[3-{[1-(2- {2-[(2 -hydroxyethyl)amino] ethoxy} phenyl)-1- © methylethyl]Jamino } -2-oxopyrazin-1 (2H)-yl]benzamide 4-Chloro-N-cyclopropyl-3-[3-({1-[2- (2-{[(2R)-2 -hydroxypropyljamino} ethoxy)phenyl }- 1-methylethyl} amino)-2-oxopyrazin-1 (2H)-yl]benzamide 4-Chloro-N-cyclopropyl-3-[3-[(1-{2-[2-(ethylamino)ethoxy]phenyl }-1- methylethyl)amino] -2-oxopyrazin-1 (2H)-yl]benzamide Ve 3-[3-({1- [2-(2-Aminoethoxy)phenyl] -1-methylethyl} amino)-2 -oxopyrazin-1(2H)-yl]-4- chloro-N-cyclopropylbenzamide : (IB) in one embodiment; The present invention provides compounds of the formula

YAAY

- 7E Rr? 3 N L" 8 0 N | FJ SN RS 7 R 720 (IB) R

where:

(CN 5 CF3 halo «alkoxy (C1-C6) «alkyl (C1-C6) select separately from R25 +1

3 and 84 separately select from 11 “alkoxy (C1-C6) “alkyl (C1-C6) tweezers “OH 0112829 alkyl (C1-C6) where “CONRIOR11 heteroaryl aryl heteroaryl caryl” ON «CF3 ©

The mentioned alkoxy (C1-C6)s mentioned JS separately has been replaced by 1 ? OR * individually selected combinations of thalo s S(O)pRS5 01812613 «alkoxy (C1-C3) «OH

(C3-C7) «heterocycloalkyl cheteroaryl heterocyclic aryl aryl 21 Via choose from ¢OR16 3 CH2R16 «SO2NR16R17 «S(O)pR16 «(CR14R15)mNR16R17 «cycloalkyl

01 6 choose from “cycloalkyl (C3-C7) “alkoxy (C1-C6) “alkyl (C1-C6) H aryl heteroaryl taryl 5 heteroaryl 7 choose from cycloalkyl (C3-C7) “alkoxy (C1-C6) “alkyl (C1 -C6) H and taryl or 6 and 17 with an atom (AY nitrogen) attached to it forming a ring having from ; to 1 atoms; and optionally containing another selected hetero-atom from 00818 8 and 0; YAAY

oy - -— RS and 1219 choose separately from “cycloalkyl (C3-C6) “alkoxy (C1-C6)” alkyl (C1-C6) H or 18 R95 with SA nitrogen atom They are connected by a SE ring with ; to 7 atoms; It optionally contains another atom of inhomogeneity selected from 00819 8 and 0; R155 4 choose from 11 “alkyl (C1-C6)s or 4 and 815 with the carbon atom to which they bond © form a ¢(C=0) carbonyl group 6 choose from the cycloalkyl (C3-C7) ) «aryl 23c 2c X LZ £ . £ 0 X where said cycloalkyl (C3-C7) can have an optionally substituent taryl 4c gana 7 choose from 1l «aryl »alkyl (C1-C6) heterocycloalkyl ¢heteroaryl Ve and (03-07) “cycloalkyl where said alkyl (C1-C6) can have an optionally substituted with 1” or ¥ individually selected groups of “cycloalkyl (C3-C10) ) “alkoxy (C1-C6) < heterocycloalkyl aryl heteroaryl and ¢NR20R21 a3 R22 from heterocycloalkyl “<NR29R30 (OH” alkoxy (C1-C6) “alkyl (C1-C6) H and an alkali, where said alkyl (C1-C6) can be optionally substituted by 1 ? or mYo groups (R28) where said aryl can be optionally substituted by 1 OR Individually selected groups of “OH 5 CF3 ¢halo “alkoxy (C1-C6) “alkyl (C1-C6) 3 choose from talkyl (C1-C6)s H YAAYX

OR R22 and 1123 with atom 0 to which they bond cycloalkyl (C3-C7) OSs or ¢heterocycloalkyl ring X is bond or group (((CR24R25)n R24 5) choose separately from (OH «alkoxy (C1-C6) alkyl (C1-C6) (H {NR39R40 3 heterocycloalkyl ° or 4 R255) with atom 8 to which they bond forming a heterocycloalkyl ring Z is aryl dda R cheteroaryl where the aryl ring or the aryl heterocycle is substituted with tR27 3 R26 R26 is contracted from <halo » aryl —O » aryl < OH » alkoxy (C1-C6) » alkyl ( C1-C6) {H Ji) cheterocycloalkyl —O < heterocycloalkyl 0 heterocycloaryl 0- aryl heteroaryl alkyl heteroaryl heteroaryl » 0 NR34R35 «S(O)pR34 «cycloalkyl «CONR34R35 5 Whereas, the said 6©-01) alkyl or alkoxy (C1-C6) can have an optionally substituted with 1 or ?separately selected groups of heterocycloalkyl “OH” or 5mVe 227 choose from the halo and (01-06) calkyl wherein said alkyl (C1-C6) has an optionally substituted with Yo or Y groups; or lao R275 R26 forming a group “methylenedioxy, where it is attached to the adjacent carbon atom of the aryl ring or the heterocyclic aryl; YAAY

Each occurrence of the 8 selects individually from: <heterocycloalkyl «(C1-C6) alkoxy «OR36 + 3); NR29R30 “halo” CH2CF3 COOR42 “CONR31R32 5 SO2NR37R38¢ R305 R29 selects separately from SO2R41 “cycloalkyl (C3-C7) “alkyl (C1-C6) {H© and 0(841); Cus that said alkyl (C1-C6) has an optionally substituted with “OH 11856857 or ¢heterocycloalkyl R31 and 1132 selected separately from 11 alkyl (C1-C6) and (03- 07) “cycloalkyl or 1 R325 with a nitrogen atom attached to it forming a ring with ; to 17 atoms; optionally containing a non-gat atom of 01823 S and 0; R359 4 Ye selects separately from cycloalkyl «cycloalkyl (C3-C7) «alkyl (C1-C6) {H bonded to © 5 alkyl C(O)O(C1-C6) where the alkyl (C1-C6) said optionally substituted with < heterocycloalkyl s C(O)OH .NR58R59 “alkoxy (C1-C6) ¢halo” OH or 4 R355 with an A nitrogen atom bonded to form A ring with from − to 7 atoms 6 choose from 11 cheterocycloalkyl 5 alkyl (C1-C6) wherein said alkyl (C1-C6) 0 can have an optionally substituted with a heterocycloalkyl group (R42 5 R41 “R40 R39” R38: R37¢R33 “R21” R20 R19 (R18 R13 “R12” R11 “R10) selects all over >32 of talkyl (C1-C6) 9 H m is zero or 1 the

ov - - n is 1 or ¢Y in each occurrence of p which JS chooses separately from zero; 1 or ?; The cycloalkyl is a non-aromatic carbon ring; optionally combined with an aryl group where the said cycloalkyl ring optionally contains; when possible » on up to © two double bonds; and where; unless otherwise stated; The said eycloalkyl pal can have an optional substitution of 1 or ? From the substituent groups select separately from “halo ys NR43R44¢ catabolism (C1-C6) alkyl “(C1-C6) alkoxy (OH” CN The heterocycloalkyl is a non-aromatic mono- or dicyclic of ?to 4 atoms bonded to © or optionally combined with an aryl group or a heteroaryl heteroaryl 0 where the heterocycloalkyl ring contains: 1 or −00845 atom or 1 atom; or an N atom one and one 1145; or one 17 atom; one 11845 S(O)ps or one 0 atom; or one Ne a and 8(0)0(0) or © atom; or one 5 atom; or one 0 atom; YAAY

um and optionally include ;. when possible; 1 or “double bond”; and having an optionally substituent with one or two separately selected substituents of the alkoxy (C1-C6) «alkyl (C1-C6) halo «CF3 «CN «OH and 1184647 Cus caryl s that said alkyl (C1-C6) can have an alkoxy group (C1-C6) “aryl” or 011 substituted; and where each © aryl group can have an optional substitution by (01-06 ) alkoxy (which in turn can have a substitution with thalo_s CF3 “OH” alkyl (C1-C6) “(NR34R35) The aryl is an aromatic ring containing 1 or 0 carbon atoms; where; what Not otherwise stated; said aryl can be an optional substitution with the 1? or ¥ substituents chosen separately from the “OH” alkoxy (C1-C6) “alkyl (C1-C6) cementum CF3 “CN and (NR48R49) 01 The aryl heterocyclic is an aromatic ring with qo or 0 atoms; contains 1 or Y atom N and optionally 01850 atom or one 0 atom and an 8 atom or ©; or one 8 atom or one 0 atom; Cua that unless otherwise noted; the heteroaryl aryl can have an optional substitution (YO) ¥ selected alkoxy (C1-C6) substitution groups ) “alkyl (C1-C6)” OH tweezer ¢(NR51R52 5 CF3 “CN 9 845 choose from aryl 5 alkyl (C1-C6) C(O)O “alkyl (C1-C6) C) O) “alkyl (C1-C6) H wherein said alkyl (C1-C6) is optionally substituted with a selection of (C1-C3) “OH” alkoxy tweezers (NR29R30 5 heterocycloalkyl) and Where That : alkyl (C1-C6) C(0)0 mentioned has an optional substitution of a caryl group YAAY

Its 0 is chosen from alkyl (C1 -C6) (H) and 0)0(0 calkyl (C1-C6) since said alkyl (C1-C6) can be optionally substituted by a selection of “OH “alkoxy (C 1 -C3) cycloalkyl (C3-C6) ¢halo f 11253254 R59 3 R58 R57 “R56 (R55” R54 “R53” (R52 “R51” R49 (R48 “R47” R46 “R44 R43) © select separately from H and an alkyl (C1-C6) or a pharmaceutically acceptable salt thereof. RT 6 RS as specified above in embodiments of the invention relating to compounds of formula (I) in one embodiment; the present invention provides compounds of formula (IC) 4c 3 R A N 0 RS l \ Re 7 R 2 © (IC) R!" R4 R3 A N 0 Re.

N | ا 1 7 R 72 © 1 R 00 where: YAAY

- 08 — 1 and 22 select separately from 51 (C1-C6) null (CN «CF3 «halo »alkoxy (C1-C6) 3 and 84 select separately from 11 «alkoxy (C1-C6) calkyl (C1-C6) tweezers OH 3018879 caryl «CN «CF3 aryl heteroaryl & 001181011 where said (C1-C6) alkyl & said (01-06) alkoxy JS separately by substituting with 1 ?or ¥ groups of © select separately from S(O)pRS5 (NR12R13 alkoxy (C1-C3) “OH” and ?m select from 1 non-contiguous aryl adhesive (C3- C7) < heterocycloalkyl cheteroaryl 'OR16 5 CH2R16 'SO2NR16R17 ¢S(O)pR16 '(((CR14R15)mNR16R17 'cycloalkyl 6 choose from (C3-C7) 'cycloalkyl (C3-C7) 'alkoxy (C1-C6) ) “alkyl (C1-C6) H “alkyl (C1-C6) cycloalkyl aryl heteroaryl aryl 5 heteroaryl where said alkyl (C1-C6) 0 can be optionally substituted with halo or (OH R7) chosen from saryl 5 cycloalkyl (C3-C7) «alkoxy (C1-C6) »alkyl (C1-C6) H or R75 R6 with the nitrogen atom to which they are attached form a ring with from 1 to 1 atoms and optionally contain another hetero-atom selected from 21018 5 and 0; R95 8 separately selected from cycloalkyl (C3-C6) alkoxy (C1-C6) « alkyl (C1 -C6) (H 1” _ with a nitrogen atom to which they bond to form a ring with ; to 1 atoms; It optionally contains another atom of inhomogeneity selected from 00819 8 and 0; 4 and 1815 choose from “alkyl (C1-C6)s H or 4 R155 with the carbon atom they bond to forming a ¢ (C=0) carbonyl group YAAY

— 11 f cycloalkyl (C3-C7) “aryl < H choose from 6 2c The mentioned R23 pw can have an optional substitution cycloalkyl (C3-C7) since 0 X taryl with a group heterocycloalkyl heteroaryl aryl heteroaryl <aryl «alkyl (C1-C6) 11 choose from 7 mentioned can have an alkyl (C1-C6) optionally substituted where cycloalkyl (C3-C7)s © cycloalkyl (C3-C10) calkoxy (C1-C6) selected separately from cle sana ¥ b1a? or ¢NR20R21 s heteroaryl Waldmakboh:)p; Heteroaryl heterocycloalkyl 12291630 «OH slave (C1-C6) «alkyl (C1-C6) H choose from 2

Said YY could have an alkyl (C1-C6) optional substitution where caryl ? or A unit of talkyl (C1-C6) and H choose from 3 or a cycloalkyl ring (C3-C7) to which they are bonded as two carbons with an R235 R22 atom or a theterocycloalkyl ¢ (CR24R25). n) AX IO “OH” alkoxy (C1-C6) “alkyl (C1-C6) (H) bond or group each separately selected from R25 5 R24 to which they bond forming a carbon ring with an R255 atom 4 and 11839840; or heterocycloalkyl ¢ heterocycloalkyl gas

111 - - 27 is the aryl ring or Gua cheteroaryl with the aryl ring or the aryl heterocycle replace with ¢R27 3 R26 R26 choose from 1 <halo »aryl —O «aryl «OH alkoxy (C1-C6) «alkyl (C1-C6) <heterocycloalkyl ©0- 1 OH6:0701 » aryl heteroaryl ¢heteroaryl 0- aryl heterocyclic alkyl cheteroaryl heteroaryl »© - NR34R35 “S(O)pR34 “cycloalkyl” CONR34R3S5 wherein said alkyl (C1-C6) or alkoxy (C1-C6) may be optionally substituted by 0 “or ¥ groups of choice each separately from heterocycloalkyl «OH OR

7 choose from 11 halo and (01-06) calkyl wherein said alkyl (C1-C6) has an optional substitution of Ye or 7 groups; or lw R275 R26 forms a methylamine dioxy group Cus methylenedioxy bonds with the adjacent carbon atom to the aryl ring or the heterocyclic aryl; Each occurrence of 228 selects separately from 01829830 “CF3” CH2CF3 ¢halo CONR31R32 “COOR42” OR36 “alkoxy (01-06) ¢ heterocycloalkyl and ¢SO2NR37R38 R305R29 0 JS chooses separately from SO2R41 “cycloalkyl (C3-C7)” alkyl (C1-C6) ¢H and 0(841); Cua that said alkyl (C1-C6) is optionally substituted with NRS6R57 “OH or theterocycloalkyl YAAY

R32 4 1 choose each separately from 11” alkyl (C1-C6) and (63-07)” cycloalkyl or 831 R325

With a nitrogen atom attached to it, it forms a ring with ; to 1 atoms; Optionally contain

on an atom of heterogeneity of 081823 5 and 0;

cycloalkyl «cycloalkyl (C3-C7) «alkyl (C1-C6) 1 separately from JS chooses R355 R34 mentioned optional substitution alkyl (C1-C6) where alkyl 0(00)01 -06) associated with © and ©

R355 R34 or sheterocycloalkyl and C(O)OH “(NR58RS9” alkoxy (C1-C6) <halo “OH” b

With a nitrogen atom to which they are attached to form a ring with ; to 1 atoms;

6 choose from 11 alkyl (C1-C6) and null 1616:00010” where the said alkyl (C1-C6)

It may have an optionally substituted with a theterocycloalkyl group

(R42 5 R41 R40 (R39 “R38¢ 23733” R21 “R20” R19 (R18 (R13 “R12” R11 “R10 0 talkyl (C1-C6)) and H select separately from ¢) are zero or m 31 or 1 is n or ?; 1 ha in each occurrence of l m choose separately from

0 the cycloalkyl is an Ala non-aromatic carbon; optionally combined with a caryl group where the said cycloalkyl ring optionally contains; when possible on up to two double links; and where; unless otherwise stated; It could be cycloalkyl

Agha

117—mentioned optional substitution by 1 or ? From the individually selected substituent groups of (C1-C6) the halo «CF3 «CN «OH alkoxy (C1-C6) and ¢{NR43R44 the heterocycloalkyl is a monocyclic or a bicyclic Non-aromatic? to 4 atoms bonded to C or (N) optionally fused to an aryl group or heteroaryl © heteroaryl where the heterocycloalkyl ring contains:

1 or ? 00845 atom or 1 N atom; or one N atom 5 NR45 one; or a single [1] atom; 11845 one and 5 (0)0 or atom 0’ or

Vo is one atom 27 and m(5)0 or © atom; or a single 5 corn; or one 33 0; and optionally include, when possible, a yo or double bond; It has an optional de sana substitution one or two separately chosen from «alkoxy (C1-C6) alkyl (C1-C6)

halo «CF3 «CN «OH 0 and 11846847 substitution group -0011201120- divalent dia (that the terminal oxygen atoms are bonded to the same carbon atom of the ring); and a substituent group - CH2NHCH2- divalent Cua) that the terminal carbon atoms are bonded to the same carbon atom of the ring) < aryl s ctetrahydro-1,1-dioxido-3-thienyl where the alkyl (C1-C6) mentioned can

The

has a J substituted with an alkoxy group (C1-C6) caryl or 011; Whereas, each aryl group can have an optionally substituted with (01-06) alkoxy (which in turn can have a ¢halo s CF3 “OH” alkyl (C1-C6) “(NR34R35) aryl substituted is an aromatic ring containing 1 or 0 carbon atoms; Cus unless otherwise noted GS © can have aryl mentioned optional substitution with 1" or ¥ substitutions choose each on >32 of “OH” alkoxy (C1-C6) “alkyl (C1-C6) mm ¢NR48R49 s CF3 “CN The aryl heterocyclic is an aromatic ring with 65 8 9 or 0 atoms; it contains 1 or ? atom L and optionally NR50” or one 0 atom and one 5 atom or 0 or one 5 atom or one 0 atom where, unless otherwise noted, the heterocyclic aryl can be substituted for sas 01 ?or ¥ substitution groups selected from (C1-C6) and “alkoxy (C1-C6) ¢NR51R52 5 CF3 “CN:halo “OH” selected from 1 “aryl s alkyl (C1-C6) C(O)O «alkyl (C1-C6) C(O) «alkyl (C1-C6) wherein said alkyl (C1-C6) has an optionally substituted with a selection of (01-03) heterocycloalkyl < halo “OH calkoxy and 2011229230;i ag that the said atkyl (C1-C6) C(O)O 06 has an optional substitution of an aryl group 0 chosen from calkyl (01-06) C) 0)O alkyl (01-06) ¢H wherein said alkyl (C1-C6) can be optionally substituted with a selection of (01-63) “OH” alkoxy tweezers ¢NR53R54 5 cycloalkyl ( C3-C6) L

eo — — R59 5 R58 “R57” R56 “R55 R54 “R53 “R52 “R51” R49 R48 R47 R46 R44 (R43) separately select from H and talkkyl (C1-C6) or A pharmaceutically acceptable salt thereof.For compounds of formula (IC) the embodiments of the invention contain those in which 1 “R4” (R3 “R2 RT RE RS ©) as specified above in the embodiments of the invention relating to the compounds of formula ().

in one of the models; The present invention provides a compound of formula (0; (ID) «(IC) «(IB) «(IA) or (IE) having a value of 38m alpha 1050m of © or greater. In the form of OAT the invention provides The present is a component of the formula (0”; (ID) (IC) “(IB)” (IA) er (IE) with a value of 38m alpha 1050m equal to + or greater.

(IE) Ar (ID) (IC) «(IB) «(IA) «(I) The present invention provides a compound of formula Al in form 0 or greater of 17 alpha 1050m of p38 has the value (E) or (ID) “(IC)” (IB) in another embodiment; The present invention provides a compound of the formula ( ) »; asphalt alpha p38 or greater in the context of previous embodiments; The values of A0 alpha 1050m are specified, and p38 has a value of . alpha which will be described here later p38 according to the selection enzyme pIC50

0 Definitions: Unless otherwise stated; The halo of Is Br ¢ F “Cl chooses the cycloalkyl is as defined above. Examples of suitable cycloalkyl groups include cyclopentene cycloheptyl cyclohexyl cyclopentyl < cyclobutyl cyclopropyl

the

11 - cyclopenta-1,3-diene, cyclohexene and cyclohexa-1,4-diene (optionally substituted as above). Examples of suitable cycloalkyl groups include; When combined with caryl to: indanyl and 1,2,3,4-tetrahydronaphthyl ( has an optional substitution as above). The heterocycloalkyl is defined as Alle and examples of suitable heterocycloalkyl© groups include oxiranyl, aziridinyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, N-methylpiperidinyl, morpholinyl, N-methyl morpholinyl, thiomorpholinyl, thiomorpholinyl-1-oxide, thiomorpholinyl-1,1-dioxide, piperazinyl, N- methylpiperazinyl, azepinyl oxazepinyl, diazepinyl, 1,2,3,4-tetrahydropyridinyl 00 and wee N go § © Aug 2 | A xX 1 Z L 2 A Rus Res (it has an optional substitution as mentioned above). Examples of suitable heterocycloalkyl groups include; When combined with a di or heteroaryl aryl at : 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, tetrahydroimidazopyrazine, tetrahydroimidazopyridine \e ) has an optional substitution as above ). YAAY

17 - The aryl is as defined above. Examples of suitable aryl groups include phenyl and naphthyl (optionally substituted as above). The aryl heterocycle is as defined above. Examples of suitable heteroaryl groups include thienyl, furanyl, pyrrolyl, pyrazolyl, imidazoyl, oxazolyl, isoxazolyl, thiazolyl, 8 isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzimidazolyl, benzotriazolyl, quinolinyl and isoquinoliny! (optionally substituted as above). 0. Unless otherwise stated; The alkyl groups can be 't' and the alkynyl group is calkenyl containing the required number of carbon atoms, branched or unbranched. Examples of suitable alkyl groups include: methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl and t-butyl. «(-OCH2CH3) ethoxy «(-OCH3) methoxy The appropriate alkoxy contains examples n-propoxy, i-propoxy, n-butoxy, sec-butoxy and t-butoxy. \o : suitable for alkenyl and examples of groups include 1,1-ethylenyl, 1,2-ethylenyl, 1,1-propylenyl, 1,2-propylenyl, 1,3-propylenyl and 2,2- propylene.

YAAY

Examples of suitable alkynyl groups include: prop-1-ynyl, but-1-ynyl, but-2-ynyl, pent-1-ynyl, pent-2-ynyl and hex-1-ynyl. b©" as heterocycloalkyl' bonded to ©"; means heterocycloalkyl 4c sana bonded via a cyclic carbon. heterocycloalkyl bound by a ring nitrogen atom The term “pharmaceutically acceptable salt” means a physiologically and toxicologically tolerable salt that appropriately contains pharmaceutically acceptable basic addition salts and acidic addition salts Pharmaceuticalally acceptable For example ( ) when the compound,Ne of the invention contains one or more acidic groups 0 for example carboxy groups and the basic addition salts that are pharmaceutically acceptable which may consist of sodium, potassium, calcium , magnesium and ammonium salts or salts with organic amines ¢ such as diethylamine, N-methyl-glucamine, diethanolamine or amino acids and amine acids (eg lysine and the like; Lexie (ii) the compound of the invention contains a basic VO group; such as the amine group; Pharmaceutical acceptable acid addition salts that can be formed contain: hydrochlorides, hydrobromides, sulfates, phosphates, acetates, citrates, lactates, tartrates, mesylates, tosylates, benzenesulfonates, maleates, fumarates, xinafoates, p-acetamidobenzoates, succinates, ascorbates, oleates, bisulfates 0” and the like. YAAY

— AA — The pharmaceutically acceptable salts contain salts of acceptable organic acids, all in one of that, but not limited to Le 10016l; alginate, ascorbate, aspartate, benzenesulfonate (besylate), benzoate, butyrate, camphorate, camphorsulfonate, camsylate, citrate, p-chlorobenzenesulfonate, 8 cyclopentate, 2,5-dichlorobesylate, digluconate, edisylate, esylate, fumarate, formate, gluconate, glucoheptanoate, glutamate, glutarate, glycerophosphate, glycolate, heptanoate, hexanoate, hippurate, 2-hydroxyethane sulfonate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, methanesulfonate, 2-naphthalenesulfonate, napsylate, nicotinate, orotate, oxalate, pantothenate, pamoate , 01 pamoic, pectinate, 3-phenylpropionate, pivalate, propionate, pivalate, saccharin, salicylate, stearate, succinate, tartrate, trans-cinnamate, trifluoroacetate, xinafoate, xylate (p-xylene-2-sulfonic acid), undecanoate; and of inorganic acids such as hydrobromide, hydrochloride, hydroiodide, sulphate, bisulfate, phosphate, nitrate, hemisulfate, thiocyanate, persulfate, phosphoric and Vosulfonic acids. Pharmacologically unacceptable salts may be used as intermediates. Hemisulfate Bll salts Half-salts of acids and bases can be calquered; For example .hemicalcium

‎VY. = — to review the appropriate salts; See: "Handbook of Pharmaceutical Salts: Properties, Selection and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) The term 'ads' prodrug is a compound that is transformed in an organism by metabolism (eg by hydrolysis ¢ reduction or oxidation) to the compound of the invention. Suitable combinations for the formation of prodrugs are described in: “The Practice of Medicinal Chemistry, 2nd Ed. pp561- 585” 2003) and in F.

I. Leinweber, Drug Metab.

Res., 18, 379. (1987). The compounds of the invention can be in both insoluble and soluble forms. The term “solubilants” is used herein to describe a complex HI comprising the compound of the invention and a stoichiometric quantity of one or more pharmaceutically acceptable solvent molecules; For example; ethanol the expression 'Lexie 'hydrate' is used the solvent is water. Compounds of the present invention exist in geometric, optical, dichotomous and one or more conjugated forms including but not limited to the 'cis trans' forms pics 12 and 27 VO pics 8, 2 and 7650 ; pics keto-, enol unless otherwise noted; reference to a particular compound contains all those Les isomeric motifs in that racemic mixtures 86016 of that and others. Say separation of isomeric ones from their mixtures using known and adapted methods (eg chromatographic techniques and sale recrystallisation techniques).

71 - In an appropriate manner” (Say) the preparation of isomeric ones by harmonizing known methods (eg asymmetric synthesis). Experienced people realize that the compounds of the invention can be prepared; The following methods are for illustrative purposes only of some of the methods that can be used to synthesize compounds of formula (I) rR? The present invention provides a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof which includes activation of a compound of formula (II) wherein RI 2p R3 said R6 and 87 are as specified That in claim ( Lis ) 1 is a leaving group; typically chalogen 01 performs one or more of the following: (i) converting a compound into another compound having f(D Ball Gif) configuration Pharmacologically acceptable salts of the compound.

Functionalization of position 05 in the 2(1H)-pyrazinone ring of a compound of formula (dD) may include the bond formula CS «C-N «C-C C-H or C-0. The reaction can be catalyzed by a transition metal such as “palladium Or copper and is traditionally in an organic solvent Jia organic solvent: N-methylpyrrolidin-2-one, tetrahydrofuran, 1 ,4-dioxane, methanol, ethanol, ethyl acetate, ~~ N,N-dimethylformamide, N, N-dimethylacetamide, 1 , 2-dimethoxyethane © and optionally in the presence of a suitable base such as : triethylamine, N,N-diisopropylethylamine, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium fert-butoxide ¢ and at a temperature In the limits for example from zero to 700 m. In chydrogenization reactions Judge 0 can be used as Jw reductase “formic acid <ammonium formate ¢sodium formate chydrogen or 1,4-cyclohexadiene ) -1,3. stereotypically; when R4 is 11 ammonium formate in ethanol in the presence of -N N,N-diisopropylethylamine alternatively; A compound of formula ( ) or its pharmaceutically acceptable salt may be prepared deli a compound of formula (111) where WI is a leaving group (eg acyloxy «alkoxy ¢hydroxyl 10] or a halogen (with a compound of formula (IV) rR? 3 R Ay 0 mia Ww 6 RN N H 0 2 1 R (II) rR" 1v) YAAY

Typically, if the compound (II) is in ester form such as ethyl ester s methyl ¢, the reaction can be carried out by treating a compound of formula (IT) with a compound of formula (IV) in the presence of organomagnesium halide organic Typically, iso-propylmagnesium chloride or cyclopentylmagnesium bromide (i.e., trialkylaluminium) in a suitable anhydrous solvent such as ang ,2-dimethoxyethane “1,4-dioxane, toluene” tetrahydrofuran ¢ diethyl ether© is heated in the limits, for example Example from VA = C to ambient temperature (Y0 C). alternatively; Reaction (I) and (77) may be carried out under thermal conditions in a suitable organic solvent or diluent; For example: Z tetrahydrofuran, 1,4-dioxane, 1 ,2-dimethoxyethane, N, N-dimethylformamide, , N N-dimethylacetamide, N-methylpyrrolidin-2-one 0 at an elevated temperature »for example The example is on the order of 11 dE m. In the case where WI is “OH”, carboxylic acid can be converted first to acid halide by hand treatment with oxalyl halide at a temperature between -# um and 8 °C in an inert solvent. solvent such as dichloromethane and thus typically the acid halide is treated with amine 1 of formula (AV) an inert solvent such as dichloromethane in the presence of a nucleophilic base such as N N, N -diisopropylethylamine or triethylamine; “ff when W1 is 011; It can convert YJ carboxylic acid to another suitable reactive derivative of formula (111); For example; mixed anhydride For example, anhydride formed by the reaction of acid chloroformate 4 such as ester “isobutyl chloroformate + formed by reaction of alcohol in the presence of yo acid or base; ester is active” eg ester formed by the reaction of an acid with a phenol such as YAAY

Vt 0 - pentafluorophenol "with pentafluorophenyl trifluoroacetate (fic ester") or an alcohol such as N N-hydroxybenzotriazole; or the acid of formula (111; (WI = OH) can be reacted with An amine of formula (IV) in the presence of an amide coupling agent such as dicyclohexylcarbodiimide ¢ Pybop (benzotriazole-1 -yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate), 1- ethyl-3-(3 '-dimethylaminopropyl)carbodiimide, HATU (2-(1H-7-azabenzotriazol-1-yl)-- © ,3,3-tetramethyluroniumhexafluorophosphate methanaminium) or PyBroP (bromo-1,1 tris-pyrrolidino-phosphonium hexafluorophosphate If compound (II) is in acid form, such compounds may be prepared by hydrolysis to a suitable ester under basic conditions (eg treatment with lithium hydroxide 0 in methanol Jada - Water) 0 Hydrolysis (eg hydrolysis in a suitable solvent in the presence of palladium on charcoal) or acidic (eg treatment with HBr 8 or trifluoroacetic acid Compounds of formula (IT) can be prepared from a compound of formula (V) where WI is a leaving group (eg “(halogen i acyloxy” alkoxy ¢ hydroxyl) and R55 183 “R2 RI is as 6 5 defined in the formula ( ) and 11 is a leaving group; A typical halogen using the described methods for preparing a compound of formula (1) from a compound of formula L (HD) A , Ww x N OR R? 0 v) 8 YAAY

additionally; Compounds of formula (I) can conventionally be prepared from a compound of formula (V) where WI is the alkoxy group and is RS 83 82 (RI and 11) as defined above; using methods described in Preparation of a compound thereof Formula (1) from a compound of formula HID (L l , 2) (0 : 0l 0 2 (VI) “RE vn a© Compounds of formula (V) can be conventionally prepared from a compound of formula (VD) where 1.1 L25 are leaving groups; typically R2 “RI < hydrogen” and 83 are as defined above Wis in an alkoxy group by making an facultative aromatic atomic substitution of the leaving group 12 with various atomic substitutions It has the formula (VII) where 7 is hydrogen (eg in amines, anilines, alcohols, phenols, thioalcohols, thiophenols) or a metal (eg (cyanides, Grignard reagents) 0. Can be made The reaction in an organic solvent is suitable as: N-methylpyrrolidin-2-one, tetrahydrofuran, 1 ,4-dioxane, methanol, ethanol, ethyl acetate, N N-dimethylformamide, N, N-dimethylacetamide, 1 , 2-dimethoxyethane and optionally in the presence of a suitable base such as: N, N-diisopropylethylamine, 1 , 8-diazabicyclo[5.4.0Jundec-7-ene 0 triethylamine Yo cesium carbonate, sodium fert- «potassium carbonate «sodium carbonate » (DBU) butoxide, sodium hydride. YAAY

In the range; For example JB from VAS to 700 m; And more appropriately at ambient temperature (75 °C). In the case where RS is CRI4RISMNRI6R1T where RIS (R14 R175 R16) is as then specified in claim (1 and -0), the reaction is typically carried out at tetrahydrofuran and ambient temperature or at elevated temperature in the presence of ternary amine N,N-diisopropylethylamine (fi) Also compounds of formula (V) where RS is alkynyl “alkenyl < heteroaryl caryl 6+ where 816 are as indicated in claim (1); may be prepared in transition metal-catalyzed cross-coupling reactions (eg, Suzuki, Negishi, (Kumada, Stille, Sonogashira, Hiyama or Heck) coupling reactions of compound of formula (VI) And the formula (ester 5 boronic acids “alkynes alkenes Jw (VII) 0 that”). 4-dioxane, methanol, ethanol, ethyl acetate, ‎N, N-dimethylformamide, N,N-dimethylacetamide, 1 ,2-dimethoxyethane in the presence of a suitable base such as : triethylamine, N,N-diisopropylethylamine, sodium carbonate, potassium carbonate, Yo cesium carbonate, potassium phosphate, sodium tert-butoxide, sodium hydride and at a temperature in the range for example from zero to Yoo C YAAY

yy — - in another way; Compounds of formula (VI) may be prepared from a compound of formula (IX) where RI 2 and 83 are as specified above Wis in the calkoxy group by treatment with suitable halogenating agents; N-halosuccinimide (fie) in the presence of a base such as N,N-dimethylformamide RY lym R? r?© R' (VII) R! (IX) © compounds of formula ( ( VI) by treating the compound of formula (VID) or its salt wherein (RI 82 83 is as specified above and 1171 is the alkoxy group with the corresponding oxalyl chloride such as oxalyl halides or oxalyl chloride In a suitable solvent such as 1517 dimethylformamide, chlorobenzene, dichlorobenzene, chloroform optionally in the presence of a suitable salt tetrathylammonium bromide Jie and at a temperature in the range 0 for example from ? to Yoo M. Typically the of ja) reaction with oxalyl bromide in 1,2-dichlorobenzene at 001 M 0 W NH, Tees R 00 [1 xn 909 (xm) compounds of formula “( VII where R35 R2 RI is as defined above Wis is an alkoxy group suitably treated by the compound of formula (X) or its salt; using a compound of formula (XI) 00 where 13 is A leaving group; typically a chydrogen and is as specified above.The reaction can be carried out in the presence of a non-nucleophilic base such as N N-diisopropylethylamine, triethylamine, sodium carbonate » in a cinert solvent such as: YAAY

YA — - N-methylpyrrolidin-2-one, tetrahydrofuran, 1 ,2-dimethoxyethane, 1,4-dioxane, “toluene ethyl acetate. And at a temperature in the limits, for example: N N-dimethylformamide , N, N-dimethylacetamide from zero to Yoo m 0 preferably in N N-diisopropylethylamine at reflux ~~ © on reflux. alternatively; Compounds of formula (VII) may be prepared in the reaction of a compound of formula (X) with a compound of formula (XII) where R3 is as defined above: sodium cyanide, potassium cyanide or trimethylsilyl cyanide in a suitable solvent acetic (Jie acid, methanol, ethanol, water, acetone, toluene optionally in the presence of suitable Lewis acid Jie trifluoromethanesulphonic acid 0 at a temperature in the limit for example from zero to aXe and the most suitable at ambient temperature (YO) m). NH, N 0 w' N R® . rR Ao 20 1 R (XIII) 0 (XIV) Compounds of formula (ITT) can also be conveniently prepared by treating the compound of formula (XI) where R5 2 (RI) is as then specified above Wis is a calkoxy group with a compound of formula Cua (XIV) Vo 83 and 1204 is as specified above in the presence of a base in a suitable organic solvent .methanol Jw YAAY

va _ - can be prepared as Blas compounds of formula (IX) where RI 82 and 1803 are as specified above Wi is an alkoxy or amine alkyl group and by treatment with a compound of formula (XID ) with a compound of formula R3 Cua (XIV) is H NH, WA i” (XV) 0 © compounds of formula (XT) can be conveniently prepared from a compound of formula (X ) and the corresponding amine acid derivative (XV) where RS is as defined above and 1772 is a hydroxy or “alkoxy” group in standard amide conjugation reactions using the described methods for preparing the compound of formula (I ) from a compound of formula (IID) semi-chiral compounds of formula VII can be prepared contiguously where RS is (CRI4RISMNRIGRIT 0 and where “ = R17 “ba = 11 and 1816 are as specified in claim (1); from a compound of formula (XVI) where R22 X and 1023 are as determined in claim (1) by treatment with a suitable acid such as hydrochloric acid or trifluoroacetic ¢ in cule organic methanol Jw “organic solvent” and ethanol 5 -1,4 dioxane/methanol and at a temperature limit, for example. more at ambient temperature (Yo m). stereotypically; The reaction is carried out with hydrogen chloride in 1,4-dioxane/methanol at ambient temperature (Yo ~). Compounds of formula R23 3 R22 7 .7 Cua (XVI) can be suitably as such and then determined in claim (1); by reacting a compound of formula (XVID) with a suitable derivative of a compound of formula “(XVID) where Xs Z is as specified in claim (1) and 14 is a metal (eg YAAY

Av — - Example (magnesium, aluminum, cerium, lithium, indium) or a semi-metaloid (such as boron in a suitable solvent) such as: toluene, tetrahydrofuran, 1,4-dioxane, diethyl ether , 1,2-dimethoxyethane or dichloromethane © and optionally in the presence of a suitable metal catalyst. dichloromethane, for example: bis(acetonitrile)[(1 ,2,5,6-n)-1,5-cyclooctadiene]-rhodium, tetrafluoroborate at 0°C in the boundary; for example; from a VAS to 001 C. Typically, the reaction is carried out using the Grignard factor in dichloromethane at a temperature in the range "for example" from SWG C to 0 C C 0 R22 0 . I R23 1 23g or So x 1 5 ~ Pn Z (XVI) (XVID) Yo The compound of formula (XVII) wherein R235 R22 as defined in claim (1) is prepared as Ake by reacting the compound of formula (XIX) with a suitable sulfinimine in a suitable solvent such as YAAY

AY — — toluene, tetrahydrofuran, 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, dichloromethane, in the presence of a suitable dehydrating agent” such as for example copper(I) “titanium( IV) ethoxide sodium(I) sulphate « sulphate and at a temperature in the range; For example". from 0 e to Yeo m and more appropriately at the ambient temperature (Yo >). Typically, the reaction takes place using (R) i.e. 2-methyl-2-propanesulfinamide in the presence of (S). titanium(IV) in ethoxide in tetrahydrofuran at ambient temperature (Yo) »( M._ RZ X acid M (XVIII) (XIX) compounds with the formula ( XIX) “(XV)” (XIV) “(XID” (X) “(X)” (VID (IV) 0 commercially available; known as previously published in this field; or may be prepared using techniques known to those with experience In this respect, 2 0 0 w! N H, WwW 1 Y R? R2 1 R 00 " xx) compounds of formula Cua «(X) 171, 112, and 3 can be discreetly prepared as specified above ( Specifically, RI = 7 and 12 - Wis (Me) is an alkoxy group in the reaction of a compound of formula (XX) Ye where 7 is bromo “chloro < hydrogen or “iodo” and 7 = nitroso “¢ nitro or .amino contain typical reducing agents, for example ¢hydrogen gas 800101710 ,4-cyclohexadiene «formic acid «ammonium formate »formate 01 -1,3. in typical form; YAAY

— Or can the reaction be catalyzed by a transition metal, palladium Jie, and take place appropriately in an organic solvent, Jie organic solvent, but not limited to: toluene, N-methylpyrrolidin-2-one, tetrahydrofuran, 1,4-dioxane, methanol, ethanol , ethyl acetate, N, N-dimethylformamide, N,N-dimethylacetamide, 1,2-dimethoxyethane © and optionally in the presence of an appropriate base such as: triethylamine, N, N-diisopropylethylamine, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium hydroxide, dic temperature in limits; For example from zero to 000 m. It is preferable when = Y «Cl = X «OMe = 1 sMe=R24F =RI nitro, the reaction takes place using pd/C 0 and either N,N-diisopropylethylamine or ammonium formate in ethanol [hydrogen] at Temperatures between room temperature ‎Avy m . Compounds of formula (XX) where Wl is an alkoxy from WI Cua (XX) is Lester Jeli OH can conveniently be prepared using an alcohol solvent such as ethanol si methanol (Caan For example acid catalysts These acids can contain sulfuric acid 0 or hydrochloric acid or by adding an excessive amount of chlorotrimethylsilane and this can be done at a temperature ranging from zero to 101 °C; preferably in methanol at room temperature using excess amounts of -chlorotrimethylsilane

AY — — compounds of (XX) gs where WI is OH, Cl = 7, 81 = F, and 82 = Me are known from previously published in this field (eg 3441788 (DE) Or it can be prepared by methods known to those experienced in this field.This route offers clear advantages over previously published alternatives which are continued by means of potentially explosive nitroaryl diazonium © 1960, Chem Soc 672-6 salts. Those experienced in the art are aware that in the processes of the present invention some functional groups (Jie carboxy hydroxyl or amino groups) in chemical initiating agents or intermediates may need protection by protecting groups. Subsequently; The preparation of compounds of formula (I) at a certain stage may include protection with or removal of one or more carrier groups. The protection and deprotection of functional groups is described in: ‘Protective Groups in Organic Synthesis’, 2nd edition, T.W.

Greene and P.G.M.

Wuts, Wiley-Interscience (1991) and 'Protecting Groups', P.J.

Kocienski, Georg Thieme Verlag (1994). Compounds of formula (1) can be converted to a pharmaceutically acceptable salt using conventional methods. Ye compounds of the present invention are effective as pharmaceutical agents. It can be treated with compounds as follows: Respiratory tract: Airway obstruction diseases, including: asthma, including bronchial asthma; allergic; allergic; intrinsic ¢ and extrinsic Lia fal from exercise sports; and drug abuse (including those arising from YAAY

At — aspirin, intermittent and permanent NSAIDs of all intensities; dust-induced asthma and other causes of (A)sed airway overreactions, chronic obstructive pulmonary disease (COPD), and Bronchitis includes led to infectious bronchitis and due to eosinophilic leukocytes bronchitis©; emphysema; bronchiectasis; cystic fibrosis ¢ and sarcoidosis Farmer's lung and related diseases Hypersensitivity pneumonitis Lung fibrosis including alveolitis of unknown origin and interstitial pneumonia of unknown origin and fibrosis Which complicates antibiotic therapy (said) recent tumors; chronic infections, including tuberculosis ¢ and aspergillosis (lila)! saspergillosis other fungal infections. complications of lung transplantation ¢ and vascular disorders arising from thromboembolism in the vascular system of the lung; pulmonary hypertension and antitussive activity and include the treatment of chronic cough with inflammatory and secretory conditions of the airways; the cough is medicated; and acute and chronic rhinitis, including rhinitis medicamentosa ¢ vasomotor rhinitis; perennial and seasonal allergic rhinitis including irritable rhinitis (hay fever “(fever) and nasal polyposis” and acute viral infections including the common cold; and Yo infection due to respiratory fused cell virus influenza, coronavirus (including SARS and adenovirus), or eosinophilic esophagitis; YAAY

- Ao —

Bone and joints: Arthritis accompanied by or involving

osteoarthritis / osteoarthritis 5 both types congenital hip hereditary iliac growth jac such as primary and secondary primary and secondary

0 dysplasia and cervical and lumbar spondylitis; and pain down

© low back and neck pain « rheumatoid arthritis 0 and disease Ji 50118; and uncharacteristic diseases of the spondylitis; septic arthritis; Other joint and bone infections related to infections such as tuberculosis ¢ include Potts' disease, Poncet's syndrome, and acute and chronic crystal-induced synovitis due to

0 Salt crystals, including urate gout, calcium pyrophosphate deposition disease, calcium apatite related tendon, bursal and synovial inflammation. and disease 12606009; primary and secondary Sjogren's syndrome ¢ systemic sclerosis 1 limited scleroderma ¢ systemic lupus erythematosus « mixed connective tissue disease and undifferentiated connective tissue disease, and inflammatory myopathies, including dermatomyositis and polymyositis, and polymalgia rheumatica. ¢ juvenile arthritis including arthritis of unknown origin and associated syndromes; rheumatic fever

‎YAAY

AY = - and its systemic complications rheumatic fever and its systemic complications ¢ and vasculitides including giant LAY arteritis; Takayasu's arteritis 716878508, Churg-Strauss syndrome ¢ and polyarteritis nodosa; microscopic polyarteritis, vasculitides associated with viral infection, hypersensitivity reactions, cryoglobulins, paraproteins, low back pain back pain 1097 and Familial Mediterranean fever and Muckle-Wells syndrome; Familial Irish Fever 0 »Hibernian 2¢ Kikuchi disease Drug-induced arthalgias ¢ Myopathies Pain or connective tissue that rebuilds muscular disorders orthopedic due to injury or causative agent (such as a sports injury); And arthritis (such as rheumatoid arthritis 21600181010 ¢ or osteoarthritis » or gout will or Jalil’s disease due to 11 salts 0 » (crystal arthropathy) and other joint diseases (such as atrophy of the cartilage between the vertebrae intervertebral disc degeneration or temporomandibular joint atrophy 0 (joint degeneration and Jia disease) osteoporosis ¢ or Paget's disease osteonecrosis and inflammation polychondritits; scleroderma ¢ and mixed connective tissue disorder 00 » arthropathies and vertebrae; disease around YAAY

— AY — (such as spondyloarthropathies or periodontal disease) ¢ (periodontitis)

skin: psoriasis ¢, atopic dermatitis ¢, contact dermatitis; And other eczematous skin infections, contact dermatitis or other

eczematous dermatoses ©; delayed-type hypersensitivity reactions; phyto- and photodermatitis, seborrheic dermatitis, dermatitis herpetiformis, lichen planus, dlichen sclerosus etatrophica, and dermatitis Purulent cutaneous edema due to gangrene

discoid; discoid skin sarcoid lupus erythematosus; and skin necrolysis (pyoderma gangrenosum 0) and epidermal necrolysis “pemphigoid, pemphigoid, bullous, lupus erythematosus

bullous 51011058 epidermolysis; urticaria; angioedema and vasculitis; toxic erythemas ¢ and cutaneous eosinophilias; and partial squash, alopecia areata, and Ye male-pattern baldness; da Dies sweet syndrome 5966178; Weber-Christian syndrome, erythema multiforme J gall, "both infective and non-infective" ¢, panniculitis ", cutaneous lymphomas ¢ and carcinoma Skin other than black tumor non-melanoma skin cancer and other dysplastic lesions » and other Yo-injuries causing poor growth and drug-induced disorders, including rash as a result of YAAY tar abuse

A — - eyes blepharitis ¢ and conjunctivitis; They include “perennial and vernal allergic conjunctivitis” and iritis 1105; And anterior and posterior uveitis “and inflammation of the eye’s vascular layer 5” and autoimmune diseases ¢ and degenerative or atrophic inflammatory disorders affecting the retina “and ophthalmitis, which includes ophthalmia sympathetic ophthalmitis » and sarcoidosis; infections include viral; innate; bacterial; gastrointestinal tract: glossitis; gingivitis; periodontitis; oesophagitis; It includes reflux 01; eosinophilic gastro-enteritis, mastocytosis, mastocytosis, and Crohn's disease; and colitis, which includes ulcerative colitis, and inflammation of the anus or rectum, pruritis ani; celiac disease ¢ and irritable bowel syndrome; and Irritable Bowel Syndrome (food-related allergies)1 and food allergies that may affect sites far from the intestine (such as migraine; rhinitis or eczema) Internal /57007770: hepatitis cali includes autoimmune liver and cirrhosis of the liver due to alcoholic and viral autoimmune; or due to alcohol or viral ¢ and cholecystitis 505; and pancreatitis; acute and chronic both acute and chronic ¢ YAAY

_ Qom - genitourinary: nephritis, such as DY, interstitial and glomerulonephritis; and nephrotic syndrome “and cystitis” which includes “acute and chronic” cystitis and Hunner's ulcer ji da jig “interstitial ¢ and acute and chronic urethritis © and prostatitis, epididymitis, oophoritis and salpingitis, vulvo-vaginitis, Peyronie's disease, and erectile dysfunction (in all from males to females); rejection of transplanted organs (allograft rejection): in acute and chronic cases following Ve, for example kidney transplantation, kidney, heart, liver, or lung Or bone marrow, or skin ala, or cornea, or blood transfusion tracking, or host rejection disease for the transplanted organ.Central nervous system: Alzheimer's disease and other dementia disorders, including: nvCID 5 “CID Vo and amyloidosis; multiple sclerosis; sclerosis 10016l00; other demyelinating syndromes; cerebral atherosclerosis and vasculitis; temporal arteritis, myasthenia gravis ha, acute and chronic pain, intermittent or continuous, with central or peripheral lite, including visceral pain; headache 01; migraine; And fifth cranial nerve pain trigeminal YAAY

neuralgia ¢ and atypical facial pain “joint and bone pain” and pain arising from cancer and tumor “invasion” and pain syndromes due to nerve disease, including Diabetic nerve diseases associated with diabetes; And after infection with herpes; HIV-associated and neuronal leishmaniasis; mutational and central nervous system complications associated with positive traits; or infectious; or related to autoimmunity; Other autoimmune and allergic disorders including Hashimoto's 05 thyroiditis » Graves' disease » Addison's disease » diabetes; and La Sal's idiopathic thrombocytopaenic purpura purpura eosinophilic fasciitis ¢ hyper-IgE syndrome ¢ antiphospholipid syndrome ¢ Other disorders with an inflammatory or autoimmune component include acquired immunodeficiency syndrome acquired immune deficiency syndrome (AIDS) ¢ and leprosy; and peripheral circulation. ) Perfusion due to localized blood AB ¢ al gill g endocarditis ¢ YAAY

ay - - and valvulitis, aortitis, including infectious (such as due to syphilis) and vasculitides; disorders of the proximal and peripheral veins, including phlebitis intravenous and thrombosis; including deep vein thrombosis and complications of varicose veins © ¢ Tumors ze : oncology Common cancers, including prostate tumors; ovarian ¢ and pancreatic ¢ and intestines; bowel and colon and stomach stomach; skin and brain; and types of malignant diseases that affect the bone marrow tumors and malignancies affecting the bone marrow 0 (includes 0 cancers of the blood (leukaemias) and lymphoproliferative systems such as Hodgkin's and non-Hodgkin's lymphoma "includes the prevention or treatment of metastatic disease and neoplastic relapses; the syndrome owners of emerging tumors; Gastrointestinal tract: Celiac disease; inflammation of the anus or rectum; Ve gastroenteritis due to acidic LAY build-up; Ail urticaria and Crohn's disease; Sells ulcerative colitis, nonspecific colitis, and irritable bowel disorder; irritable bowel syndrome; non-inflammatory diarrhea; food allergies that affect areas far from the gut, such as migraines; rhinitis; And eczema 26012 AH. accordingly; The present invention also provides a compound of formula (; (ID) «(IC) «(IB) «(IA) Ar (IE) Ye as specified above; or its pharmaceutically acceptable salt; for use as a remedy. YAAY

ay _ — in another attribute; The present invention provides use of a compound of formula (ID) «(IC) «(IB) «(IA) (I) or (IE) as specified above; Or its pharmaceutically acceptable salt in the manufacture of a drug used for treatment. In the context of the present full description; The expression “therapy” also includes “prophylaxis” unless there are clear indications to the contrary. The expressions HNL! disease in a breast suffering from, or at risk of, the aforementioned disease” which includes administering to the breast in need of such treatment a therapeutically effective amount of a compound of the formula “(ID)” (IC) “(IB) (IA)” (T) or (IE) as described herein before; or a pharmaceutically acceptable salt 0 thereof. The present invention provides use of a compound of formula 0 (08; (ID) “(IC)” (IB) or ( IE) as specified above; or dale is pharmaceutically acceptable in the manufacture of a drug used in the treatment of irreversible COPD (fiw) (COPD). The present invention also provides a compound of formula (0; (ID) ) “(IC) “(IB)” (IA) or (IE) as 0 is specified above; or dale is pharmaceutically acceptable for the treatment of COPD. The present invention provides use of a compound of formula (0 (ID) «(IC) «(IB) «(1A) or (IB) as specified above; or dale Pharmaceutically acceptable in the manufacture of a drug used in the treatment of asthma asthma YAAY

en - _ Lind of the present invention provides a compound of the formula (](“ (ID) ”(IC) “(IB) ”(IA) or (IB) as specified above; or its acceptable salt Pharmaceutical for the treatment of asthma The present invention Lif provides a method for the treatment of chronic obstructive pulmonary disease (COPD) (such as irreversible COPD) in a warm-blooded animal such as a human, which includes administration of i 5 who is in need of that treatment a therapeutically effective amount of a compound of the formula “(IB)” (IA) “(I) (10; (ID) or (IB) as described herein before); or a pharmaceutically acceptable salt thereof. The present invention also provides a method for the treatment of asthma in a warm-blooded animal, such as man, which comprises administering to a mammal in need of that treatment a therapeutically effective amount of a compound of formula (0; “(IB) “(IA) (©0; (ID) or (IE) as described herein before; or a pharmaceutically acceptable salt Ve) thereof. For the use of the compound of the invention for the pharmacological treatment of an animal with lal blood such as human; Said ingredient is naturally formulated in accordance with standard pharmaceutical practice for a pharmaceutical formulation.Therefore, the present invention in another aspect thereof provides a pharmaceutical composition comprising the compound of the invention as specified herein above and an adjuvant or diluent carrier ls Vo is pharmaceutically acceptable. In another aspect the present invention provides a process for preparing said composition; Which includes mixing an active ingredient with a pharmaceutically acceptable adjuvant, diluent, or carrier. Depending on the route of administration, the pharmaceutical composition will include; For example from 0.06 to 7959 wt (percentage by weight); For example from 00 to 788 wt; such as 11 to 770 by weight; For example from 1.1 to 7500 by weight of the active ingredient; where all proportions, Ye_weigh, are based on the total composition. YAAY

The pharmaceutical compositions of the present invention can be administered in a standard manner for a disease condition to be treated, for example topically (such as in the lungs and/or airways, or on the skin, in the mouth, in the rectum, or via the gastrointestinal tract). For these symptoms the compounds of the invention Jad are formulated by methods known in the field in the form of, for example (Jaa) 0 aerosols; dry powder formulations; tablets; capsules; syrups; powders ¢ granules granules; aqueous or oily solutions or suspensions (fat) 0 dispersible powders; suppositories; ointments; creams; injectable drops and aqueous or oily solutions or suspensions. The Jal of the invention are those suitable for oral administration ORAL 0 in a dosage unit of, for example a tablet or capsule, which contain from 11 mg to 1 g of the active ingredient. The present invention is pharmaceutical in those suitable for intravenous administration » subcutaneous delivery » or intramuscular. ie a dose of intravenous ¢ induces subcuteanous delivery allall 0 or intramuscular dose ranges from 1.00 mg/kg to 100 mg/kg of the compound; for example in the limits of 11 mg/kg to 10 mg/kg of the compound of the invention; The combination can be given from 1 to ; times a day. The dose may be given into a vein; Subcutaneously and intramuscularly, by injecting a bulk injection of a drug. Alternatively, the dose may be given into a vein by continuous infusion over a period of time. alternatively; The patient may receive a daily oral dose which is equivalent to YAAY

- ao to; Approximately 1 times daily dose by non-gastrointestinal tract; The composition may be administered daily. Another suitable pharmaceutical composition of the present invention is that suitable for administration by inhalation; inhalation may be a particularly useful method of administering the compounds according to the invention when treating patients with Asthma or COPD Chronic Obstructive Pulmonary Disease Jie Respiratory Diseases Effectively in doses in the range (I) given by inhalation Formula compounds can be used micrograms; or on to 110 μg; or 5000 to 1.1 micrograms; for example from 0.1 µg; or 01 to 11 micrograms; or Te to 11 µg; or te to 1 "1 µg; or © to 60 µg.; or © to 0*0 µg; or © to 10 to 1 µg; 000 to 10 µg; or 01 µg; or © to 10 µg; or © to 0 µg; 10 to 10 µg; or 1" to 10 µg; or te to 01 or the active ingredient. In one embodiment of the invention; A pharmaceutical composition comprising the compound of the invention as specified herein is provided; with a pharmaceutically acceptable adjuvant, diluent, or carrier which is formulated for inhalation administration. titrated to give active ingredient; de jay when administered by inhalation; Vo inhalers can be used as hypotensive agents ethanol dispersed in a suitable propellant and with or without additional excipients such as chloro chydrocarbon surfactants; Lubricants or stabilizing agents. Suitable propellants contain or mixtures of heptafluoroalkane (eg hydrofluoroalkane s chiorofluorocarbon) each of which can be (P2275 P134a) from any of these propellants. The preferred propellants are to use it alone or in combination With other propellants and/or a surfactant and/or 0

YAAY

other excipients. Suspensions may also be used or preferably nebulized aqueous solutions; with or without suitable pH and/or sgl adjusting agent either as unit or multiple dose formulations Dry powder inhalers may be used to deliver the active ingredient; alone or in combination with a pharmaceutically acceptable carrier; In the latter case, it is either a finely crumbled powder or as a mixture upon request. The dry powder inhaler can be single-dose or multiple-dose and can use either a dry powder or a powder-containing capsule. The metered dose inhaler knows; Atomizers and dry powder inhalers are good, and there are many different types of these devices available.

0 The invention also relates to combination therapies; Where the compound of the invention is given; or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition or formula comprising the compound of the invention simultaneously or in series or as a combination preparation with another therapeutic agent or other therapeutic agents for the treatment of one or more of the aforementioned conditions. It can specifically treat inflammatory diseases, for example, but not limited to arthritis

Ve sub-rheumatic 0 and osteoarthritis osteoarthritis; allergic rhinitis; chronic obstructive pulmonary disease (COPD) and psoriasis; and cola) the combination of the compounds of the invention with the agents listed below: non-steroidal anti-inflammatory agents (NSAIDs) can hereinafter include non-selective inhibitors of COX-2/COX-1 cyclo-oxygenase whether used Topically or Ji) Nights

‎YAAY

piroxicam¢ or diclofenac; And propionic acids such as naproxen or flurbiprofen ¢ or

fenoprofen or ketoprofen or ibuprofen; Or compounds phenamates methyl acid

mefenamic” or sulindac’s “indomethacin” or azapropazone “and pyrazolones such as

salicylates of » phenylbutazone such as 0 (aspirin) or selective Cox-2 inhibitors (eg meloxicam, celecoxib, rofecoxib, valdecoxib, lumarocoxib, parecoxib and etoricoxib); ©

Glucocorticosteroids and compounds (CINODs) nitric oxide inhibitor of cyclo-oxygenase donors

(whether given topically; oral, intramuscular, or intravenous)

intravenous (or in a joint) or

methotrexate ¢ or leflunomide ¢ or hydroxychloroquine ¢ or d-penicillamine ¢ or auranofin 0; or 5-AY gold preparations given non-intestinal or intragastric

oral route; or to analgesics; or diacerein; Or treatments given into the joint, such as:

hyaluronic acid derivatives; And nutritional supplements such as glucosamine.

The present invention also relates to a combination of the compound of the invention or a pharmaceutically acceptable salt thereof with

Auxiliary or antagonist of cytokine function (includes factors acting on cytokine Vo signaling pathways such as regulators of the socs system including alpha-, beta-, and gamma-interferons; growth factor-like

insulin type 1 Jal (IL) interleukins (IGF-1) 1.17-11.11 and antigens or

inhibitors of interleukins such as canakinra and inhibitors of tumor necrosis factor alpha (TNF-a) such as antibody

Monoclonal anti-TNF antibody (such as “CPD-870 5”) infliximab; adalimumab

TNF receptor antagonists include immunoglobulin molecules (eg

A: 0 (NAAA) and low molecular weight agents such as -pentoxyfylline YAAY

aA — - - The invention further relates to a combination of a compound of the invention or a pharmaceutically acceptable salt thereof with a monoclonal antibody targeting B lymphocytes (MRA-5 ¢(rituximab) CD20 ¢Ail16R) lymphocytes. (HuMax IL-15 5 «CTLA4-Ig 5 «T] The present invention also relates to a combination of a compound of the invention; or a pharmaceutically acceptable salt thereof with a regulator of chemokine receptor function such as an antagonist — CCRI, CCR2, CCR2A, CCR2B, CCR3 , CCR4, CCR5, CCR6, CCR7, CCR8, CCRY, CCR10 and 0811 (for the C-C family ¢ and for CXCRS 3 CXCR1, CXCR2, CXCR3, CXCR4 (for the C-X-C family) and for the 013081 family C-X3-C The present invention also relates to a combination of a compound of the invention; or a pharmaceutically acceptable salt thereof with an inhibitor of group 0 “matrix metalloproteases (MMPs) i.e. collagenases enzymes “stromelysins” gelatinases in addition to an aggrecanase ¢ Similar to collagenase-2 «(MMP-1) collagenase-1 MMP-) stromelysin-2 « (MMP3) stromelysin-1 «(MMP1 3) collagenase-3 » (MMP8) ¢ (MMP9 5 ( MMP-11 (stromelysin-3) (10) and MMP-12 include agents such as -doxycycline The present invention also relates to a combination of a compound of the invention or a pharmaceutically acceptable salt thereof; VO and an inhibitor of leukotriene biosynthesis; or (5-10) S-lipoxygenase inhibitor or anti-5-lipoxygenase activating protein (fenleuton) of <ABT-761 ¢zileuton “Jia (FLAP)” or “tepoxalin” or “Abbott-79175 or “Abbott-85761 or N-thiophene has an in-position (5-substituted)- 2-alkylsulfonamide; 2,6-di-tert-butylphenolhydrazones; or YAAY

methoxytetrahydropyrans | such as ¢Zeneca ZD-2138 or compound SB-210661; 4 pyridinyl 2-cyanophthalene - substituent in position " as L-739010 or compound 2-cyanoquinoline as 1-746530; or indole ie quinoline as 116-591 5 "MK -886 and 1005 © BAYX -Lad The present invention relates to a combination of a compound of the invention or a pharmaceutically acceptable salt thereof and a leukotrienes (LT) receptor antagonist such as <LTC4 5 <B4 and 1,104; and 1124 selected from A group consisting of Jie phenothiazin-3-1s 1.561392; ¢CGS-25019C Je amidino and ontazolast Jw benzoxalamines; benzenecarboximidamides such as BIL 0; and compounds such as: zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro- Voiralukast (CGP 45715A), and BAY x 7195. 245913, furthermore the present invention relates to a combination of a compound of the invention or a pharmaceutically acceptable salt thereof; of a phosphodiesterase enzyme (PDE) such as methylxanthanine comprising theophylline; an aminophylline; and a selective inhibitor of PDE isoenzyme comprising PDE4 Lie as an activator with its homolog 0 of PDE4D or an inhibitor of PDES. Lad of the present invention relates to a combination of a compound of the invention or a pharmaceutically acceptable salt thereof; An antagonist of the histamine receptor of the first type, such as: cetirizine, loratadine, desloratadine, fexofenadine, acrivastine, terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine, promethazine, cyclizine, or mizolastine; YAAY

— 110 Or by channel, ctopically or topically, orally, and it is used orally. parenterally digestive The present invention also relates to a combination of a compound of the invention or a pharmaceutically acceptable salt thereof; and a histamine-type gastroprotective antagonist or proton pumping omeprazole receptor antagonist (e.g. II. ©) in combination of the compound of the invention or a pharmaceutically acceptable salt thereof and the Jad antagonist of the fourth type also relates. histamine receptor The present invention also relates to a combination of the compound of the invention or a pharmaceutically acceptable salt with it and an agent: Jie alpha-1/alpha-2 adrenoceptor due SU receptor cofactor propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine , pseudoephedrine, Ve naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, tramazoline hydrochloride or ethylnorepinephrine hydrochloride. Anti-secretory 0: such as (M33 and 1412 M1) anti-atropine, hyoscine, glycopyrrolate, ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine.

YAAY

1011 - - The present invention also relates to a combination of one of the compounds of the invention or a pharmaceutically acceptable salt thereof; With a beta-adrenoceptor adjuvant (including beta receptor subtypes 1 through ;) such as: isoprenaline, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, pirbuterol, or indacaterol 8 Or a chiral enantiomer of which it is chiral enantiomer. The present invention also relates to a combination of a compound of the invention or a pharmaceutically acceptable salt thereof and sodium cromoglycate or nedocromil sodium Jie. The present invention also relates to a combination of a compound of the invention; Or a pharmaceutically acceptable salt thereof with: glucocorticoid, such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate. Nuclear hormone receptors such as PPARs The present invention also relates to a combination of the compound of the invention; or a pharmaceutically acceptable salt thereof; With Yo immunoglobulin (Ig), an Ig preparation, an antibody, or an antibody that modulates Ig function such as an IgE antibody (such as omalizumab). The present invention also relates to a combination of the compound of the invention; or acceptable salt to fish from it; And another anti-inflammatory agent used topically or systemically, such as: YAAY

— VY — thalidomide or a derivative thereof, a retinoid, dithranol or calcipotriol. The present invention also relates to a combination of the compound of the invention; or a pharmaceutically acceptable salt thereof;

Jie corticosteroids, compounds ¢ thiopurines, and immunomodulatory agents such as olsalazine © . budesonide The present invention relates to a combination of the compound of the invention; or a pharmaceutically acceptable salt thereof with an antibacterial agent such as a penicillin derivative, a tetracycline, a macrolide, a beta-lactam, a fluoroquinolone, metronidazole, an inhaled aminoglycoside; Ve: or an antiviral agent including acyclovir, famciclovir, valaciclovir, ganciclovir, cidofovir, amantadine, rimantadine, ribavirin, zanamavir and oseltamavir; a protease inhibitor such as indinavir, nelfinavir, ritonavir, and saquinavir; a nucleoside reverse transcriptase inhibitor such as didanosine, lamivudine, stavudine, zalcitabine or zidovudine; or a non-nucleoside reverse Vo transcriptase inhibitor such as nevirapine or efavirenz. The present invention also relates to a combination of the compound of the present invention; or a pharmaceutically acceptable salt thereof; or a receptor blocker » calcium channel blocker and a cardiovascular agent such as an angiotensin-converting enzyme inhibitor » beta-adrenoceptor blocker liu adrenaline

1.

“converting enzyme (ACE) or vascular tensor receptor-7 antagonist; or a lipid-reducing agent such as

fibrate statin; Or a regulator for the shape of the blood cell, pentoxyfylline Jie ¢, or a clot analyzer, or an antidote

For clotting, such as a platelet aggregation inhibitor.

The present invention also relates to a combination of the compound of the invention; or a pharmaceutically acceptable salt terminating agent and © agent affecting Jie ONS an antidepressant (eg sertraline ); Or an anti-Parkinson's drug

Parkinsonian drug such as deprenyl, L-dopa, ropinirole, pramipexole) ¢ and an MAOB comb such as

selegine and rasagiline; and a comp inhibitor such as tasmar-2, an A-2 antagonist, and a sale inhibitor (sale) uptake

dopamine; an NMDA antagonist, a nicotine adjuvant, a dopamine adjuvant, or a synthase inhibitor

0

The present invention also relates to a combination of the compound of the invention or a pharmaceutically acceptable salt thereof with an agent

For the treatment of acute or chronic pain, such as analgesics that act centrally or peripherally (such as opioids or

carbamazepine, phenytoin, sodium valproate, or (opioid or derivative 4—i derivative)

camitryptiline or other anti-depressant agent-s » or other antidepressant agent

-non-steroidal anti-inflammatory agent 0

The present invention also relates to a combination of the compound of the invention or a pharmaceutically acceptable salt thereof with an agent

A local anesthetic used locally or through the digestive tract (including inhalation) such as

lignocaine or a derivative thereof. YAAY

The compound of the present invention, or a pharmaceutically acceptable salt or solute thereof, may also be used in combination with raloxifene, or a biphosphonate anti-osteoporosis agent comprising a hormonal agent such as veg. alendronate as the present invention further relates to a combination of the compound of the invention; or a pharmaceutically acceptable salt or solute thereof Inhibitor (Y) (PAF) Anti-platelet activating factor (¥) ctryptase inhibitor Enzyme (i): with © Molecule adhesion inhibitors including (©) IMPDH (;) ¢ (ICE) interleukin tyrosine kinase converting enzyme inhibitor Jie kinase inhibitor (V) ¢ cathepsin (1) “VLA-4 anti-serine / any” Gefitinib or Imatinib mesylate (eg ~MAP 4 Jak3) can see J BtK (eg 8) or “kinase A” or protein INK 038 (eg kinase MAP Jase (eg threonine kinase) A) ¢ (cylin dependent kinase Jie) involved in cell cycle regulation kinase O (KK J. O0 (V+) B23 BI; (9) glucose-6 phosphate kinin receptor antagonist dehydrogenase inhibitor allopurinol as xanthine oxidase inhibitor (11) ¢ colchicine Jue anti-gout agent probenecid, sulfinpyrazone or as ¢ uricosuric agent uric acid (VY) « growth hormone secretagogue sail Hormone stimulating factor (YY) « benzbromarone V0 ((TGFB) transforming growth factor saill transforming factor (V€) 05 fibroblast growth factor as fibroblast growth factor Essential (11) (PDGF) Platelet 014-(colony-stimulating factor for granulocyte macrophage (VV) colony-stimulating factor (bFGE)

NKP- or 11163 as tachykinin NK1 receptor antagonist (V4) “capsaicin aS (VA) $(CSF 101-77 as elastase inhibitors) €D-4418 (01) or “(talnetant) SB-233412 or “608C nitric oxide (YY) alpha reductase inhibitor; TNF factor-converting enzyme inhibitor (71) or 20-0892; (YY) «(INOS) synthase

YAAY

#01 — transgenic on 1112 cells (eg antigen 087112); (Y£) p38 inhibitor; (Y0) an agent modulating the function of a Toll-like receptor §(TLR) (77) an agent modulating the activity of purine receptors such as 027©7; or (77) an inhibitor of transcription factor activation such as 007168 or <API or STATS Lind may use the compound of the invention; or a pharmaceutically acceptable salt or solute thereof in combination with an existing therapeutic agent for the treatment of cancer; Suitable agents include: an anti-proliferative/anti-neoplastic drug or a combination die as used in the medical treatment of tumors such as an alkylating agent - (eg cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil , busulphan or a ¢(nitrosourea) an antitumor antibiotic (such as an anthracycline such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin or mithramycin); or an antimitotic agent similar to venica vinca alkaloid such as vincristine, vinblastine, vindesine or vinorelbine, or a 12-M Yo-taxol or taxotere ¢ or a topoisomerase inhibitor (such as etoposide, teniposide, amsacrine, topotecan or a camptothecin 'cytostatic agent' such as an antioestrogen (such as tamoxifen, (toremifene, raloxifene, droloxifene or iodoxyfene) or an oestrogen receptor antagonist (such as fulvestrant or antagonist) of bicalutamide, flutamide, nilutamide or Ji) antiandrogen (cyproterone acetate Y) or anti-LHRH (eg goserelin, leuprorelin or YAAY)

011 — — (buserelin or a progestogen (eg megestrol acetate ); or an aromatase inhibitor (eg od (anastrozole, letrozole, vorazole or exemestane) a Ji Sa-reductase inhibitor) finasteride; an agent that inhibits the proliferation of cancer cells (such as a metalloproteinase inhibitor such as Jmarimastat) an inhibitor of the function of the urokinase ¢ (urokinase plasminogen Lads hada) function of growth factor Jie antibody to a growth factor such as anti-2b antibody trastuzumab or antibody to [C225] cetuximab or a famesyl transferase inhibitor or a tyrosine kinase PA inhibitor or a serine/threonine kinase inhibitor EGFR 4lilal tyrosine kinase such as: N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine Ye (gefitinib, AZD1839), N-( 3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) or 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3 - morpholinopropoxy)quinazolin-4-amine (CI 1033)), or an inhibitor of the platelet-derived growth factor family; or to an inhibitor of the hepatocellular growth factor family; VO anti-angiogenic agent such as that which inhibits the effects of vascular endothelial growth factor (eg anti-VEGF bevacizumab; compound disclosed in IPOs A 770: and Ao 71/7 9 and +o YO L8, 7; or a compound acting by another mechanism (eg linomide; an inhibitor or antagonist of integrin ovp3 function); YAAY

11 - Vascular destroying agent combretastatin A4 Jie ¢ or compound disclosed in international patent applications: 4474 0/1774 Gu Y/w tqq/l rmtmt and SANIT 7 agent used in Treatment with antistimulants such as those related to targets mentioned by Je © 19152503 or an antistimulant anti-tras agent used in a gene therapy method such as the method of replacing abnormal genes such as the 53m abnormal gene or abnormal genes (BRCAI or 88* 02 or GDEPT (gene related proprietary enzyme therapy); or methods such as those using cytosine deaminase, thymidine kinase, or bacterial nitroreductase and methods to increase patient tolerance to chemotherapy or 0 Radiation therapy such as multi-drug resistant gene therapy; an agent used in a Jie immunotherapy method Methods used outside and inside the body to increase the generation of immunity to patient tumor cells such as infection transmission to cells by cytokines such as 4 interleukin 2, interleukin or Lad factor, to colonize large phagocytic cells of granulosa cells; methods to reduce the energy of oT cells and methods using LDA immunity such as dendritic cells that have been infected with cytokines or methods using tumor cell lineages that have been transmission of infections to it by cytokines; methods using antibodies to Jal gad's genetic variants; In form AT the present invention provides a pharmaceutical product that includes in combination; contains an active ingredient that is a compound of the formula ( ); (H); “(ID) “(IC)” (IB) or (IE) as described here before; or a pharmaceutically acceptable salt thereof; And at least one other active ingredient selected from: YAAY

C101 — phosphodiesterase-cofactor enzyme - adrenoceptor activator .82. The rate of chemokine receptor function. 0 protease inhibitorsteroidal glucocorticoid receptor agonist .anticholinergic agent methylxanthines .non- non-steroidal glucocorticoid .steroidal glucocorticoid receptor agonist A pharmaceutical product according to this model can be for example a pharmaceutical composition comprising 0 of the first and additional active ingredient in a mixture. alternatively; A pharmaceutical product may include; For example, the first active ingredient separately from the additional active ingredient, each in a formulation suitable for simultaneous, sequential, or separate administration to a patient in need. The pharmaceutical product of the current model is for special use in the case of treating diseases of the respiratory system (frequency COPD 0 asthma or rhinitis Ve) Examples of phosphodiesterase inhibitors that are used in the pharmaceutical product according to this model contain an inhibitor PDE4 inhibitor as isoform 00140; PDE3 inhibitor and inhibitor; [0 Examples contain the following compounds:- YAAY

- 101 = (Z)-3-(3,5-dichloro-4-pyridyl)-2-[4-(2-indanyloxy-5-methoxy-2-pyridyl]propenenitrile,

N-[9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk][1,4]benzodiazepin-3(R)-yl]pyridine-3 -carboxamide (CI-1044), 3-(benzyloxy)-1-(4-fluorobenzyl)-N-[3-(methylsulphonyl)phenyl]-1H-indole-2-carboxamide, ©(1S-ex0)-5- [3-(bicyclo[2.2.1]hept-2-yloxy)-4-methoxyphenyl]tetrahydro-2(1H)-pyrimidinone (Atizoram),

N-(3,5,dichloro-4-pyridinyl)-2-[ 1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2- oxoacetamide (AWD-12-281),

B-[3-(cyclopentyloxy)-4-methoxyphenyl]-1,3-dihydro-1,3-dioxo-2H-isoindole-2- 01 propanamide (CDC-801),

N-[9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk][1,4]benzodiazepin- 3(R)-yl]pyridine-4 -carboxamide (CI-1018), cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid (Cilomilast), Yo 8-amino-1,3-bis(cyclopropylmethyl)xanthine (Cipamphylline),

N-(2,5-dichloro-3-pyridinyl)-8-methoxy-5-quinolinecarboxamide (D-4418),

YAAY

— Vy. — 5-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-iminothiazolidin-4-one (Darbufelone), 2-methyl-1-[2-(1-methylethyl)pyrazolo[1,5-] a]pyridin-3-yl]-1-propanone (Ibudilast), 2-(2,4-dichlorophenylcarbonyl)-3-ureidobenzofuran-6-yl methanesulphonate (Lirimilast), (-)-(R)-5-(4 -methoxy-3-propoxyphenyl)-5-methyloxazolidin-2-one (Mesopram), ©(-)-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b- hexahydro-6-(4- diisopropylaminocarbonylphenyl)-benzo[c][1,6]naphthyridine (Pumafentrine), 3-(cyclopropylmethoxy)-N-(3,5-dichloro-4-pyridyl)-4-(difluoromethoxy)benzamide (Roflumilast), the N-oxide of Roflumilast, Ye 5,6-diethoxybenzo[b]thiophene-2-carboxylic acid (Tibenelast), 2,3,6,7-tetrahydro-2-(mesitylimino)-9,10- dimethoxy-3-methyl-4H-pyrimido[6,1- alisoquinolin-4-one (trequinsin) and 3-[[3-(cyclopentyloxy)-4-methoxyphenyl]-methyl]-N-ethyl-8-(1- methylethyl)-3H-purine-6-amine (V-11294A). Yo, which can be used in the pharmaceutical product, Bo-adrenoceptor. Examples of auxiliary receptors contain metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol according to this form.

YAAY

111 - - (eg (sie) formoterol o sulphate eg s—¢)salmeterol ' (fumarate eg terbutaline, orciprenaline, bitolterol ' (xinafoate) (eg '(mesylate) pirbuterol or indacaterol Br-adrenoceptor can be a long-acting adjuvant 82; (eg J) formoterol «(xinafoate eg Jour (Ic) bambuterol « fumarate eg » TA 2005) carmoterol «( hydrochloride, known chemically as: 2(1H)-Quinolone, 8-hydroxy-5-[1-hydroxy-2-[[2-(4-methoxy-phenyl)-1-methylethyl]- amino Jethyl]-monohydrochloride, [R-(R*,R*)], which was also specified by Chemical Abstract Service Registry Number 137888-11-0.

CAS no. 312753-06-3; QAB-) disclosed in US Application No. 4597494854); Indecterol 0 9) Ju formanilide derivatives: 3-(4-{[6-({(2R)-2-[3-(formylamino)-4-hydroxyphenyl]-2-hydroxyethyl} amino) hexyl]oxy }-butyl)-benzenesulfonamide as disclosed in International Application No. Yoo Y/VIAFVY; Jie benzenesulfonamide derivatives: 3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxy-methyl)phenyl]ethyl }amino)- Vo hexyl]oxy}butyl)benzenesulfonamide as disclosed on 88157//7007; aryl aniline receptor cofactors disclosed in YO000/Y uo 7114/7107 1) indole derivatives disclosed in 077971/7004; in YAAY

111 - US dial “a0 for 4???”; Compounds of series 159797 GSK “GSK 159802” GSK GSK 642444 +1 and 678007 .GSK Examples of a chemokine receptor function modifier that can be used in a pharmaceutical product according to the present embodiment contain receptor antagonist 0011. © Examples contain inhibitor The protease enzyme that can be used in the pharmaceutical product according to the current model contains the neutrophil elastase enzyme MMP12 inhibitor. Examples of the steroidal glucocorticoid receptor agonist that can be used in the current model contain budesonide, fluticasone (eg mometasone ) propionate ester (eg “(furoate ester) beclomethasone Ve (eg propionate —VV) or “(17,21-dipropionate esters) ciclesonide , loteprednol (eg etabonate); , «( propionate ester ‎Ji prednisone, tipredane, steroid esters : 6a,9a-difluoro-17a-[(2-furanylcarbonyl)oxy]-11B-hydroxy-16a-methyl-3-oxo-androsta- Yo 1,4-diene-17B-carbothioic acid S-fluoromethyl ester, 6a,,9a-difluoro-11p-hydroxy-16a.- methyl-3-0xo-17a-propionyloxy-androsta-1,4-diene- 17B-carbothioic acid S-(2-oxo- ‎tetrahydro-furan-3S-yl) ester and 6a, 9a-difluoro-11B-hydroxy-16c-methyl-17o-[(4- methyl-1,3 -thiazole-5-carbonyl)oxy]-3-oxo-androsta-1,4-diene-17p-carbothioic acid S- fluoromethyl ester, steroid esters Ye.YAAY

11” - - according to 4129535 steroids “DE according to 2002/00679” 2005/041980 or GSK steroids 870086 “685695 0816 and 799943. Examples of antisecretory agent include methylxanthines that can be used In the present embodiment on a muscarinic receptor antagonist (eg antagonist M1 142 or M3 alias Jie M3 (eg ipratropium (eg le)tiotropium ) bromide Example “(bromide oxitropium (eg Jiu eg tolterodine, pirenzepine, telenzepine, ) bromide R R-glycopyrronium bromide) glycopyrronium bromide A mixture of R,S- and S,R- glycopyrronium bromide ); mepensolate (eg “(bromide) Jw quinuclidine derivative : 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)- 1 - azonia- Ye bicyclo[2.2.2]octane bromide as disclosed in US Patent No. 00 cv +00 AL /Y quinuclidine derivatives as disclosed in International Applications No. 0870432/7007 16439//7006 and German order 015448; or GSK 656398 or GSK 961081 Ve. Examples of a non-steroidal A) glucocorticoid receptor modifier that can be used in the present model contain those that have been Described in International Application 416417 6/0 .001 YAAY

1100 Experimental Method: The following abbreviations were used:

N,N-dimethylformamide No. dimethylsulphoxide i DMSO el 1

N,N-dimethylacetamide IN .dichloromethane Na at the proton frequency of Varian Unity Inova on the NMR spectrometer. In the examples, spectra were measured and a megahertz. The reaction mixture was heated with microwave radiation 5000 nm or 9060 nm. Examples with the Kiraly Center in CEM Discover Microwave may show this done using ©.

Agilent 1100 on either MS spectra as a mixture of rotomers. NMR spectra measured Hewlett Packard HP 1100 MSD G1946A, MSD 019460 spectrometer, or preparative Waters Symmetry® using HPLC column separations

Le) or aqueous acetonitrile: ammonia 71,1 using Xterra® lysate

Phenomenex from NH2 and SCX resin was obtained. acetonitrile : ammonium acetate 0 : Names of the compounds were identified using the Gemini® Commercial Chemical Nomenclature Software Package Indicator -ACDLABS 8.0

YAAY

-110- A brief explanation of the drawings free base 17 X-ray diffraction model for image M in an example: 1) Free base figure 117 X-ray diffraction model for image 3 in example: 71 Free-base figure You (©): X-ray diffraction pattern for the m-image in the free-base example 7610 Fig. (;): X-ray diffraction pattern for the m-image in the free-base example © 117 Figure (0) X-ray diffraction model for image M in the free base example 167 Figure (6): X-ray diffraction model for image 3 in the free base example 117 Figure (7): X-ray diffraction model for image © In the example of the free base VAY Figure (4): X-ray diffraction pattern for image 5 In example saccharide salt 111 In example A Figure (9): X-ray diffraction pattern for image 0

Tosylate salt 067 X-ray diffraction pattern of image M in example 01:) Fig. Tosylate salt 167 X-ray diffraction pattern of image 38 in example 11: Fig. hydrochloride in . Example 67 Salt A X-ray diffraction model of the image Ka

YAAY

- 111 - Detailed description (1) Example N-Cyclopropyl-3-[3-(2-fluoro-benzylamino)-2-oxo0-2H-pyrazin-1-yl}-4-methyl-benzamide 0 2: F > ory 0

N N

H H

0 © ¢ 3-[(Cyanomethyl)amino]-4-methyl-benzoic acid, methyl ester (00 g) in +,+) + 3-amino-4-methyl-benzoic acid, methyl ester from lia To a solution followed by the addition of (Je 17,1( N,N-diisopropylethylamine) tetrahydrofuran hydrogen was added ml. The reaction mixture was heated on reflux under an atmosphere of 51 (bromoacetonitrile

A gall jue is done. ethyl acetate h. Water was added and the mixture, VY, was extracted with stirring for 00 minutes. The collected organic matter was mixed with brine 3, dried (504 p11), filtered, and the solvent was removed under pressure. g) 1) Reduced to obtain the subtitle compound as a solid

MS: APCI(+ve) 178 (M+H+). 1H NMR (101150-06, 300MHz) 7.31 (1H, dd), 7.23 - 7.17 (2H, m), 5.91 (1H, t), 4.33 (2H, d), 3.83 (3H, s), 2.17 ( 3H, s). Yo

YAAY

117-(b): 3-(3,5-Dibromo-2-oxo-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methyl ester to ¢3-[(cyanomethyl) amino]-4-methyl-benzoic acid, methyl ester (ex. 1 0 g) (Je©+) 1,2-dichlorobenzene and oxalyl bromide (11.0 mL) added. The reaction was heated at 100 C for ; Hours before removing the volatiles under reduced pressure and subjecting the remaining © to residue azeotroped twice using p (p1h). After purification (chromatograph 2 and filtering with (dichloromethane) the subtitle compound was obtained as solid V,Y g) .04+11 405 /403 /401 MS: APCI(+ve) 1H NMR 5 (DMSO-d6, 400MHz) 8.08 (1H, dd), 7.87 (1H, d), 7.46 (1H, d) , 7.29 (1H, s), (3H, 5), 2.25 (3H, 3). 3.92 0 (c): N-Cyclopropyl-3-[3-(2-fluoro-benzylamino)- 2-oxo-2H-pyrazin-1-yl]-4-methyl- benzamide to a stirred solution of: 3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)- 4-methyl-benzoic acid, methyl ester (Example Ab (a > 1, VO) in a Jala (Je) tetrahydrofuran vial microwaved (YA) triethylamine μl) YY) 2-fluoro-benzenemethanamine μl was added ). The reaction mixture was stirred overnight before adding (+,)Y) amine cyclopropyl mL) and Y) cyclopentylmagnesium bromide mL in 150 “diethyl ether) µl) dropwise. After stirring for 1 minute; Y) ethanol mL) and then ammonium formate (¥, + g) and 10 palladium were added to YAAY

- VA =

Jip Vee is accurate at To carbon (0 mg). The reaction mixture was heated in a microwave for filtrate concentrated in ethanol cooling to room temperature; Filtration and washing with: ammonia 7,1 filter solution “Gemini” (vacuum HPLC column. After purification in aug mg). 0A) the title compound was obtained as a solid (acetonitrile

MS: APCI(+ve) 393 (M+H+). © 111 NMR & 101150-06, 400MHz) 8.44 (1H, d), 7.90 - 7.85 (2H, m), 7.76 (1H, d), 7.50 (1H, d), 7.35 - 7.26 (2H, m), 7.20 - 7.13 (2H, m), 6.82 (1H, d), 6.72 (1H, d), 4.64 (1H, dd), 4.54 (1H, dd), 2.89 - 2.81 (1H, m), 2.12 (3H, 5 ), 0.72 - 0.66 (2H, m), 0.58 - 0.53 (2H, m). (C1) and purified in a manner similar to example 1) The following examples were prepared £97 (Table 0 (7) as N-Cyclopropyl-4-methyl-3-[3-(4-methyl-1- piperazinyl)-2-oxo-1 (2H)-pyrazinyl]-benzamide (V) Example N-Cyclopropyl-3-[3-[[3-(dimethylamino)propyl]amino]-2-oxo-1 ( 2H)-pyrazinyl]-4- Yo methyl- benzamide (4) as N-Cyclopropyl-4-methyl-3-[3-[[3-(4-methyl-1 -piperazinyl)propyl]amino]- 2-oxo-1(2H)- pyrazinyl]-benzamide

YAAY

- #11 - (5) Example N-Cyclopropyl-3-[3-[[2-(dimethylamino)ethyl]Jamino]-2-oxo-1(2H)-pyrazinyl]-4-methyl- benzamide (1) Example N-Cyclopropyl-4-methyl-3-[3-[[3-(4-morpholinyl)propyl]amino]-2-oxo-1(2H)- © pyrazinyl]- benzamide (V ) Ex. N-Cyclopropyl-4-methyl-3-[3-(methylamino)-2-oxo-1(2H)-pyrazinyl]-benzamide, (A) Ex. N-Cyclopropyl-3-[ 3-[(3-methoxypropyl)amino]-2-oxo- 1 (2H)-pyrazinyl]-4-methyl- Ve benzamide (4) Example N-Cyclopropyl-4-methyl-3-[2-ox0 -3-[[2-(2-pyridinyl)ethyl Jamino]-1(2H)-pyrazinyl]- benzamide (01) as 5

N-Cyclopropyl-4-methyl-3-[2-ox0-3-[(2-phenylethyl)amino]-1(2H)-pyrazinyl]-benzamide

— 1071 (VY) eg N-Cyclopropyl-4-methyl-3-[2-0x0-3-[(phenylmethyl)amino}-1(2H)-pyrazinyl]- benzamide ( VY ) Fig. N-Cyclopropyl-4-methyl-3-[2-0x0-3-(phenylamino)-1(2H)-pyrazinyl]-benzamide © ( 1 9 Example N-Cyclopropyl-3-[3-[[ (3-methoxyphenyl)methyl[amino]-2-oxo- 1(2H)-pyrazinyl]-4- methyl-benzamide ( \¢ ) Example -(2-0*:0-1)211-[absorbed [Al-Bataas 1[1-to-interrupt (a nysta: haram-1-interruption-4-7)-4]]]-3]-3-Et4-1,161 Ye pyrazinyl]-N-(1-methylpropyl)-benzamide (10) like N-Cyclopropyl-4-methyl-3-[2-0x0-3-[[(1R)-1-phenylethylJamino]-1 (2H)-pyrazinyl]- benzamide (V1) Example Ne

N-Cyclopropyl-4-methyl-3-[2-ox0-3-[[(1R)-1,2,3,4-tetrahydro-1-naphthalenyl] amino]- 1(2H)-pyrazinyl}-benzamide

YAAY

1710 - (1 example (No

N-Cyclopropyl-3-[3-[[(1R)-2,3-dihydro-1H-inden-1-ylJamino]-2-oxo- 1(2H)-pyrazinyl]- 4-methyl-benzamide ( 1 A ) Example N-Cyclopropyl-4-methyl-3-[3-[(1-methyl-1-phenylethyl)amino]-2-oxo-1(2H)-pyrazinyl]- © benzamide (V4) Example N-Cyclopropyl-4-methyl-3-[3-[methyl(phenylmethyl)amino]-2-oxo- 1 (2H)-pyrazinyl]- benzamide (01) to 0

N-Cyclopropyl-3-[3-[[(4-methoxyphenyl)methylJamino]-2-oxo0-1(2H)-pyrazinyl]-4- methyl-benzamide (VV) Example N-Cyclopropyl-4-methyl -3-[2-0x0-3-[[(1S)-1-phenylethylJamino]-1(2H)-pyrazinyl]- benzamide Yo ( YY ) Example N-Cyclopropyl-3-[3-[[ (3-fluorophenyl)methyl[Jamino]-2-oxo-1(2H)-pyrazinyl] -4-methyl-benzamide

YAAY

- NYY - ( ¥ ¥) Example N-Cyclopropyl-4-methyl-3-[2-0x0-3-[(2-pyridinylmethyl)amino]-1(2H)-pyrazinyl]- benzamide (Y ¢) Example N-Cyclopropyl-4-methyl-3-[2-0x0-3-[(3-pyridinylmethyl)amino]-1(2H)-pyrazinyl]- © benzamide (Yo) Example N Example Ye

N-Cyclopropyl-3-[3-[[(2-methoxyphenyl)methyl]amino]-2-oxo0-1(2H)-pyrazinyl]-4- methyl-benzamide (YV) Example 3-[3- [(1H-Benzimidazol-2-ylmethyl)amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-4- methyl-benzamide Yo (YA) Ex. N-Cyclopropyl-4-methyl -3-[2-0x0-3-[(3-quinolinylmethyl)amino]- 1(2H)-pyrazinyl]- benzamide

YAAY

1" — ( Y4) Example N-Cyclopropyl-4-methyl-3-[2-ox0-3-[[(1,2,3,4-tetrahydro-3-quinolinyl)methylJamino]- 1( 2H)-pyrazinyl]-benzamide (V+) eg N-Cyclopropyl-3-[3-(3,4-dihydro-2(1H)-isoquinolinyl)-2-oxo-1(2H)-pyrazinyl]- 4- © methyl-benzamide Example (1a) N-Cyclopropyl-4-methyl-3-[2-0x0-3-[(2-thienylmethyl)amino]-1(2H)-pyrazinyl]- benzamide 0 Y ) Example > 0 3-[3-[(1,3-Benzodioxol-5-ylmethyl)amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-4- methyl- benzamide (eg) ¥0

N-Cyclopropyl-3-[3-[[(4-fluorophenyl)methyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl- benzamide Yo ( ve ) Example N-Cyclopropyl- 4-methyl-3-[2-0x0-3-[[ 1-phenyl-2-(1-pyrrolidinyl)ethylJamino]-1(2H)- pyrazinyl]-benzamide (Ve) Ex. N-Cyclopropyl-4 -methyl-3-[3-[[(1-methyl-4-phenyl-4-piperidinyl) methyl ]amino]-2-oxo- Ye 1(2H)-pyrazinyl]-benzamide

YAAY

- 1174 — ( 1 ) Example N-Cyclopropyl-4-methyl-3-[2-0x0-3-[(3-phenylpropyl)amino]-1(2H)-pyrazinyl]- benzamide (vv ) Example N-Cyclopropyl-3-[3-[[[4-(1,1-dimethylethyl)phenylJmethyl]amino]-2-o0x0-1(2H)- © pyrazinyl]-4-methyl-benzamide (YA ) Example N-Cyclopropyl-4-methyl-3-[2-0x0-3-[[(1R)-1-phenylpropyl]amino]-1(2H)-pyrazinyl]- benzamide ( Ya ) Example > 0

Example N-Cyclopropyl-4-methyl-3-[3-[[[3-[(4-methyl-1-piperazinyl)methyl] phenyl methyl] amino]-2-oxo-1(2H)-pyrazinyl]-benzamide Vo ( 1 ) Example N-Cyclopropyl-4-methyl-3-[3-[[[2-[(4-methyl-1-piperazinyl)methyl |phenyl Jmethyl] amino]-2-oxo-1(2H) )-pyrazinyl]-benzamide (example) L

N-Cyclopropyl-4-methyl-3-[3-[[(4-methylphenyl)methyl]amino]-2-oxo-1(2H)- Ye pyrazinyl]-benzamide

YAAY

—\Yo — ( ¢ ¥) Example 3-[3-[(Cyclohexylmethyl)amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl- benzamide ( ¢ ) Example 3-[3-[([1,1'-Biphenyl]-2-ylmethyl)amino]-2-oxo0-1(2H)-pyrazinyl]-N-cyclopropyl-4-© methyl-benzamide ( £0) Ex. N-Cyclopropyl-4-methyl-3-[2-0x0-3-[[(4-phenoxyphenyl)methyl}amino]-1(2H)- pyrazinyl]-benzamide ( £1 ) Jas Ve

N-Cyclopropyl-4-methyl-3-[3-[[(3-methylphenyl)methylJamino]-2-oxo0-1(2H)- pyrazinyl]-benzamide (example) P

Example N-Cyclopropyl-4-methyl-3-[2-0x0-3-[[(1S)-1,2,3,4-tetrahydro- 1-naphthalenylJamino]-1(2H)-pyrazinyl]-benzamide ( £4 ) Example N-Cyclopropyl-3-[3-[(2,2-dimethylpropyl)amino]-2-oxo- 1 (2H)-pyrazinyl]-4-methyl- Ye benzamide

YAAY

171 - . μL (YA) triethylamine as salt More amine is used when there is (0 min in a microwave) before cooling Te for 2 VY) (b) heating was required for initial displacement

Y) cyclopentylmagnesium bromide 5 ml) +, ¥) cyclopropyl amine and then add μl) dropwise. YOu » diethyl ether molar in

La) preparative “Gemini” elutriate solution (HPLC column final purified with (z)©). acetonitrile : trifluoroacetic acid (1) table 0 ZN “yy oN

H0

MS

IH NMR. 5 (DMSO-d6) [M+H]+ R Example m/z 8.43 (1H, d), 7.85 (1H, dd), 7.71 368 x (1H, d), 7.47 (1H, d) , 6.99 (1H, d), 6.97 (1H, d), 3.76 - 3.64 (4H, m), 7 2.88 - 2.81 (1H, m), 2.39 (4H, 1), (UN 2.19 (3H) , 5), 2.09 (3H, 5), 0.71 - > 0.66 (2H, m), 0.58 - 0.53 (2H, m) 8.44 (1H, d), 7.86 (1H, dd), 7.73 370 “~NH » ( 1H, d), 7.50 - 7.44 (2H, m), 6.84 (1H, d), 6.65 (1H, d), 3.43 - 3.26 (2H, m), 2.89 - 2.81 (1H, m), 2.26 (2H, 1), 2.12 (6H, 5), 2.10 (3H, 5), m 1.69 (2H, quintet), 0.71 - 0.65 (2H, m), 0.58 - 0.53 (2H, m) 8.44 (1H, d ), 7.86 (1H, dd), 7.73 425 ~~ .(1H, d), 7.52 - 7.46 (2H, m), 6.84 (1H, d), 6.65 (1H, d), 3.43 - 3.27 (2H, m ), 2.89 - 2.81 (1H, m), 2.43 - 2.23 (10H, m), 2.13 (3H, 5), 2.10 07 (3H, 5), 1.76 - 1.66 (2H, m), 0.72 - (Ne 0.66 ( 2H, m), 0.58 - 0.53 (2H, m)

YAAY

— 111 - 8.44 (1H, d), 7.86 (1H, dd), 7.73 356 (1H, d), 7.48 (1H, d), 7.08 (1H, 1), SNH 6.86 (1H, d), 6.68 (1H , d), 3.48 - 3.32 (2H, m), 2.89 - 2.80 (1H, m), 2.45 (2H, td), 2.18 (6H, s), 2.10 J (3H, 5), 0.72 - 0.66 (2H, m), 0.58 - x 0.53 (2H, m 8.44 (1H, d), 7.86 (1H, d), 7.73 412 “Ny 1 (1H, s), 7.65 (111, 0, 7.49 (1H, d) ), H 6.85 (1H, dd), 6.66 (1H, dd), 3.58 (4H, 1), 3.46 - 3.28 (2H, m), 2.90 - 2.79 (1H, m), 2.41 - 2.30 (6H, m) , 2.10 (3H, s), 1.73 (2H, quintet), N 7 0.73 - 0.65 (2H, m), 0.60 - 0.52 the (2H, m) 8.44 (1H, d), 7.86 (1H, dd ), 7.73 299 v (1H, d), 7.48 (1H, d), 7.41 - 7.36 (1H, m), 6.86 (1H, d), 6.66 (1H, SNH d), 2.88 - 2.81 (4H, m) , 2.10 (3H, s), 0.71 - 0.66 (2H, m), 0.58 - 0.53 2H, m 8.44 (1H, d), 7.86 (1H, dd), 7.74 357 A (1H, d), 7.48 (1H, d), 7.35 (1H, 1), 685 (1H, d), 6.66 (1H, d), 3.45 - SSN 28 (4H, m), 3.23 3H, 5), 2.89 - 2.81 (1H, m), 2.10 (3H, s), 1.81 H (2H, quintet), 0.72 - 0.66 (2H, m), 0.58 - 0.53 (2H, m 8.51 - 8.48 (1H, m), 8.43 (1H, d), 390 a 7.86 ( 1H, dd), 7.74 - 7.68 (2H, m), 7.48 (1H, d), 7.44 (1H, 1), 7.29 7 (1H, d), 7.24 - 7.20 (1H, m), 6.87 ~~ “ ( 1H, d), 6.69 (1H, d), 3.77 - 3.62 N N (2H, m), 3.09 - 3.01 (2H, m), 2.88 & -2.81 (1H, m), 2.10 (3H, 5), 0.71 - 0.66 (2H, m), 0.58 - 0.53 (2H, m) 8.44 (1H, d), 7.86 (1H, dd), 7.73 1 389 (1H, d), 7.48 (1H, d), 7.38 - 7.17 (6H, m), 6.88 (1H, d), 6.68 (1H, ~ 0 d), 3.64 - 3.47 (2H, m), 2.94 - 2.80 N (3H, m), 2.10 (3H, 5), 0.72 - 0.65 A ( 2H, m), 0.58 - 0.52 (2H, m) 8.43 (1H, d), 7.92 (1H, 1), 7.87 375 ~_ 0 (1H, dd), 7.75 (1H, d), 7.49 (1H, NH d), 7.36 - 7.28 (4H, m), 7.25 - 7.20 (1H, m), 6.82 (1H, d), 6.70 (1H, d), 4.59 (1H, dd), 4.48 (1H, dd), 2.89 - 2.81 (1H, m), 2.11 (3H, 5),

YAAY

- 11/0 - L 2H, m 9.27 (1H, s), 8.46 (1H, d), 8.02 - 361 \Y 7.98 (2H, m), 7.89 (1H, dd), 7.81 (1H, d), 7.52 (1H, d), 7.32 (2H, 1), L 7.04 - 6.99 (2H, m), 6.96 (1H, d), « 2.89 - 2.82 (1H, m), 2.16 (3H, s), N 0.72 - 0.67 (2H, m), 0.59 - 0.54 H (2H, m) 8.43 (1H, d), 7.94 - 7.84 (2H, m), 405 yy 7.75 (1H, d), 7.49 (1H, d), 7.22 ~_ (1H, 1), 6.92 - 6.87 (2H, m), 6.84 - NH 6.77 (2H, m), 6.70 (1H, d), 4.56 0 (1H, dd), 4.45 (1H, dd), 3.73 3H, 5), 2.90 - 2.79 (1H, m), 2.11 (3H, 5), 0.73 - 0.65 (2H, m), 0.59 - 0.51 (2H, m 8.42 (1H, d), 7.86 (1H, dd) , 7.76 - 473 \ 7.72 (2H, m), 7.48 (1H, d), 7.19 (2H, d), 6.89 - 6.85 (2H, m), 6.83 SN (1H, d), 6.68 (1H, d) , 4.47 (1H, TL dd), 4.37 (1H, dd), 3.08 (4H, 1), bin 2.88 - 2.81 (1H, m), 2.43 (4H, 1), NS 2.21 (3H, s), 2.10 (3H, 5), 0.71 - 0.65 (2H, m), 0.57 - 0.53 (2H, m) 8.47 - 8.37 (1H, m), 7.86 (1H, d), 389 \o 7.74 (1H, d), 7.63 — 7.53 (1H, m), 7.52 - 7.45 (1H, m), 7.44 — 7.38 (2H, m), 7.36 - 7.27 (2H, m), 7.25 -7.17 (1H, m), 6.83 - 6.78 (1H, SN m), 6.71 - 6.65 (1H, m), 5.15 (1H, quintet), 2.90 - 2.79 (1H, m), 2.13 H (1.5H, 5), 2.08 (1.5H, s), 1.51 (3H, t), 0.73 - 0.63 (2H, m), 0.61 - 0.50 2H, m 8.48 — 8.40 (1H, m), 7.87 (1H, d), 415 V4 7.78 (1H, d), 7.49 (1H, d), 7.25 - 7.08 (5H, m), 6.90 (1H, d), 6.75 (1H, d), 5.26 (1H, quintet), 2.91 - OL 2.67 (3H, m), 2.15 (1.5H, 5), 2.13 N (1.5H, s), 2.03 - 1.84 (3H, m), 1.83 H - 1.69 (1H, m), 0.74 - 0.64 (2H, m), 0.60 - 0.51 (2H, m) 8.51 - 8.40 (1H, m) ), 7.93 - 7.84 401 yy (1H, m), 7.83 - 7.74 (1H, m), 7.55 > - 7.46 (1H, m), 7.43 - 7.12 (5H, N © m), 6.96 - 6.87 (1H, m ), 6.81 - H 6.73 (1H, m), 5.67 - 5.52 (1H, m),

YAAY

- 19 - 3.09 - 2.94 (1H, m), 2.93 - 2.77 (2H, m), 2.60 - 2.40 (1H, m), 2.21 - 2.00 (4H, m), 0.76 - 0.64 (2H, m), 0.62 - 0.53 (2H, m 8.44 (1H, d), 7.87 (1H, dd), 7.76 403 CVA (1H, d), 7.49 (1H, d), 7.41 - 7.36 (2H, m), 7.33 - 7.27 (2H, m), 7.21 > -7.16 (1H, m), 6.93 (1H, 7 N (2H, s), 2.89 - 2.81 (1H, m), 2.12 "0 (3H, 5), 1.76 (3H, 5), 1.72 (3H, s), 0.72 - 0.66 (2H, m), 0.58 - 0.53 2H, m 8.45 (1H, d), 7.85 (1H, dd), 7.74 389 \q (1H, d), 7.47 (1H, d), 7.36 - 7.30 (2H, m), 7.27 - 7.21 (3H, m), 6.98 ha 0) (1H, d), 6.91 (1H, d), 5.09 (1H, d), 4.95 (1H, d) ), 3.03 (3H, s), 2.88 - 2.81 (1H, m), 2.09 (3H, s), 0.72 - 0.66 (2H, m), 0.58 - 0.54 2H, m 8.43 (1H, d), 7.86 (1H , dd), 7.82 405 Y. (1H, t), 7.74 (1H, d), 7.49 (1H, d), ~_ 7.27 (2H, dd), 6.90 - 6.85 (2H, m), N 6.83 (1H , d), 6.69 (1H, d), 4.51 TL (1H, dd), 4.41 (1H, dd), 3.72 (3H, H 0 s), 2.88 - 2.81 (1H, m), 2.11 (3H, s) , 0.71 - 0.66 (2H, m), 0.57 - 0.53 2H, m) 8.46 — 8.37 (1H, m), 7.86 (1H, 389 Y dd), 7.75 = 7.71 (1H, m), 7.62 — 7.53 (1H, m), 7.51 — 7.46 (1H, m), 7.44 —7.38 (2H, m), 7.34 - 7.28 (2H, m), 7.24 - 7.19 (1H, m), 6.82 ~~ love - 6.78 (1H , m), 6.70 — 6.65 (1H, m), 5.15 (1H, quintet), 2.88 - 2.80 H (1H, m), 2.12 (1.5H, s), 2.08 (1.5H, s), 1.51 3H, t ), 0.72 - 0.65 (2H, m), 0.59 - 0.51 2H, m 8.43 (1H, d), 8.01 (1H, t), 7.87 393 yy (1H, dd), 7.76 (1H, d), 7.49 (1H , d), 7.36 (1H, td), 7.17 (1H, plc 7.15 -7.11 (1H, m), 7.08 - 7.02 nN F (1H, m), 6.82 (1H, d), 6.71 (1H, Or d), 4.60 (1H, dd), 4.49 (1H, dd), H 2.88 - 2.81 (1H, m), 2.12 3H, s), 0.71 - 0.66 (2H, m), 0.58 - 0.53 (2H, m)

YAAY

1.” 8.53 - 8.51 (1H, m), 8.45 (1H, d), 376 - 7.92 (1H, t), 7.87 (1H, dd), 7.78 - 7.73 (2H, m), 7.50 (1H, d), 7.31 ~ N (1H, d), 7.28 - 7.24 (1H, m), 6.82 ag (1H, d), 6.74 (1H, d), 4.68 (1H, H _ dd), 4.59 (1H, dd), 2.89 - 2.82 (1H, m), 2.13 (3H, s), 0.72 - 0.66 (2H, m), 0.59 - 0.53 (2H, m 8.56 (1H, d), 8.46 - 8.40 (2H, m), 376 Ys 8.05 (1H , t), 7.89 - 7.84 (1H, m), 7.77 - 7.71 (2H, m), 7.49 (1H, d), >< > 7.34 (1H, dd), 6.83 (1H, d), 6.72 1 t ]‎ (1H, d), 4.60 (1H, dd), 4.50 (1H, H _ dd), 2.90 - 2.79 (1H, m), 2.11 (3H, 5), 0.73 - 0.65 (2H, m), 0.59 - 0.52 2H, m 8.44 (1H, d), 8.13 (1H, 1), 7.87 453 Yo (3H, d), 7.76 (1H, d), 7.57 (2H, d), ~~ 7.49 (1H, d) , 6.81 (1H, d), 6.72 CL o (1H, d), 4.68 (1H, dd), 4.57 (1H, H J dd), 3.19 (3H, s), 2.91 - 2.80 (1H, 2 m), 2.12 (3H, s), 0.73 - 0.65 (2H, 0 m), 0.59 - 0.52 2H, m 8.44 (1H, d), 7.87 (1H, dd), 7.77 405 i. (1H, d), 7.58 (1H, 1), 7.50 (1H, d), 7.25 - 7.20 (1H, m), 7.12 (1H, d), 0 6.99 (1H, d), 6.89 (1H, 1), 6.81 (1H, d), 6.70 ( 1H, d), 4.56 (1H, > aS dd), 4.47 (1H, dd), 3.83 (3H, s), 2.89 - 2.82 (1H, m), 2.13 (3H, s), H 0.72 - 0.66 (2H , m), 0.58 - 0.54 2H, m 12.19 (1H, s), 8.48 (1H, d), 7.92 - 415 " 7.85 (2H, m), 7.76 (1H, s), 7.57 - 7.48 (2H, m) , 7.47 - 7.41 (1H, m), > N 7.18 - 7.09 (2H, m), 6.84 (1H, dd), NTP 6.76 (1H, dd), 4.80 (1H, dd), 4.71 H N (1H, dd) , 2.91 - 2.81 (1H, m), 2.15 (3H, s), 0.74 - 0.65 (2H, m), 0.60 - 0.53 (2H, m) 8.94 (1H, d), 8.42 (1H, d), 8.23 426 YA (1H, d), 8.16 (1H, t), 7.98 (2H, dd), 7.86 (1H, dd), 7.76 - 7.70 ~ (2H, m), 7.62 - 7.57 (1H, m), 7.49 0 ] LOL (1H, d), 6.84 (1H, d), 6.72 (1H, d), H F 4.78 (1H, dd), 4.69 (1H, dd), 2.88 - 2.81 (1H, m), 2.12 ( 3H, 5), 0.71 - 0.65 (2H, m), 0.57 - 0.53 (2H, m)

YAAY

- 1171 - 8.43 (1H, d), 7.87 (1H, dd), 7.75 430 i” (1H, t), 7.54 - 7.47 (2H, m), 6.86 - 6.81 (3H, m), 6.68 (1H, d ), 6.44 - 6.38 (2H, m), 5.62 (1H, s), 3.43 - TTC 3.27 (2H, m), 3.27 - 3.20 (1H, m, CC) 2.91 -2.81 (2H, m), 2.48 - 2.39 N (1H, m), 2.31 - 2.21 (1H, m), 2.75 - 2.68 (1H, m), 2.12 3H, 5), 0.72 - 0.66 (2H, m), 0.58 - 0.53 (2H, m) 8.43 (1H, d), 7.86 (1H, dd), 7.73 401 v. (1H, d), 7.48 (1H, d), 7.18 - 7.15 (4H, m), 7.02 (1H, d), 6.96 (1H , y d), 4.86 (2H, dd), 4.09 - 3.98 (2H, m), 2.91 (2H, 1), 2.88 - 2.81 (1H, m), 2.11 (3H, s), 0.71 - 0.66 ( 2H, m), 0.57 - 0.53 (2H, m 8.43 (111, d), 7.93 (1H, 1), 7.87 381 0 (1H, dd), 7.74 (1H, d), 7.49 (1H, d), 7.35 (1H, dd), 7.02 (1H, dd), ~ 5 6.95 (1H, dd), 6.89 (1H, d), 6.73 N (1H, d), 4.73 (1H, dd), 4.63 (1H, 0 ) dd), 2.88 - 2.81 (1H, m), 2.10 (3H, s), 0.71 - 0.65 (2H, m), 0.57 - 0.53 (2H, m 8.42 (1H, d), 7.89 - 7.82 (2H, m) ), 419 b 7.74 (1H, d), 7.49 (1H, d), 6.92 (1H, d), 6.86 - 6.79 (3H, m), 6.69 Su 0 (1H, d), 5.97 (2H, d), 4.48 (1H, CL > dd), 4.38 (1H, dd), 2.88 - 2.81 0 (1H, m), 2.11 3H, 5), 0.71 - 0.66 (2H, m), 0.57 - 0.53 (2H, m 8.43 (1H, d), 7.96 (1H, 1), 7.86 393 or (1H, dd), 7.75 (1H, d), 7.49 (1H, d), 7.40 - 7.34 (2H, m), 7.17 - 7.10 ~_ (2H, m), 6.83 (1H, d), 6.70 (1H, N “TL. d), 4.56 (1H, dd), 4.45 (1H, dd), H 2.88 - 2.81 (1H, m), 2.11 (3H, 5), F 0.72 - 0.66 (2H, m), 0.58 - 0.53 2H, m 8.44 (0.5H, d), 8.40 (0.5H, d), 7.86 | 458 Toe (1H, d), 7.75 (0.5H, d), 7.72 (0.5H, d). 7.54 - 7.46 (2H, m), i 7.43 -7.38 (2H, m), 7.34 - 7.28 (2H, m), 7.25 - 7.19 (1H, m), 6.78 - 6.76 (1H, m), 6.69 - 6.67 ( 1H, YSN m), 5.10 - 5.01 (1H, m), 3.07 - v 2.99 (1H, m), 2.89 - 2.80 (1H, m), 2.70 - 2.57 (1H, m), 2.52 - 2.44

YAAY

- 1117 - (4H, m), 2.13 (1.5H, s), 2.08 (1.5H, s), 1.68 - 1.62 (4H, m), 0.72 - 0.65 (2H, m), 0.58 - 0.51 (2H, m) 8.41 (1H, d), 7.85 (1H, dd), 7.70 472 vo (1H, d), 7.46 (1H, d), 7.43 - 7.32 (4H, m), 7.21 (1H, t), 6.81 (1H, d), 6.66 (1H, d), 6.27 - 6.20 (111, m), ~_ 3.61 (1H, dd), 3.44 (1H, dd), 2.88 N - 2.80 (1H, m), 2.54 - 2.43 (2H , H m), 2.16 - 2.03 (4H, m), 2.08 (3H, z 5), 2.05 (3H, s), 1.91 - 1.82 (2H, m), 0.71 - 0.65 (2H, m), 0.57 - 0.52 (2H, m 8.44 (1H, d), 7.86 (1H, dd), 7.74 403 - (1H, d), 7.48 (1H, d), 7.40 (1H, 1), 7.31-7.25(QH, m), 7.24 - 7.15 ~ (3H, m), 6.84 (1H, d), 6.66 (11, 0 - r] d), 3.43 - 3.27 (2H, m), 2.89 - 2.81 H (1H, m), 2.63 (2H, t), 2.10 (3H, s), 1.89 (2H, quintet), 0.72 - 0.66 (2H, m), 0.58 - 0.53 (2H, m) 8.42 (1H, d), 7.90 - 7.84 (2H, m), 431 vy 7.74 (1H, d), 7.49 (1H, d), 7.35 - 7.31 (2H, m), 7.28 - 7.24 (2H, m), SN 6.82 (1H, d), 6.69 (1H, d) ), 4.57 - 1] ew 4.51 (1H, m), 4.47 - 4.41 (1H, m), 2.88 - 2.81 (1H, m), 2.11 (3H, s), 1.26 (9H, 5), 0.71 - 0.66 ( 2H, m), 0.58-0.53 (2H, m 8.44 (0.5H, d), 8.38 (0.5H, d), 7.88 | - 3 5 - 7.84 (1H, m), 7.76 (0.5H, d), 7.71 (0.5H, d), 7.61 - 7.56 (1H, m), 7.51 - 7.46 (1H, m), 7.45 - 7.39 (2H , m), 7.34 - 7.28 (2H, m), 7.24 - 7.19 (1H, m), 6.81 — 6.78 ~_ (1H, m), 6.68 — 6.65 (1H, m), 4.91 N (1H, dd), 2.89 - 2.79 (1H, m), 2.13 H (1.5H, s), 2.06 (1.5H, s), 2.03 - 1.90 (1H, m), 1.88 - 1.74 (1H, m), 0.86 (3H, td) , 0.72 - 0.64 (2H, m), 0.59 - 0.50 (2H, m) 8.44 (1H, d), 7.87 (1H, dd), 7.81 - 389 vq 7.74 (2H, m), 7.50 (1H, d), 7.23 - 7.10 (4H, m), 6.82 (1H, d), 6.71 ~_ (1H, d), 4.61 - 4.52 (1H, m), 4.50 - N 4.41 (1H, m), 2.90 - 2.80 (1H, m), hy 2.33 3H, s), 2.13 3H, 5), 0.73 - 0.65 (2H, m), 0.59 - 0.52 (2H, m)

YAAY

- 111 —- 8.44 (1H, d), 7.90 (1H, 6 487 Tie (1H, dd), 7.74 (1H, d), 7.49 (1H, d), 7.28 - 7.18 (3H, m), 7.13 (1H , d), 6.82 (1H, d), 6.70 (1H, d), 4.56 - (1H, dd), 4.48 (1H, dd), 3.42 (2H, ! thats 5), 2.88 - 2.81 (1H , m), 2.43 - 2.21 (8H, m), 2.13 3H, 5), 2.12 (3H, 5), 0.71 - 0.66 (2H, m), 0.58 - 0.53 2H, m 8.42 (1H, d), 7.85 ( 1H, dd), 7.77 487 Te (1H, 1), 7.74 (1H, d), 7.48 (1H, d), 7.37 - 7.34 (1H, m), 7.27 - 7.18 ad (3H, m), 6.86 (1H , d), 6.69 (1H, lb“ d), 4.69 (1H, dd), 4.59 (1H, dd), 8 3.60 (1H, d), 3.50 (1H, d), 2.88 - N 2.81 (1H , m), 2.45 - 2.26 (8H, m), H 2.10 (6H, 5), 0.71 - 0.66 (2H, m), 0.57 - 0.52 (2H, m 8.43 (1H, d), 7.88 - 7.82 (2H, m), 389 2 7.74 (1H, d), 7.49 (1H, d), 7.22 (2H, d), 7.11 (2H, d), 6.82 (1H, d), SN CL 6.69 (1H, d), 4.53 (1H, dd), 4.43 (1H, dd), 2.88 - 2.81 (1H, m), 2.27 H (3H, 5), 2.11 (3H, 5), 0.71 - 0.65 (2H, m), 0.58 - 0.53 ( 2H, m 8.43 (1H, d), 7.86 (1H, dd), 7.74 381 i” (1H, d), 7.48 (1H, d), 7.30 (1H, t), 6.84 (1H, d), 6.65 ( 1H, d), 3.29 - ~_ 3.19 (1H, m), 3.17 - 3.06 (1H, m), ag 2.90 - 2.80 (1H, m), 2.10 (3H, s), H 1.75 - 1.55 (6H, m ), 1.27 - 1.09 (3H, m), 1.00 - 0.82 (2H, m), 0.73 - 0.65 (2H, m), 0.59 - 0.52 (2H, m 8.47 (1H, d), 7.87 (1H, dd), 7.77 451 cit (1H, d), 7.51 - 7.45 (3H, m), 7.43 - L 7.32 (7H, m), 7.25 - 7.21 (1H, m), 6.79 (1H, d), 6.76 (1H, d), 4.56 (1H, dd), 4.48 (1H, dd), 2.89 - SN 2.81 (1H, m), 2.12 3H, 5), 0.72 - 0.67 (2H, m), 0.59 - 0.54 (2H, m) H button 8.43 (1H, d), 7.92 (1H, 1), 7.87 467 - co (1H, dd), 7.75 (1H, d), 7.49 (1H, CL d), 7.41 - 7.34 (4H, m ), 7.15 - 7.10 H o (1H, m), 7.01 - 6.95 (4H, m), 6.84 (1H, d), 6.70 (1H, d), 4.57 (1H, dd), 4.46 (1H, dd), 2.89 - 2.81 2 1H, m), 2.12 (3H, 5), 0.72 - 0.66

YAAY

16 — (2H,m),058-053QHm) | [| ~~] 8.43 (111, d), 7.89 - 7.83 (211, m), 389 1 7.75 (1H, d), 7.49 (1H, d), 7.19 (1H, t), 7.15 - 7.10 (2H, m) , 7.04 ~_ (1H, d), 6.83 (1H, d), 6.69 (1H, d), N 4.55 (1H, dd), 4.44 (1H, dd), 2.88 H - 2.81 (1H, m), 2.28 (3H, 5), 2.11 (3H, s), 0.71 - 0.66 (2H, m), 0.58 - 0.53 (2H, m 8.46 - 8.42 (1H, m), 7.86 (1H, dd), | 1 Ley 7.74 ( 1H, d), 7.70 (1H, d), 7.49 (1H, d), 7.30 - 7.24 (2H, m), 7.19 - 7.14 (3H, m), 6.86 (1H, d), 6.72 (1H, d) , 3.04 - 2.98 (1H, m), 2.88 - 2.81 (1H, m), 2.11 (3H, s), 2.15 - 2.04 (1H, m), 1.52 - 1.42 (1H, m), SN 1.25 - 1.15 (1H , m), 0.72 - 0.66 A 2H, m), 0.58 - 0.53 (2H, m 8.47 - 8.41 (1H, m), 7.87 (1H, dd), | 415 'A 7.80 — 7.76 (1H, m), 7.49 (1H, d), 7.25 - 7.09 (5H, m), 6.91 — 6.89 (1H, m), 6.77 — 6.74 (1H, m), 5.31 - 5.22 (1H, m), 2.89 - 2.69 (3H, ™y m) ), 2.15 (1.5H, 5), 2.13 (1.5H, s), 2.03 - 1.85 (3H, m), 1.82 - 1.71 H (1H, m), 0.72 - 0.66 (2H, m), 0.59 - 0.53 ( 2H, m 8.44 (1H, d), 7.87 (1H, dd), 7.76 355 9 (1H, d), 7.49 (1H, d), 6.98 (1H, 1), “NH 6.84 (1H, d), 6.68 (1H, d), 3.35 - 3.28 (1H, m), 3.14 (1H, dd), 2.89 - 2.81 (1H, m), 2.10 (3H, s), 0.91 pe (9H, s), 0.71 - 0.66 ( 2H, m), 0.58 - 0.53 (2H, m) (0+) Example N-Cyclopropyl-4-methyl-3-[2-0x0-3-[[(2S)-2-phenylpropylJamino]-1 (2H)- pyrazinyl]benzamide A 1 © J

N

CT YH

! R: .

YAAY

1# 3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methyl Then stir a mixture of (S)-2-phenyl-1- 4 0,1 mL) N,N-diisopropylethylamnie and 1,pa (example B) cester at room temperature overnight. (Ja 1) tetrahydrofuran s (Ja +,+ ©) propylamine cyclopentylmagnesium bromide This was followed by the addition of (Js +,Y) cyclopropylamine (minutes were added; quenched by adding 10 ml). The mixture was stirred for 1.8 M; The organic phase was in vacuo. Saturated ethyl acetate was extracted in NHA4CI on carbon (£0 mg) palladium 701, adding (Je ©) ethanol and treating the residue with ammonium (g). formate 5 mL (1) N,N-diisopropylethylamnie followed by a minute addition. The mixture was filtered through a 70-gauge for 1 V + at nitrogen. The mixture was stirred under a preparatory atmosphere (column HPLC celite and concentration of the filtrate in vacuo, after rehydration with Vo, a compound (acetonitrile: ammonia 7 1) was obtained in an epoxyfiltration solution “Gemini

Title as a solid (18 mg). MS: APCI(+ve) 393 (M+H+).(DMSO-d6, 400MHz) 8.42 (1H, t), 7.85 (1H, dd), 7.72 (1H, t,), 7.47 (1H, d), E NMR 111 (4H, m), 7.23 - 7.13 (3H, m), 6.87 and 6.86 (1H, 2 x d), 6.68 and 6.67 (1H, 2 Yo 7.23 - 7.34 x d) , 3.59 - 3.38 (2H, m), 3.25 - 3.14 (1H, m), 2.84 (1H, m), 2.08 and 2.06 (3H, 2 x 5), (3H, d), 0.68 (2H, m ), 0.55 (2H, m). -methyl-benzoic acid, methyl ester (Example 1ap) the appropriate Ye amines using the general procedure described in Example 05. YAAY

11 - (1) as [[3-[[[4-[5-[(Cyclopropylamino)carbonyl]-2-methylphenyl]-3,4-dihydro-3- oxopyrazinyl]amino]methyl]phenyl] methyl]-carbamic acid, 1,1-dimethylethyl ester ( oY ) Example [[4-[[[4-[5-[(Cyclopropylamino)carbonyl]-2-methylphenyl]-3,4-dihydro-3 - 2 oxopyrazinyl[amino]methyl]phenyl]methyl]-carbamic acid, 1,1-dimethylethyl ester (57) Ex. N-Cyclopropyl-4-methyl-3-[2-0x0-3-(3-phenyl) -1-piperazinyl)-1(2H)-pyrazinyl]- benzamide (4) as 0

N-Cyclopropyl-4-methyl-3-[2-0x0-3-(3-phenyl-1-pyrrolidinyl)- 1 (2H)-pyrazinyl]- benzamide ( oo ) Example N-Cyclopropyl-3-[ 3-[[(2R)-2-hydroxy-2-phenylethylJamino]-2-0x0-1(2H)-pyrazinyl]-4- methyl-benzamide Vo

YAAY

17 — (*0) as N-Cyclopropyl-3-[3-[[(2S)-2-hydroxy-2-phenylethylJamino]-2-oxo-1(2H)-pyrazinyl]-4- methyl -benzamide (ov) as N-Cyclopropyl-4-methyl-3-[2-0x0-3-[[(2R)-2-phenylpropyl]Jamino]-1(2H)-pyrazinyl]-©benzamide ( A) Example N-Cyclopropyl-4-methyl-3-[2-0x0-3-[[(2S)-2-phenylpropylJamino]-1(2H)-pyrazinyl]- benzamide )*4 (ex. 0

N-Cyclopropyl-4-methyl-3-[2-0x0-3-[3-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-1- piperidinyl]-1(2H)-pyrazinyl]-benzamide ( Te ) Example, N-Cyclopropyl-4-methyl-3-[2-0x0-3-(3-phenyl-1-piperidinyl)-1(2H)-pyrazinyl]- benzamide

YAAY

— 1/8 (MY) eg N-Cyclopropyl-3-[3-[[2-(dimethylamino)-2-phenylethylJamino]-2-oxo0-1(2H)-pyrazinyl]- 4-methyl- benzamide ( TY ) Example -Cyclopropyl-3-[3-[[[2-(4-fluorophenyl)-1,1-dimethylethyl]Jamino]-2-0x0-1(2H)- © pyrazinyl]-4- methyl-benzamide (17) Example N-Cyclopropyl-4-methyl-3-[2-0x0-3-[[2-phenyl-2-(1-pyrrolidinyl)ethylJamino]-1(2H)- pyrazinyl ]-benzamide (le) eg Ne

N-Cyclopropyl-3-[3-[(2,3-dihydro- 1H-inden-2-yl)amino]-2-oxo-1(2H)-pyrazinyl]-4- methyl-benzamide (le) Jha

N-Cyclopropyl-3-[3-[(1,1-dimethyl-2-phenylethyl)amino]-2-oxo-1(2H)-pyrazinyl]-4- methyl-benzamide Yo

YAAY

1” - ( 1 ) Example N-Cyclopropyl-4-methyl-3-[3-[methyl(2-phenylethyl)amino]-2-oxo-1(2H)-pyrazinyl] benzamide ( v ) Example N-Cyclopropyl-4-methyl-3-[2-0x0-3-(2-phenyl-4-morpholinyl)-1(2H)-pyrazinyl]- © benzamide ( TA) Example N-Cyclopropyl -3-[3-[[(2-hydroxyphenyl)methylJamino]-2-oxo0-1(2H)-pyrazinyl]-4- methyl-benzamide ( 14 ) Example 0

N-Cyclopropyl-3-[3-[[[3-[(cyclopropylamino)carbonyl]phenyl methyl Jamino]-2-oxo- 1(2H)-pyrazinyl]-4-methyl-benzamide ( Ve ) Example N -Cyclopropyl-3-[3-[[2-(4-hydroxyphenyl)ethyl Jamino]-2-0x0-1(2H)-pyrazinyl]-4- methyl-benzamide Yo

—— VE. — (v 1( eg N-Cyclopropyl-3-[3-[[2-(3-hydroxyphenyl)ethylJamino]-2-oxo-1(2H)-pyrazinyl]-4- methyl-benzamide (Vv) Y ) Example N-Cyclopropyl-4-methyl-3-[3-[[2-(2-methylphenyl)ethyl Jamino]-2-o0x0-1(2H)- © pyrazinyl]-benzamide (V ¥) Example N-Cyclopropyl-4-methyl-3-[3-[[2-(3-methylphenyl)ethyl |amino|-2-0x0-1(2H)- pyrazinyl]-benzamide (V £) Example Ve

N-Cyclopropyl-4-methyl-3-[3-[[2-(4-methylphenyl)ethyl]amino]-2-oxo0-1(2H)- pyrazinyl]-benzamide (v °) Example N- Cyclopropyl-3-[3-[2-[(2-fluorophenyl)methyl]-1-pyrrolidinyl}-2-oxo0-1(2H)- pyrazinyl]-4-methyl-benzamide Yo ( 75 ) Example N-Cyclopropyl-4-methyl-3-[2-0x0-3-(1-piperidinyl)-1(2H)-pyrazinyl]-benzamide

YAAY

- 1611 - (VY) Example N-Cyclopropyl-4-methyl-3-[3-[[3-(4-morpholinyl)- 1 -phenylpropylJamino]-2-oxo-1(2H)- pyrazinyl]- benzamide (VA) Example N-Cyclopropyl-3-[3-[[(2-ethoxyphenyl)methyl]amino]-2-0x0-1(2H)-pyrazinyl]-4- © methyl-benzamide (V4) Example N-Cyclopropyl-4-methyl-3-[2-0x0-3-[[[2-(trifluoromethyl)phenyl methyl Jamino]-1(2H)- pyrazinyl]-benzamide (A) as 0

N-Cyclopropyl-3-[3-[[(1S)-2-hydroxy-1-phenylethyl Jamino]-2-oxo0-1(2H)-pyrazinyl]-4- methyl-benzamide (AY) Example N -Cyclopropyl-3-[3-[[(IR)-2-hydroxy-1-phenylethylJamino]-2-0x0-1(2H)-pyrazinyl]-4- ‎methyl-benzamide Yo

AY Example N-Cyclopropyl-i-[[4-[5-[(cyclopropylamino)carbonyl]-2-methylphenyl]-3,4-dihydro-3- oxopyrazinyl|amino]-benzenepropanamide YAAY

— VEY-

AY Example N-Cyclopropyl-3-[3-[(3-hydroxy-1-phenylpropyl)amino]-2-oxo-1(2H)-pyrazinyl]-4- methyl-benzamide

At Example N-Cyclopropyl-4-methyl-3-[3-[[(1R)-1-(1-naphthalenyl)ethyl]amino]-2-ox0-1(2H)- ° pyrazinyl]-benzamide

Ao eg N-cyclopropyl-4-methyl-3-[2-0x0-3-[[(1S)-1-phenylpropylJamino]-1(2H)-pyrazinyl]- benzamide

AT Example 0

N-Cyclopropyl-4-methyl-3-[2-0x0-3-(2-phenyl-1-pyrrolidinyl)-1(2H)-pyrazinyl]-benzamide

AY Example (BR)-0-[[4-[5-[(Cyclopropylamino)carbonyl]-2-methylphenyl]-3,4-dihydro-3- oxopyrazinyl]amino]-benzenepropanoic acid, 1,1 -dimethylethyl ester Vo

AN Example N-Cyclopropyl-3-[3-(cyclopropylamino)-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

YAAY

- 17 -

Example (OR)-N-cyclopropyl-0-[[4-[5-[(cyclopropylamino)carbonyl]-2-methylphenyl]-3,4- dihydro-3-oxopyrazinyl]amino-benzenepropanamide 60 Example N-Cyclopropyl-4-methyl-3-[2-ox0-3-[[(tetrahydro-2H-pyran-4-yl)methyl Jamino]-1(2H)- © pyrazinyl]-benzamide 11 Example ‎ N-Cyclopropyl-3-[3-[[(2,3-dihydro-1,4-benzodioxin-5-yl)methyl]amino]-2-oxo-1(2H)- pyrazinyl]-4- methyl-benzamide 7 Example Ve

N-Cyclopropyl-3-[3-[[(2,3-dimethylphenyl)methyl]Jamino]-2-oxo-1(2H)-pyrazinyl]-4- methyl-benzamide 9 Example N-Cyclopropyl-4 -methyl-3-[2-0x0-3-[[[3-(trifluoromethyl)phenyl Jmethyl Jamino]-1(2H)- pyrazinyl]-benzamide Yo 94 Example N-Cyclopropyl-4-methyl-3- [3-[2-(3-methylphenyl)-1-piperidinyl]-2-oxo-1(2H)- pyrazinyl]-benzamide

YAAY

- 1446 — do Example N-Cyclopropyl-3-[3-[[(3,5-dimethylphenyl)methyl]amino]-2-oxo0-1(2H)-pyrazinyl]-4- methyl-benzamide 7 Example N-Cyclopropyl-4-methyl-3-[3-[2-(3-methylphenyl)-1-pyrrolidinyl]-2-oxo0-1(2H)- © pyrazinyl]-benzamide 917 Example N-Cyclopropyl-3-[3-[2-(2-methoxyphenyl)-1-pyrrolidinyl]-2-oxo-1(2H)-pyrazinyl]-4- methyl-benzamide

IA Example 0

N-Cyclopropyl-3-[3-[[(2,5-dimethylphenyl)methyl]Jamino]-2-oxo-1(2H)-pyrazinyl]-4- methyl-benzamide 94 Example 3-[3- [[[3,5-Bis(trifluoromethyl)phenyl]methyl]Jamino]-2-oxo-1(2H)-pyrazinyl]-N- cyclopropyl-4-methyl-benzamide Vo

- 1 © - (¥ ) Table 0 m oN eC 9

So 0 onion automatically xa 1H NMR. § (DMSO-d6) [M+H]+ Example m/z 8.43 (1H, d), 7.87 (2H, m), 7.74 (1H, 504 0) s), 7.49 (1H, d), 7.37 (1H, t), 7.25 (1H, 1), 7.19 (2H, m), 7.09 (1H, d), - I 6.82 (1H, d), 6.69 (1H, d), 4.57 (1H, ! ] “ 1 dd), 4.46 (1H, dd), 4.10 (2H, d), 2.84 9 (1H, m), 2.12 3H, s), 0.68 (2H, m), 0.55 (2H, m 8.43 (1H) , d), 7.88 (2H, m), 7.75 (1H, 504 oY s), 7.49 (1H, d), 7.35 (1H, m), 7.27 (2H, d), 7.17 (2H, d), 6.82 ( 1H, d), - 6.69 (1H, d), 4.56 (1H, dd), 4.47 (1H, ! maha 1 dd), 4.09 (1H, d), 2.85 (1H, m), 2.11 TT (3H , s), 0.67 (2H, m), 0.56 (2H, m) © 7.72 and 7.70 (1H, 2 x dd), 7.58 and 430 oy 7.54 (1H, 2 x d), 7.44 (2H, m), 7.40 and 7.38 (1H, 2 x d), 7.33-7.23 (4H, m), 7.01 (1H, d), 6.57 (1H, d), 4.78 > (1H, m), 3.98 (1H, d), 3.25-3.00 ( 3H, N m), 2.93-2.79 (2H, m), 2.22 and 2.18 (nN (3H, 2 x 5), 0.86 (2H, m), 0.59 (2H, m) 8.44 (1H, d), 7.84 ( 1H, dd), 7.71 (1H, | 415 of t), 7.47 (1H, d), 7.36 - 7.28 (3H, m), 7.29 - 7.19 (2H, m), 6.88 (1H, d), 6.72 and 6.71 (1H, 2 x d), 4.38 - 4.17 ~~ (1H, m), 4.08 - 3.91 (1H, m), 3.85 - button(3.56 (2H, m), 3.42 (1H, m), 2.85 (1H) , m), 2.35 - 2.20 (1H, m), 2.14 and 2.11 3H, 2 x 5), 1.98 (1H, m), 0.68 2H, m), 0.56 (2H, m)

YAAY

-167- 8.44 (1H, d), 7.86 (1H, dd), 7.73 (111, 1 405 s), 7.49 (1H, d), 7.42 - 7.31 (4H, m), 7.30 - 7.22 (1H, m) , 7.08 (1H, m), 6.86 and 6.85 (1H, 2 x d), 6.71 and - 6.70 (1H, 2 x d), 5.62 (1H, 5), 4.87 N (1H, m), 3.61 (1H, m) , 3.42 (1H, m), for OH 2.84 (1H, m), 2.09 (3H, 2 x 5), 0.69 2H, m), 0.56 (2H, m), 8.44 (1H, d), 7.86 (1H, dd), 7.73 (1H, | 1 5 on 5), 7.49 (1H, d), 7.42 - 7.31 (4H, m), 7.30 - 7.22 (1H, m), 7.08 (1H, m), 6.86 and 6.85 ( 1H, 2 x d), 6.71 and 8 6.70 (1H, 2 x d), 5.62 (111) 4.87 NT b (1H, m), 3.61 (1H, m), 3.42 (1H, m), H on 2.84 (1H , m), 2.09 (3H, 2 x 5), 0.70 2H, m), 0.55 2H, m 8.42 (1H, 1), 7.85 (1H, dd), 7.72 (1H, | 403 ov t,), 7.47 ( 1H, d), 7.34 - 7.23 (4H, m), 7.23 -7.13 (2H, m), 6.87 and 6.86 (1H, 2 x d,), 6.68 and 6.67 (1H, 2 x - d), 3.59 - 3.38 ( 2H, m), 3.25 - 3.14 N (1H, m), 2.84 (1H, m), 2.08 and 2.06 i (3H, 2 x 5), 1.22 (3H, d), 0.68 (2H, m), 0.55 ( 2H, m) 8.42 (1H, 1), 7.85 (1H, dd), 7.72 (1H, | 1 3 CoA t), 7.47 (1H, d), 7.34 - 7.23 (4H, m), 7.23 - 7.13 (2H , m), 6.87 and 6.86 (1H, 2 x d,), 6.68 and 6.67 (1H, 2 x - d), 3.59 - 3.38 (2H, m), 3.25 - 3.14 Ng (1H, m), 2.84 (1H, m), 2.08 and 2.06 L (3H, 2 x 5), 1.22 (3H, d), 0.68 (2H, m), 0.55 (2H, m) 8.44 (1H, br), 7.85 (1H, dd ), 7.73 and | 542 8 7.71 (1H, 2 x d), 7.48 and 7.36 (1H, 2 x d), 7.17 (2H, dd), 6.99 (1H, d), 6.95 s and 6.94 (1H, 2 x d), 6.87 ( 2H, dd); m), 1.83 - 1.58 (8H, m), 0.69 (2H, m), 0.56 (2H, m 8.43 (1H, br), 7.85 (1H, dd), 7.73 and | 429 + 7.71 (111, 2 x d) , 7.48 and 7.36 (1H, 2 x d), 7.35 - 7.17 (SH, m), 7.00 (1H, d), 6.95 and 6.94 (1H, 2 x d), 4.72 ~ (2H, m), 2.97 - 2.74 (4H , m), 2.11 N and 2.08 (3H, s), 1.95 (1H, m), 1.84 - 1.59 (3H, m), 0.69 (2H, m), 0.56 (2H, m)

YAAY

- VEY — 8.43 (1H, d), 7.85 (1H, dd), 7.71 (1H, | _ 432 0 d), 7.48 (1H, d), 7.40 - 7.23 (5H, m), 6.86 (1H, d) , 6.83 (1H, m), 6.69 (1H, ~~ d), 3.93 - 3.50 (3H, m), 2.83 (1H, m), N 2.12 (6H, 5), 2.07 3H, 5), 0.69 (2H , HN m), 0.54 (2H, m 8.44 (1H, d,), 7.86 (1H, dd), 7.75 435 y (1H, d), 7.49 (1H, d), 7.14 - 7.03 (4H, F m) , 6.95 (1H, d), 6.78 (1H, d), 6.16 ww LT (1H, 5), 3.28 (1H, d), 3.06 (1H, d), O’ 2.85 (1H, m), 2.11 3H, s), 1.44 (3H, 5), 1.36 (3H, 5), 0.69 (2H, m), 0.55 H 2H, m 8.43 (14, 1), 7.85 (1H, dd), 7.70 (1H, | 458 s), 7.47 (1H, dd), 7.36 - 7.18 (5H, m), 6.83 and 6.82 (1H, 2 x d), 6.72 (1H, m), 6.67 and 6.66 (1H, 2 x d), 3.81 “SN (1H, m), 3.65 - 3.51 (2H, m), 2.83 oo (1H, m), 2.40 (2H, m), 2.06 and 2.04 (3H, 2 x 5), 1.66 (4H, m), 0.68 ( 2H, \ ] m), 0.55 CH, m 8.43 (1H, d), 7.86 (1H, d), 7.75 (1H, 401 + 5), 7.49 (1H, d), 7.41 (1H, d), 7.30 - 7.07 (4H, m) 6.91 (1H, d), 6.73 (1H, d), 4.70 (1H, m), 3.27 - 3.18 (2H, m), ~~ 3.12 - 2.92 (2H, m), 2.85 (1H , m), N 2.12 (3H, 5), 0.69 (2H, m), 0.55 (2H, Ny m 8.45 (1H, s), 7.87 (1H, d), 7.76 (1H, 417 + s), 7.49 ( 1H, d), 7.31 - 7.16 (3H, m), 7.09 (2H, d), 6.96 (1H, d), 6.77 (1H, d), 6.16 (1H, s), 3.04 (1H, d), 2.91 - ~~ wv 2.80 (1H, m), 2.11 (3H, 5), 1.46 (3H, N s), 1.37 3H, 5), 0.75 - 0.64 (2H, m), H 0.62 - 0.50 (2H, m) 8.45 (1H, d), 7.85 (1H, dd), 7.69 (1H, | _ 403 - d), 7.47 (1H, d), 7.29 - 7.22 (2H, m), 7.22 - 7.14 (3H, m), 6.93 (1H, d), 6.79 (1H, d), 4.11 - 4.01 (1H , m), 0 3.99 - 3.89 (1H, m), 3.11 (3H, 5), SN 2.91 - 2.80 (3H, m), 2.08 (3H, s), 0.74 - 0.65 (2H, m), 0.59 - 0.53 (2H, m) 8.44 (1H, 0, 7.86 (1H, dd), 7.77 and 431 wv 7.71(1H, 2 x d), 7.49 and 7.47 (1H, 2 x d), 7.42 - 7.27 (5H, m), 7.05 - 7.01 “NN (2H, 5), 4.70 (1H, t), 4.61 (1H, dt), rn 4.57 - 4.48 (1H, dd), 4.05 (1H, dd), 0

YAAY

— YEA — 3.77 (1H, tt), 3.07 (1H, tt), 2.89 - 2.79 (2H, m), 2.12 and 2.09 3H, 2 x 5), 0.73 - 0.65 (2H, m), 0.60 - 0.52 1H, m 9.93 (1H, s), 8.42 (1H, d), 7.86 (1H, 391 A dd), 7.78 - 7.71 (2H, m), 7.49 (1H, OH d), 7.13 (1H, dd), 7.09 ( 1H, dt), 6.84 (1H, d), 6.81 (1H, dd), 6.76 (1H, dt), rt” 6.72 (1H, d), 4.56 - 4.36 (2H, m), 2.89 - 2.79 (1H, m), 2.15 3H, 5), H 0.73 - 0.64 (2H, m), 0.59 - 0.51 (2H, m 8.42 (2H, m), 7.99 (1H, 1), 7.87 (1H, 458 +4) dd), 7.78 (1H, 5), 7.75 (1H, d), 6 (1H, d), 7.49 (1H, d), 7.46 (1H, d), PA 7.37 (1H, 1), 6.82 (1H, d), 6.71 (1H, > d), 4.62 (1H, dd), 4.51 (1H, dd), 2.90 H H - 2.79 (2H, m), 2.16 (3H, 5), 0.73 - 0.64 ( 4H, m), 0.60 - 0.52 (4H, m) 8.43 (1H, d), 7.86 (1H, dd), 7.73 (1H, | _ 405 v.d), 7.48 (1H, d), 7.27 (1H, t), 7.03 OH (2H, d), 6.87 (1H, d), 6.71 - 6.65 (3H, - Lr m), 3.58 - 3.41 (2H, m), 2.90 - 2.70 N (3H, m), 2.10 ( 3H, s), 0.69 (2H, m), H 0.55 (2H, m) 9.26 (1H, s), 8.43 (1H, d), 7.86 (1H, 405 7 dd), 7.73 (1H, d), 7.48 (1H, d), 7.32 (1H, 1), 7.08 (1H, 1), 6.88 (1H, d), Qu 6.69 (1H, d), 6.67 - 6.63 (2H, m), rt” on 6.60 (1H, m), 3.52 (2H, m), 2.90 - 2.76 (3H, m), 2.10 (3H, 5), 0.69 (2H, m), 0.55 (2H, m), 8.44 (1H, d), 7.86 ( 1H, dd), 7.74 (1H, | _ 403 vy d), 7.49 (1H, d), 7.43 (1H, t), 7.20 - 7.07 (4H, m), 6.88 (1H, d), 6.68 (1H, - SL d), 3.59 - 3.44 (2H , m), 2.96 - 2.79 N (3H, m), 2.33 GH, 5), 2.10 (3H, s), 0 0.69 (2H, m), 0.56 (2H, m 8.44 (1H, d), 7.86 (1H) , dd), 7.73 (1H, | _ 403 vo d), 7.49 (1H, d), 7.34 (1H, 1), 7.18 (1H, 1), 7.03 (3H, m), 6.88 (1H, d), 2 6.69 (1H, d), 3.61 - 3.47 (2H, m), rub 2.93 - 2.78 (3H, m), 2.28 (3H, s), 2.10 (3H, s), 0.69 (2H, m) , 0.55 (2H, H m

YAAY

- 1698 - 8.44 (1H, d), 7.86 (1H, dd), 7.73 (1H, | 3 in d), 7.48 (1H, d), 7.30 (1H, 1), 7.11 (4H, m), 6.88 ( 1H, d), 6.68 (1H, d), . Lr 3.62 - 3.45 (2H, m), 2.91 - 2.77 (3H, N m), 2.26 (3H, 5), 2.09 (3H, s), 0.69 H 2H, m), 0.55 (2H, m) 8.45 (1H , d), 7.86 (1H, m), 7.74 and 447 vo 7.68 (1H, 2 x d), 7.48 (1H, d), 7.38 - 7.20 (2H, m), 7.18 - 7.06 (2H, m), 6.95 and 6.91 (1H, 2 x d), 6.76 and 6.71 (1H, 2 x d), 4.95 (1H, br) 3.87 - 3.73 (1H, br), 3.70 - 3.56 (1H, br), ~ 3.02 -2.71 3H, m) , 2.13 and 2.11 N (3H,2xs), 1.92 - 1.75 (3H, m), 1.69 - 1.60 (1H, m), 0.69 (2H, m), 0.56 2H, m) 8.43 (1H, d), 7.85 ( 1H, dd), 7.71 (1H, | 3 vi d), 7.47 (1H, d), 6.98 (1H, d), 6.92 pa 7) (1H, d), 3.75 - 3.62 (4H, m), 2.85 ( 1H, m), 2.09 (3H, s), 1.66 - 1.50 (6H, m), 0.69 (2H, m), 0.56 (2H, m) 8.52 and 8.38 (1H, 2 x d), 8.45 and 488 vy 8.41 ( 1H, 2 x d), 7.87 (1H, dd), 7.74 (1H, dd), 7.50 and 7.49 (1H, 2 x d), 7.40 - 7.16 (5H, m), 6.76 and 6.75 (1H, 2 x d), 6.66 (1H, d), 5.16 (1H, - m), 3.73 - 3.51 (4H, m), 2.84 (1H, N NY m), 2.44 - 2.18 (8H, m), 2.12 and 0 m 2.08 ( 3H, 2 x 5), 0.69 (2H, m), 0.55 (2H, m) 8.44 (1H, d), 7.87 (1H, dd), 7.76 (1H, | 419 VA d), 7.55 (1H, t), 7.49 (1H, d), 7.21 (1H, dt), 7.12 (1H, dd), 6.97 (1H, d), (Pham 6.88 (1H, dt), 6.82 (1H, d), 6.70 (1H, d), 4.61 - 4.44 (2H, m), 4.08 (2H, q), yet” 2.85 (1H, m), 2.12 (3H, s), 1.36 ( 1H, 1), 0.69 (2H, m), 0.55 (2H, m H 8.46 (1H, d), 7.99 (1H, 1), 7.88 (1H, 443 va dd), 7.79 (1H, d), 7.73 ( 1H, d), 7.64 (1H, 1), 7.51 (1H, d), 7.49 - 7.42 (2H, F m), 6.80 (1H, d), 6.75 (1H, d), 4.80 F (1H, d) , 4.69 (1H, d), 2.86 (1H, m), and “ 2.14 (3H, 5), 0.70 (2H, m), 0.56 (2H, m) H

YAAY

— Vo. — 8.44 and 8.41 (1H, 2 x d), 7.87 (1H, 405 ~ dd), 7.75 and 7.73 (1H, 2 x d), 7.52 - 7.47 (1H, m), 7.46 - 7.28 (SH, m), 7.23 ( 1H, m), 6.79 and 6.77 (1H, 2 x d), 6.70 and 6.69 (1H, 2 x d), 5.02 - OH (2H, m), 3.73 (2H, m), 2.85 (1H, m), N 2.13 and 2.09 (3H, 2 x 5), 0.68 (2H, 0 m), 0.55 2H, m 8.44 and 8.41 (1H, 2x d), 7.87 (1H, 405 A dd), 7.75 and 7.73 (1H, 2 x d) , 7.52 - 7.47 (1H, m), 7.46 - 7.28 (SH, m), l 7.23 (1H, m), 6.79 and 6.77 (1H, 2 x : d), 6.70 and 6.69 (1H, 2 x d) , 5.02 : (2H, m), 3.73 (2H, m), 2.85 (1H, m), ES Ya 2.13 and 2.09 (3H, 2 x 5), 0.68 (2H, m), 0.55 (2H, m 8.45 and 8.40 (1H, 2 x d), 7.96 - 7.88 472 AY (2H, m), 7.87 (1H, dd), 7.74 and 7.72 (1H, 2 x d), 7.49 and 7.48 (1H, 2 x d), 7.39 - 7.27 ( 4H, m), 7.25 - 7.19 (1H, m), 6.80 and 6.79 (1H, 2 x d), 6.69 and 6.69 (1H, 2 x d), 5.43 - 5.34 0 A (1H, m), 2.89 - 2.80 (1H , m), 2.70 “SN N (1H, dd), 2.61 - 2.49 (1H, m), 2.13 0 0 and 2.08 (3H, 2 x 5), 0.73 - 0.63 (2H, m), 0.59 - 0.50 (4H , m), 0.30 — 0.15 (2H, m 8.44and 8.39 (1H,2x d), 7.90- 7.77 | 419 AY (2H, m), 7.73 (1H, d), 7.49 and 7.48 (1H, 2 x d), 7.43 - 7.35 (2H, m), 7.35 -7.26 2H, m), 7.21 (1H, m), 6.77 (1H, d), 6.66 and 6.65 (1H, 2 x d), 5.18 (1H, m), 4.61 (1H, m), 3.48 - ~- 3.35 (2H, m), 2.85 (1H, m), 2.13 and N OH 2.07 (3H, 2x 5), 2.15 - 1.87 (2H, m), 0 0.74 - 0.62 (2H, m), 0.61 - 0.48 (2H, m) 8.45 and 8.41 (1H, 2 x d), 8.23 (1H , 439 ne m), 7.91 (1H, d), 7.84 (1H, d), 7.81 (1H, m), 7.78 - 7.69 (2H, m), 7.65 - CI 7.44 (5H, m), 6.78 and 6.75 ( 1H, 2 x d), 6.69 and 6.68 (1H, 2 x d), 5.95 ~ (1H, m), 2.85 (1H, m), 2.14 and 2.08 N (3H,2 xs), 1.64 and 1.63 (3H, 2 x d ), for 0.68 (2H, m), 0.55 (2H, m)

YAAY

— Ye — 8.44 and 8.38 (1H, 2 x d), 7.86 (1H, 403 AD d), 7.71 and 7.61(1H, 2 x 9 (1H, d), 7.49 (1H, m), 7.46 - 7.37 (2H, m), 7.31 2H, 1), 7.26 - 7.17 (1H, m), 6.80 (1H, m), 6.67 (1H, m), : 4.91 (1H, , le 2.84 (1H, m), 2.13 ( 3H, SO 27 80, 2.04 - 1.90 (1H, m), 1.88 - 1.73 (1H, m), 0.86 (3H, t), 0.68 (2H, H m), 0.55 (2H, m 8.45 - 8.37 (1H, m), 7.84 - 7.77 (1H, 415 AY m), 7.68 and 7.58 (1H, 2 x s), 7.44 and 7.36 (1H, 2 x d), 7.29 - 7.23 (3H, m), 7.19 - 7.06 (3H, m) ), 6.87 - 6.78 (1H, m), 6.71 and 6.68 (1H, d), 5.70 (1H, br), 4.10 (1H, br), 3.83 (1H, br), ~ N 2.83 (1H, m), 2.41 - 2.27 (1H, m), 2.1 (1H, s), 1.93 - 1.64 (6H, m), 0.68 (2H, m), 0.54 (2H, m 8.47 and 8.39 (1H, 2 x d), 7.90 - 7.78 489 AY (2H, m), 7.72 and 7.71 (1H, 2 x d), 7.51-7.41 3H, m), 7.35 - 7.28 (2H, m), 7.26 - 7.20 (1H, m), 6.84 and 6.83 (1H, 2x d), 6.71 and 6.70 (1H, 2 0 x d), 5.54 - 5.40 (1H, m), 3.02 - 2.92 ~ > (1H, m), 2.89 - 2.77 (2H, m), 2.10 N 0 and 2.07 ( 3H, 2 x 99. 1.28 and 1.27 H (9H, 2 x 5), 0.68 (2H, m), 0.54 (2H, m) 8.43 (1H, d), 7.86 (1H, d), 7.73 (1H, 325 AA 5), 7.48 (1H, d), 7.40 (1H, d), 6.89 * A (1H, d), 6.72 (1H, d), 2.92 - 2.71 (2H, N m), 2.10 (3H, s) , 0.78 - 0.45 (8H, m) H 8.45 and 8.40 (1H, 2 x d), 7.96 - 7.88 472 Ad (2H, m), 7.87 (1H, dd), 7.74 and 7.72 (1H, 2 x d), 7.49 and 7.48 (1H, 2 x d), 7.39 - 7.27 (4H, m), 7.25 - 7.19 (1H, m), 6.80 and 6.79 (1H, 2 x d), 6.69 and 6.69 (1H, 2 x d), 5.43 - 5.34 0 A (1H, m), 2.89 - 2.80 (1H, m), 2.70 SN N (1H, dd), 2.61 - 2.49 (1H, m), 2.13 m 0 and 2.08 (3H, 2 x s), 0.73 - 0.63 (2H, m), 0.59 - 0.50 (4H, m), 0.30 — 0.15 (2H, m)

YAAY

— 1©7 - 8.43 (1H, d), 7.86 (1H, dd), 7.74 (1H, 383 0 9 d), 7.48 (1H, d), 7.40 (1H, ¢), 4 (1H, d), 6.66 (1H, d), 3.84 (2H, dd), 3.30 - 3.09 (4H, m), 2.84 (1H, m), 2.10 (3H, 5), 2.01 - 1.82 (1H, m), “e 1.57 ( 2H, d), 1.27 - 1.10 (2H, m), N 0.69 (2H, m), 0.55 (2H, m) H 433 0 a) 8.44 (1H, d), 7.87 (1H, dd), 7.77 (1H , d), 7.59 (1H, 1), 7.50 (1H, d), 6.82 ) (1H, d), 6.77 - 6.65 (4H, m), 4.55 0 (1H, dd), 4.44 (1H, dd), 4.35 - 4.21 (4H, m), 2.85 (1H, m), 2.13 (3H, 5), SN 0.69 (2H, m), 0.56 (2H, m) 0 8.44 (1H, d), 7.87 (1H, dd ), 7.76 (1H, 403 ay d), 7.63 (1H, 1), 7.49 (1H, d), 7.09 - 6.97 (3H, m), 6.82 (1H, d), 6.70 (1H, os d), 4.58 (1H, dd), 4.47 (1H, dd), 2.85 (1H, m), 2.25 3H, 5), 2.20 (3H, s), “SN 2.12 (3H, 5), 0.69 (2H, m), 0.56 (2H, m) H 443 F . qv 8.43 (1H, d), 8.10 (1H, t), 7.87 (1H, " dd), 7.75 (1H, d), 7.72 - 7.52 (4H, m), 7.49 (1H, d), 6.82 (1H, d), 6.72 (1H, d), 4.66 (1H, dd), 4.56 (1H, dd), 2.85 (1H, m), 2.11 3H, s), 0.69 (2H, > m), 0.55 (2H, m ) N

H

8.44 (1H, d), 7.84 (1H, d), 7.75 and 443 as 7.71 (1H, 2 x 5), 7.46 (1H, 1), 7.27 - 6.90 (SH, m), 6.16 and 6.05 (1H, 2) x brs), 4.47 (1H, t), 2.98 (1H, m), 2.84 (1H, m), 2.38 - 2.22 (1H, m), 2.29 ~~ (3H, 5), 2.13 and 2.02 (3H, 2 x 5), N 1.97 - 1.80 (1H, m), 1.72 - 1.37 (4H, m), 0.69 (2H, m), 0.56 (2H, m) 8.44 (1H, d), 7.86 (1H, dd), 7.79 (1H, 403 io 1), 7.75 (1H, d), 7.49 (1H, d), 6.93 (2H, 5), 6.86 (1H, 5), 6.83 (1H, d), 6.69 (1H, d) , 4.52 (1H, dd), 4.40 (1H, dd), 2.85 (1H, m), 2.25 (6H, d), 2.11 SN (3H, s), 0.69 (2H, m), 0.55 (2H, m) V

YAAY

1” 8.45 - 8.37 (1H, m), 7.80 (1H, m), 429 5 7.68 and 7.59 (1H, 2 x s), 7.44 and 7.37 (1H, 2 x d), 7.19 - 7.08 (1H, m), 7.01 - 6.76 (4H, m), 6.71 and 6.68 (1H, 2 x d), 5.81 - 5.55 (1H, br), 4.18 - 3.97 (1H, br), 3.93 - 3.72 (1H, br), ~ 2.83 (1H , m), 2.29 - 2.21 (2H, m), N 2.26 and 2.25 (3H, 2 x 5), 2.08 (1H, 5), 1.92 - 1.66 (4H, m), 0.67 (2H, m), 0.54 ( 2H, m 8.43 - 8.38 (1H, m), 7.84 - 7.77 (1H, 445 ay m), 7.69 and 7.59 (1H, 2 x 5), 7.44 and 7.36 (1H, 2 x d), 7.19 - 7.11 (1H, m), 6.94 (1H, , 6.87 - 6.77 3H, m), 6.68 and 6.66 (1H, 2 x d), 6.05 5.89 (1H, br), 4.21 — 4.05 (1H, br), 3.80 cm (1H, br), 3.80 and 3.79 (3H, 2 x 5), and “ 2.84 (1H, m), 2.30 - 2.13 (2H, m), 2.09 (1H, s), 1.93 - 1.81 ( 2H, m), 1.80 - 1.63 (4H, m), 0.67 (2H, m), 0.55 (2H, m) 8.45 (1H, d), 7.87 (1H, dd), 7.98 (1H, | _ 403 an s ), 7.77 (1H, d), 7.64 (1H, t), 7.50 (1H, d), 7.08 - 7.01 (2H, m), 6.95 (1H, d), 6.83 (1H, d), 6.71 (1H, d), 4.53 (1H, dd), 4.42 (1H, dd), 2.85 (1H, m), 2.27 3H, 5), 2.22 (3H, 5), TSN 2.12 3H, s), 0.69 (2H, m) , 0.56 (2H, 0 m) 511 F F aq

F F

8.44 (1H, d), 8.20 (1H, 1), 8.03 (2H, s), 7.87 (1H, dd), 7.76 (1H, d), 7.49 F F (1H, d), 6.82 (1H, d), 6.74 (1H, d), 4.80 - 4.57 (2H, m), 2.84 (1H, m), 2.10 (3H, s), 0.69 (2H, m), 0.55 (2H, ~_

Nm)

H

CDCI3 in IH NMR (i) o. For example, Lad (b) is included

YAAY

16 — - Example (Veo) N-Cyclopropyl-4-methyl-3-[2-ox0-3-[[[2-[2-(1-pyrrolidinyl)ethoxy] phenyl methyl ‎Jamino] -1(2H)-pyrazinyl]-benzamide l AN 0 bm 0 N line N N H H 0 to a stirred solution of: ¢3-(3,5-dibromo-2- ox0-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methyl ester (ex. Ab 0.1 g) in (Ja Y) tetrahydrofuran in a microwave vial added triethylamine (YA) μl) and YE ( 2-(aminomethyl)-phenol mg). The reaction mixture was stirred overnight before removing the solvent. The dry residue NN- (Ja ¥) dimethylformamide V+ was dissolved; The residue was dissolved in: YY 1) 1-(2-chloroethyl)-pyrrolidine hydrochloride mg) and cesium carbonate AA (mg) was added. The mixture was heated at Av C for 11 hours. Volatiles were removed under reduced pressure. ethyl acetate was added and the mixture was jue with water and brine; Then it (MgSO4) was dried, filtered, and the solvent removed. Then (Ja ¥) tetrahydrofuran was added to the vial and this was followed by the addition of amine cyclopropyl (© ), + (Jo rang JY 5a Y) cyclopentylmagnesium bromide in 1 1 diethyl ether ml) dropwise. After YAAY

—\Voo — stir for 70 minutes; (Je ¥) ethanol was added, followed by the addition of ammonium formate (.7 g) + palladium ZY on Wo (carbon mg). The reaction mixture was heated in Jala microwave for 10 minutes at 100 °C before cooling to room temperature, filtering and washing with ethanol after purification with HPLC ° (Gemini column) acetonitrile filtration solution: ammonia 7 0,1 (. (poe ¥Y) title compound obtained as a solid

MS: APCI(+ve) 488 (M+H+). 1H NMR 5 (DMSO-d6, 400MHz) 8.44 (1H, d), 7.87 (1H, dd), 7.76 (1H, d), 7.53 (1H, 1), 7.49 (1H, d), 7.24 - 7.18 (1H) , m), 7.14 - 7.11 (1H, m), 6.99 (1H, d), 6.91 - 6.86 (1H, m), 6.81 (1H, d), 6.70 (1H, d), 4.57 (1H, dd), 4.48 (1H, dd), 4.12 (2H, 0.2.89 - 2.81 (3H, m), 01 2.59 - 2.53 (4H, m), 2.12 (3H, s), 1.71 - 1.65 (4H, m), 0.72 - 0.66 (2H, m), 0.58 - 0.53 (2H, m) (Ye ) Example N-Cyclopropyl-4-methyl-3-[2-ox0-3-[[(R)-phenyl-4- piperidinylmethyl]Jamino]-1(2H)- pyrazinyl]-benzamide, trifluoroacetate Vo H N NN N -

N b N Te < 7

H

0 - YAAY's secret

—- A (): 4-[(R)-[[(R)-(1,1-Dimethylethyl)sulfinylJamino]phenylmethyl]-1- piperidinecarboxylic acid, phenylmethyl ester A mixture of: 4- was stirred formyl-piperidine-1-carboxylic acid, benzyl ester © » (971, g); and +,©V) (R)-2-methyl-2-propanesulfinamide g) 5 anhydrous copper(I) sulphate )0,} (Je Y +) dichloromethane 5 (a> at room temperature for £A h. The (IT) copper sulfate was separated by filtration and the filtrate was concentrated. The residue was treated with (Je V0) dichloromethane and cooled to VA = 1. A solution of phenylmagnesium was added bromide 0 in “Ysa YY) diethyl ether; (Je) drip. The mixture was slowly warmed to zero 1; then quenched by adding an aqueous solution of 1111401. The mixture was stirred for 10 min and extracted in dichloromethane. The organic phase (0482504) was stirred, filtered, and concentrated in culture media. The residue was purified ( Chromatograph 102 and bombardment with ethyl : iso-hexane acetate (0-001# (((to obtain the title compound Ty 9 mg) 1H NMR 5 (CDCI3, 400MHz) 7.38-7.27 (8H, m) ), 7.22 (2H, m), 5.08 (2H, 5), 4294.13 00 (3H, m), 3.41 (1H, d), 2.87-2.58 (2H, m), 2.04 (1H, m), 1.88 (1H, m), 1.50 (1H, m), 1.23 (9H, 5), 1.20-1.01 (2H, m). YAAY

— \oV — 4-[(R)-Aminophenylmethyl]-1-piperidinecarboxylic acid, phenylmethyl ester (<) : L methyl phenyl ester A mixture of 4-[(R)-[[(R)-) was stirred (1,1-dimethylethyl)sulfinylJamino[phenylmethyl]-1- piperidinecarboxylic acid. Molar (ml) £) of 1,4-dioxane in hydrogen chloride 5 (Js ©) methanol g (g) +,04) © minutes and then concentrate it in vacuo. The residue was diluted in 01 at room temperature for 1 hour to obtain the title compound diethyl ether and pulverized with (Je Y) dichloromethane mg. 70) by sub-solid 1H NMR 6 (DMSO-d6, 400MHz) 8.56 (2H, d), 7.51-7.26 (10H, m), 5.05 (2H, s), 4.13- 4.01 (2H, m), 3.92 (1H, d), 2.90-2.59 (2H, m), 2.02 (1H, m), 1.92 (1H, m), 1.18 2H, m), 0 0 1.00 (1H, m). (c) N-Cyclopropyl-4-methyl-3-[2-ox0-3-[[(R)-phenyl-4-piperidinylmethyl]Jamino]-1(2H)- pyrazinyl]-benzamide To a stirred solution of VO 3-(3,5-dibromo-2-oxo0-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methyl ester in a microwave vial was added (Je V, 0) tetrahydrofuran g) in 0 μl (JB) co (JB) and VY) N,N-diisopropylamine

M 1 - (pe 4 A) «4-[(R)-aminophenylmethyl]-1-piperidinecarboxylic acid, phenylmethyl ester . The reaction mixture was heated at 1101°C for 00 minutes in a microwave. The reaction mixture was cooled to room temperature before amine cyclopropyl (?1, mL) Y) cyclopentylmagnesium bromide in diethyl ether was added; 1 ml) by drip. after flipping © for VO min; (Ja 1) ethanol was added, followed by ethyl acetate. The solvent was washed with water and brine, dried (Na2S04), filtered, and the solvent removed. The product was dissolved in t-butanol (7 ml), followed by addition 1(1,4-cyclohexadiene mL) and 107 Pd on carbon Yo) mg). The reaction mixture was heated in a microwave at 1011 °C for 1 min; cooled at room temperature, filtered, and purified by preparative HPLC (Column “Gemini” 70.1 lysate 0 trifluoroacetic acid: 20610010716) to obtain:

N-cyclopropyl-4-methyl-3-[2-0x0-3-[[(R)-phenyl-4-piperidinylmethyl Jamino]-1(2H)- pyrazinyl]-benzamide 0A) and -4 [(R)-[[4-[5-[(cyclopropylamino)carbonyl]-2-methylphenyl]-3,4-dihydro-3- ‎oxopyrazinyl]amino]phenylmethyl]-1-piperidinecarboxylic acid, phenyl ester 1 MS: APCI(+ve) 458 (M+H+). (mg). , 7.51 — 7.43 (3H, m), 7.37 — 7.31 (2H, m), 7.28 — 7.23 (1H, m), 6.83 — 6.80 (1H, m), 6.72 — 6.68 (1H, m), 4.86 — 4.79 ( 1H, m), 3.37 — 3.29 (1H, m), 3.24 — 3.17 (1H,

YAAY

- 159 — m), 2.89 - 2.70 (3H, m), 2.29 - 2.18 (1H, m), 2.13 (1.5H, s), 2.10 — 2.00 (1H, m), 2.04 (1.5H, s), 1.45 — 1.22 (4H, m), 0.72 — 0.63 (2H, m), 0.58 — 0.49 (2H, m). (Y+Y) Example 4-[(R)-[[4-[5-[(Cyclopropylamino)carbonyl]-2-methylphenyl]-3,4-dihydro-3- oxopyrazinyl]Jamino]phenylmethyl] -1-piperidinecarboxylic acid, phenylmethyl ester 5 oo

N

68 0 7 M- A 2 0 : to a stirred solution of 3-(3,5-dibromo-2-ox0-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methyl ester Anhydrous (ml) into a microwave vial to which THF (g) was added in 0.1 (eg B) 0 μl and 001) triethylamine (eg 4-[(R)-aminophenylmethyl]-1 piperidinecarboxylic acid phenylmethyl ester 10 minutes before 10 pm for 171 minutes, the reaction mixture was heated in a microwave at (peed A ch 0) μl (001) amine cyclopropyl cooled to room temperature and part by part added. After (Je +, YO; diethyl ether molar in Y) cyclopentylmagnesium bromide ammonium formate followed by the addition of (Ja ¥) ethanol min; 00 sad was added by stirring Vo

YAAYX

-111 — (¥, + g) and 1107 palladium on carbon 1 (mg) The mixture was heated in a microwave for 00 minutes at 5 001 before being cooled to room temperature; It was filtered and washed with ethanol, then the filtrate was concentrated in an incubator medium. After purification by HPLC (Gemini column filtrate (acetonitrile : ammonia Ze) the title compound 1 © 1 mg) was obtained. MS: APCI(+ve) 592 (M+H+). 1H NMR 6 (DMSO-d6, 400MHz) 8.46 (0.5H, d), 8.36 (0.5H, d), 7.86 - 7.82 (1H, m), 7.80 -7.71 2H, m), 7.49 - 7.42 (3H, m) ), 7.36 -7.29 (7TH, m), 7.26 - 7.20 (1H, m), 6.81 - 6.78 (1H, m), 6.67 - 6.63 (1H, m), 5.50 (2H, s), 4.82 - 4.73 (1H , m), 4.12 - 4.0 (1H, m), 4.0 - 3.90 (1H, m), 2.90 - 2.75 (1H, m), 2.20 - 2.10 (1H, m), 2.13 (1.5H, s), 2.04 ( 1.5, 5), Ve 2.00-1.88 (1H, m), 1.23 - 1.00 (4H, m), 0.7 - 0.64 (2H, m), 0.57 - 0.51 (2H, m). ( 0 ¥) Example N-Cyclopropyl-4-methyl-3-[2-0x0-3-[[(S)-phenyl-4-piperidinylmethyl]amino]-1(2H)- pyrazinyl] -benzamide trifluoroacetate H N 0 2

A.N

N2 aN2

H H

YAAY

111 - The title compound was prepared and purified according to Example 011 using: (S)-2-methyl-2-propanesulfinamide.

MS: APCI(+ve) 458 (M+H+). 1H NMR § (DMSO0-d6, 400MHz) 8.46 (0.5H, d), 8.36 (0.5H, d), 7.91 - 7.84 (2H, m), 7.71 (1H, dd), 7.51 - 7.43 (3H, m) , 7.37 - 7.30 (2H, m), 7.29 - 7.22 (1H, m), 6.82 — 6.80 © (1H, m), 6.72 — 6.68 (1H, m), 4.86 - 4.80 (1H, m), 3.38 - 3.29 (1H, m), 3.25 - 3.17 (1H, m), 2.89 - 2.70 (3H, m), 2.30 - 2.18 (1H, m), 2.13 (1.5H, s), 2.04 (1.5H, s), 2.10 - 2.00 (1H, m), 1.43 - 1.21 (4H, m), 0.73 - 0.63 (2H, m), 0.58 - 0.49 (2H, m).

(V+§) Example 3-[5-Cyano-2-ox0-3-[(phenylmethyl)amino]-1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl- Ye benzamide

N 0 ZN > x

‎N N

H H] 1 t)].

to a stirred solution of: 3-(3,5-dibromo-2-ox0-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methyl ester VO (example 1ap; 0,4 g) in (Je Y) tetrahydrofuran in a microwave vial added: YAAY

17 -

Vo) benzenemcthanamine 5 (ids Sue ¥¥'+) N,N-diisopropylethylamnie μl). The reaction mixture was stirred overnight before amine cyclopropyl (©, + mL) Y) cyclopentylmagnesium bromide in diethyl ether was added; ¥ (Je drip). The reaction mixture was stirred 0 32d min before adding (Ja Y) ethanol followed by the addition of © ammonium chloride. The ethyl acetate solution was extracted and the dyin all was washed with brine and dried (0482504; filtered and solvent removed to obtain amide as a solid 08Y mg). (Js A) N,N-dimethylformamide Z tetrakis(triphenylphosphine)palladium(0) )+© mg) zine cyanide s (17; mg) was added and the reaction mixture was heated in a microwave at 176 C for 0 minutes 0 then cool the reaction mixture to room temperature Cuddy. Add water and extract the mixture Ye ethyl acetate . The collected inorganic layers were juiced with brine and dried

(Na2504) and filtered and removed the solvent to obtain the title compound (OV) (mg). MS: APCI(+ve) 400 (M-+H-+). 1H NMR 6 (DMSO-d6, 400MHz) 8.50 (1H, 0.8.42 (1H, d), 7.87 (1H, dd), 7.81 (1H, d), (1H, 5), 7.50 (1H, d), 7.37 - 7.31 (4H, m), 7.29 - 7.23 (1H, m), 4.62 - 4.55 (1H, m), 7.76 (1H, m), 2.88 - 2.81 (1H, m), 2.14 (3H, s), 0.73 - 0.67 (2H, m), 0.58 - 0.53 V 4.44 - 4.52 (2H, m)

(V0) Example N-Cyclopropyl-3-[5-[(dimethylamino)methyl]-2-o0x0-3-[(phenylmethyl)amino]-1(2H)- pyrazinyl]-4-methyl- benzamide

‎YAAY

17 -

N.0 x N

N N

H H rv : to a stirred solution of 3-[5-cyano-2-o0x0-3-[(phenylmethyl)amino]-1(2H)-pyrazinyl]-N-cyclopropyl-4-methy!-benzamide mg) V4) cobalt(Il) chloride (Jo Y) methanol mg) was added in 001 Nef (example ©

AY mg) part by part. After 10 minutes, sodium borohydride (90) was added, followed by the addition of (ane 051) sodium and 086610:700:070:106 (Je »,*) formaldehyde solution to the reaction mixture and the mixture was extracted using (de ©) mixture overnight. Water (Na2S04) collected organic layers were added with brine, dried, Jue dichloromethane 70.1 Gemini filter solution (HPLC column), filtered, and solvent removed. After Purification with 0 mg. YE) The title compound (acetonitrile : ammonia) was obtained.

MS: APCI(+ve) 432 (M+H+). 1H NMR 6 (DMSO-d6, 400MHz) 8.43 (1H, d), 7.88 - 7.81 (2H, m), 7.75 (1H, d), 7.48 (1H, d), 7.38 - 7.34 (2H, m), 7.33 - 7.28 (2H, m), 7.25 - 7.19 (1H, m), 6.56 (1H, 5), 4.59 (1H, dd), 4.47 (1H, dd), 3.13 (2H, d), 2.88 - 2.80 (1H , m), 2.15 (6H, 5), 2.11 (3H, 5), 0.71 0 - 0.65 (2H, m), 0.57 - 0.53 (2H, m)

YAAY

115 (V+) Example 4-[5-[(Cyclopropylamino)carbony!]-2-methylphenyl]-4,5-dihydro-5-oxo0-6- [(phenylmethyl)amino]- 2-pyrazinecarboxamide

Os NH, 0 x X N

A N Or B N

N N UO

0 : to a stirred solution of 3-[5-cyano-2-oxo0-3-[(phenylmethyl)amino]-1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl- benzamide (de 1) ( JS » ammonia A solution (1 Ja (methanol mg) was added in 10014 001 (eg an hour; VY ml water was added) after 1) 7700 hydrogen peroxide followed by the addition of the layered solution The combined organic matter was treated with a solution of Jue dichloromethane and the mixture was extracted using 0 “Gemini (HPLC saline column; dried (182504), filtered, and solvent removed. After purification in mg. ¥V) a compound was obtained. Title ) acetonitrile: ammonia 701 filtering solution

MS: APCI(+ve) 418 (M+H+). 1H NMR 6 (DMSO-d6, 400MHz) 8.44 (1H, d), 8.19 (1H, 0, 7.86 (1H, dd), 7.77 (1H, d), 7.58 (1H, d), 7.49 (1H, d) , 7.45 - 7.40 (3H, m), 7.32 (2H, td), 7.26 - 7.21 (2H, m), 4.72 Vo (1H, dd), 4.57 (1H, dd), 2.88 - 2.80 (1H, m), 2.11 (3H, s), 0.71 - 0.66 (2H, m), 0.57 - 0.53 (2H, m).

YAAY

- 1010 — (0117) Example 3-[5-Chloro-3-(4-methyl-1-piperazinyl)-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-4- methyl- benzamide

Cl9 AN

A 1 ab 1 © 0 . No 3-(3,5-Dichloro-2-ox0-1(2H)-pyrazinyl)-4-methyl-benzoic acid, methyl ester : 0 © (— 1 1 (Ex. 3-[(cyanomethyl)amino]-4-methyl-benzoic acid, methyl ester : to ml). The mixture of Y)oxalyl chloride (Je 01( 1,2-dichlorobenzene) was heated. Add m for hours before removing the volatile substances under reduced pressure. The reaction 001 was purified to obtain the remaining dichloromethane compound (chromatograph 5:02) and filtered using

MS: APCI(+ve) 313 (M+H+). mg). 4-methyl-benzoic acid, methyl ester : to a solution of a mixture of (example » 3-(3,5-dichloro-2-oxo-1(2H)-pyrazinyl)-4-methyl-benzoic acid, methyl ester © ml. +,Y) 1-methyl-piperazine (Ja ©) acetonitrile mg) added in 0 Jyev

YAAY

117 - - after 11 hours; The reaction mixture was concentrated in incubator medium. The residue was diluted with dichloromethane, washed with saturated water 11811003, dried (MgSO4), filtered, and the solvent removed to obtain the subtitle compound. MS: APCI(+ve) 377 (M+H+).

He) © 3-[5-Chloro-3-(4-methyl-1-piperazinyl)-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-4- methyl-benzamide

into a stirred solution of: 3-[5-chloro-3-(4-methyl-1-piperazinyl)-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzoic acid, methyl ester (Ex. V + (0) in (Je 1) tetrahydrofuran under nitrogen amine cyclopropyl (Jo 0,0) was added, followed by JY sa Y) iso-propylmagnesium chloride in +A ¢ tetrahydrofuran (Je; part part. After an hour, saturated aqueous NHAC was added and the mixture extracted in ethyl a. acetate. The organic extracts were washed with brine; dried (MgSO04) and filtered. VO and the solvent was removed in vacuo After purification by HPLC (Gemini column filtration buffer 70.1 acetonitrile: ammonia) the title compound (YO) (mg) was obtained. MS: APCI(+ve) 402 (M+H+). YAAY

197 - 1H NMR 5 (DMSO-d6, 400MHz) 8.42 (1H, d), 7.84 (1H, dd), 7.73 (1H, d), 7.46 (1H, d), 7.18 (1H, 5), 3.88 - 3.74 (4H, m), 2.88 — 2.80 (1H, m), 2.43 - 2.36 (4H, m), 2.19 GH, s), 2.12 (3H, 5), 0.72 - 0.66 (2H, m), 0.58 - 0.53 ( 2H, m). (VA) Example 3-[5-Chloro-3-[[3-(dimethylamino)propyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-© cyclopropyl-4-methyl-benzamide

Cl 0 of 0

A N

N OY b NNN

H H

0 : to a stirred solution of

Ji) «3-(3,5-dichloro-2-o0x0-1(2H)-pyrazinyl)-4-methyl-benzoic acid, methyl ester : (Jo ¥) tetrahydrofuran was added in (pase 0 dey microliters) and the mixture was stirred at a temperature of (4+) (N,N-dimethyl-1,3-propanediamine: microliters) then added ?0 (cyclopropyl amine) h. VY was added to the room for ml ) part by part. 1 µM tetrahydrofuran in Y) iso-propylmagnesium chloride was stirred in 1 µl iso-propylmagnesium chloride (iso-propylmagnesium chloride) min and 01 of the reaction mixture was added for an additional min and 10 mL aqueous 1111401 was added. The mixture was stirred for 1 time; tetrahydrofuran) © Organic Layers Jue Done. ethyl acetate is saturated. The aqueous solution was extracted using

HPLC, filtration, and solvent removal. After purification with (Na28S04) collected with brine; And dried

YAAY

- 18 - Obtained acetonitrile : ammonia 7.1 filter solution “Gemini” (MS column: APCI(+ve) 404 (M+H+). 1H NMR 6 (DMSO-d6, 400MHz ) 8.43 (1H, d), 8.03 (1H, t), 7.85 (1H, dd), 7.76 (1H, d), 7.48 (1H, d), 6.89 (1H, s), 3.41 - 3.26 (2H, m ), 2.89 - 2.81 (1H, m), 2.27 (2H, t), 2.14 © (6H, s), 2.12 (3H, s), 1.71 (2H, quintet), 0.72 - 0.66 (2H, m), 0.58 - 0.53 (2H, m) (5) Example 3-[5-Chloro-2-o0x0-3-[(phenylmethyl)amino]-1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl- benzamide Cl 0 2

Or b A N N Ae

H H

0 101 : To a stirred solution of 3-(3,5-dibromo-2-ox0-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methyl ester Jala was added (ml) in a microwave vial ¥) tetrahydrofuran 4 PEN 0,1 (Example B mg). The reaction was stirred overnight with 1¢) benzylamine 5 μl) V1) tetrahydrofuran mol in 7) iso-propylmagnesium chlorides (Js +,YY) amine cyclopropyl before adding 1°' (Ja Y) ethanol min. Added 0 drip after stirring for a period of (#0 Jo) tetrahydrofuran

YAAY

119 — - formic acid (€, + ml) and 10 palladium over yo carbon (mg). The reaction mixture was heated in a microwave for 10 minutes at 110°C before being cooled to room temperature, filtered, and washed with ethanol. The filtrate was concentrated in vacuo. After purification by HPLC (Column “Gemini acetonitrile filtrate: ammonia Le”) the title compound (he) (© mg) was obtained. MS: APCI(+ve) 409 (M+H+). 1H NMR § (DMSO-d6, 400MHz) 8.47 - 8.39 (2H, m), 7.86 (1H, dd), 7.78 (1H, d), 7.48 (1H, d), 7.37 - 7.31 (4H, m), 7.28 - 7.22 (1H, m), 6.94 (1H, s), 4.52 (2H, ddd), 2.88 - 2.80 (1H, m ), 2.13 (3H, s), 0.72 - 0.66 (2H, m), 0.57 - 0.53 (2H, m). ( 0 ) Example Yo 3-[5-Chloro-2-0x0-3-[(2-phenylethyl)amino]-1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl- benzamide Cl 0 A iN Co 0 (1 +9) The title compound was prepared and purified according to the example

MS: APCI(+ve) 423 (M+H+). Vo

YAAY

111 NMR 6 (DMSO-d6, 300MHz) 8.43 (1H, d), 7.94 - 7.82 (2H, m), 7.76 (1H, s), 7.48 (1H, d), 7.35 - 7.18 (5H, m), 6.92 (1H, d), 3.64 - 3.46 (2H, m), 2.96 - 2.80 (3H, m), 2.12 (3H, 5), 0.74 - 0.63 (2H, m), 0.61 - 0.50 (2H, m). (111) Example N-Methoxy-4-methyl-3-[3-[[[2-[(4-methyl-1-piperazinyl)methyl]phenylJmethylJamino]- © 2-0x0-1(2H)- pyrazinyl]-benzamide yr

N

ZN p09 2 for oo. N

N likes CCT 0 : to a stirred solution of

J) «3-(3,5-dibromo-2-ox0-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methyl ester triethylamine (Je ¥) tetrahydrofuran g) was added in a microwave vial in 0.1 in 1 0 mg).4 +) 2-[(4-methyl-1-piperazinyl)methyl]-benzenemethanamine 5 µl) YO +)

AY) O-methylhydroxylamine hydrochloride The reaction mixture was stirred overnight before adding dropwise. after (Je ¥ “diethyl ether m in ¥ ) cyclopentylmagnesium bromide mg) (a> +,¢) ammonium formate and then add (Ja Y) ethanol min; T+ was added stirred for 0.6 on carbon (£0 mg). The reaction mixture was heated in a microwave for palladium 7201 and 0 mm ethanol was concentrated before it was cooled to room temperature; It was filtered and washed for 100 minutes at

YAAY

1971 -

filtrate in vacuo. After purification by HPLC (column “Gemini” filtration solution 70,1

acetonitrile : ammonia (title compound VY was obtained mg). TTA 477 MS: APCI(+ve) 1H NMR 5 (DMSO-d6, 400MHz) 7.77 (1H, d), 7.67 (1H, 5), 7.51 (1H, d), 7.41 (1H, d), 3H, m), 6.90 (1H, d), 6.75 (1H, d), 4.72 (1H, d), 4.62 (1H, d), 3.80 — 3.69 ° 7.27 7.33 (2H, m), 3.69 (3H, 5), 3.44 — 3.25 (4H, m), 2.70 (3H, 5), 2.50 — 2.35 (2H, m), 2.12 GH, s).

(11”) Example, N-Methoxy-4-methyl-3-[3-[(1-methyl-1-phenylethyl)amino]-2-oxo-1(2H)-pyrazinyl]- benzamide

= A Ham 9 O.

N 8 0 to a stirred solution of : ¢3-(3,5-dibromo-2-ox0-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methyl ester (Example 1ab) (aa To 0.1 (V) tetrahydrofuran mL) Jala microwave vial added (YA) triethylamine 0 μL and VE (a,0-dimethyl-benzenemethanamine mg). The reaction mixture was heated in A microwave for 171 minutes before being cooled to room temperature and the addition of (AY) O-methylhydroxylamine hydrochloride MG) and the addition of 1) M cyclopentylmagnesium bromide in diethyl ether; 7 (Ja) DRIP BY FLIPPING YAAY

- 177 - mg) +,£) ammonium formate and then add (Jo Y) ethanol min; 70 for 01 has been added to carbon (£0 mg). The reaction mixture was heated in a microwave for palladium 70 and ethanol concentration before being cooled to room temperature, filtered, and washed with Ar min at

Ze) filter solution “Gemini” (HPLC column filtered in vacuo. After purification b the title compound was obtained as a solid (£1 mg). ) acetonitrile : ammonia ©

MS: APCI(+ve) 393 (M+H+).

IH NMR 5 (DMSO-d6, 400MHz) 11.78 (1H, 5), 7.79 (1H, dd), 7.67 (1H, 5), 7.52 (1H, d), 7.41 - 7.37 2H, m), 7.34 - 7.27 2H , m), 7.21 - 7.16 (1H, m), 6.93 (1H, 5), 6.67 (2H, 5), 3.70 3H, 5), 2.13 (3H, 5), 1.76 (3H, 5), 1.73 (3H , 5). (VF) Example Ve

N-Methoxy-4-methyl-3-[2-0x0-3-[[(1R)- 1-phenylpropylJamino]-1(2H)-pyrazinyl]- benzamide, trifluroacetate 9 0 OCT or

N N

H H

0 to a stirred solution of : ¢3-(3,5-dibromo-2-oxo0-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methyl ester Vo (ex. 2« 0.7 g) in ‎ (Y) tetrahydrofuran mL) In a microwave vial added (A+) triethylamine (µL) and Vt)- benzenemethanamine - (aR) - ethyl mg). It was completed

YAAY

177 -

Stir the reaction mixture for VY hour and add 1.7 (ammonium formate g) palladium 701 on carbon 71 (mg) ethanol s (¥ ml). The reaction mixture was heated in a Fos al microwave for 1 min at 1°C before being cooled to room temperature, filtered, and washed with ethanol. The filtrate was concentrated in vacuo. The remaining dallas was ethyl acetate and washed with water. The organic phase was concentrated and the residue was taken in (Je ©) tetrahydrofuran and O-methylhydroxylamine hydrochloride (17 mg) was added, followed by dropwise addition of Y) cyclopentylmagnesium bromide

molar in (Ja ¢ “diethyl ether). After 70 minutes, saturated aqueous 1111401 was added and the mixture was extracted by ethyl acetate. The organic phase was concentrated in an incubator medium. After purification by HPLC (Gemini column) filter solution ‎acetonitrile : ammonia 71 ) the title compound was obtained

01 as a solid (1 vv mg). MS: APCI(+ve) 393 (M+H-+). 1H NMR 5 (DMSO-d6, 400MHz) 11.84 - 11.71 (1H, m), 7.78 (1H, d), 7.67 (1H, d) ), 7.52 (2H, 1), 7.46 - 7.41 (2H, m), 7.35 - 7.30 (2H, m), 7.26 - 7.21 (1H, m), 6.82 - 6.79 (1H, (1.5H, 5), 2.09 2.15 .l m), 6.73 - 6.70 (1H, m), 4.90 (1H, q), 3.71 (1.5H, s), 3.68 (1.5H, (1.5H, s), 2.03 - 1.95 (1H, m), 1.90 - 1.78 (1H, m), 0.87 (3H, t) Vo Example ) N-Cyclopropyl-4-methyl-3-(2-0x0-3-phenyl-1) 2H)-pyrazinyl)-benzamide : ( 1001 ZN 0 N H 0 to a stirred solution of : YAAY

176 - ¢3-(3,5-dibromo-2-ox0-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methyl ester (ex. (aa +, Y cc) in (Jo Y) tetrahydrofuran and water (Je V) added phenylboronic acid (1 mg) Y + ©) sodium carbonate s mg) 5 tetrakis(triphenylphosphine)palladium(0) V1) mg). The reactants were heated in a microwave at 171 °C for Te min. © The reaction mixture was cooled to room temperature; And adding “0 ( phenylboronic acid mg) was heated in a microwave at Ar C for 0 £ min. The reaction mixture was cooled to room temperature and then palladium ZY + (a > »4 ( ammonium formate on carbon) was added +¥ mg) 3 formic V) ethanol 5 (Je +, Y) acid mL). The reaction mixture was heated in a microwave for 100 minutes at 100°C before cooling to room temperature. Water was added and extracted the mixture using ethyl acetate 0. The combined organic layers were washed with water, dried (Na2S04), filtered, and concentrated.The product was taken in (Ja £) tetrahydrofuran and then +,YY) amine cyclopropyl Y) cyclopentylmagnesium was added bromide (Ja m in diethyl ether « 1.0 ml) drop by drop. After stirring for (A383 10) ethanol was added and the mixture was purified by preparative HPLC (Gemini column Lysate (acetonitrile : ammonia 761 to obtain V0 for the title compound as a solid Vo) mg. MS: APCI(+ve) 346 (M+H+). IH NMR 5 (DMSO- d6, 400MHz) 8.46 (1H, d), 8.30 - 8.24 (2H, m), 7.90 (1H, dd), 7.83 (3H, m), 2.89 - 2.82 (1H, 7.44 - 7.48 , his ( 1H, d), 7.66 (1H, d), 7.60 (1H, d), 7.53 (1H, m), 2.16 (3H, 5), 0.72 - 0.67 (2H, m), 0.59 - 0.54 (2H, m).

- 1105© - (1 0) Example N-Ethyl-4-methyl-3-[2-0x0-3-[(phenylmethyl)amino]-1(2H)-pyrazinyl]-benzamide 0 =~ ° N2

H

0

Y) amine ethyl 3 benzylamine using (z 1) (the title compound was prepared and purified according to example) tetrahydrofuran molar in ©.

MS: APCI(+ve) 363 (M+H+). 1H NMR 6 (DMSO-d6, 400MHz) 8.47 (1H, t), 7.92 (1H, t), 7.88 (1H, dd), 7.77 (1H, d), 7.50 (1H, d), 7.36 - 7.29 (4H) , m), 7.25 - 7.20 (1H, m), 6.83 (1H, d), 6.71 (1H, d), 4.59 (1H, dd), 4.49 (1H, dd), 3.30 - 3.24 (2H, m), 2.12 (3H, 5), 1.11 3H, 1). (11) Example 0

N-Cyclopropyl-4-methyl-3-(2-0x0-3-phenoxy-1(2H)-pyrazinyl)-benzamide 0 27 yum A Or 0

N Yo 0 A mixture of: ¢3-(3,5-dibromo-2-ox0-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methyl ester (Example 1) phenol PEN Yet is heated. “od 5 mg); (Ja 0 ,( N,N-diisopropylethylamnie) and YAAY

177 - 1 tetrahydrofuran mL) in a microwave for 10 minutes for 10 minutes at YE.C before being cooled to room temperature. The mixture was converted to a mixture of palladium on YA carbon (JN) 1 5 mg (tetrahydrofuran ml). (Je 1) 1,4-Cyclohexadiene was added and the mixture was heated under nitrogen in a microwave for 10 minutes at 0 °C before being cooled to room temperature. The mixture was filtered and concentrated. The residue was treated with V+) tetrahydrofuran (Je and water (¥ ml) 197 ( lithium hydroxides mg). The mixture was stirred for two hours” and diluted with ethyl acetate; And washed it with 1 M hydrochloric acid and water. The organic phase (Na2S04) was dried and concentrated. The solid was washed with a small amount of diethyl ether and treated with (Je Y) dichloromethane then added N,N-dimethylformamide (one 0 drop) oxalyl chloride (© 0, + mL). The mixture was stirred until the disappearance of the solid and Achloro acid was transferred to a solution of amine cyclopropyl (¥, +* ml) in dichloromethane (© (Jo). The mixture was stirred for 0 min and then diluted with ethyl acetate (04 ml). The mixture was washed with ¥ M hydrochloric acid twice with water. The organic shall (Na2S04) was dried and concentrated in incubator medium. After purification by HPLC (Gemini column 70,1 filtration buffer) acetonitrile: ammonia 08 (the title compound was obtained as a solid (70 mg). MS: APCI(+ve) 362 (M+ H-+).(CDCI3, 400MHz) 7.74 (1H, dd), 7.65 (1H, d), 7.44 (3H, m), 7.27 (3H, m), 1H NMR (1H, d), 6.80 (1H, d), 6.28 (1H, br 5), 2.90 (1H, m), 2.28 (3H, 5), 0.62 (2H, m), 8 6.85 (2H, m). a

1797 - (VV) Example N-Cyclopropyl-4-methyl-3-[2-0x0-3-(phenylthio)-1(2H)-pyrazinyl]-benzamide 0 =~ °N

A J.O

N 5 0 : A mixture of

AAT (eg N-cyclopropyl-4-methyl-3-(2-0x0-3-phenoxy-1(2H)-pyrazinyl)-benzamide ~~ © in microwave nitrogen under atmosphere of (Je 1) THF 5 (Je +, )) benzenethiol mg) 00

Ze) filter solution “Gemini” (HPLC column after 4800 B . 1 1171 min at 00 mg for. YY) The title compound was obtained as a solid (acetonitrile : ammonia

MS: APCI(+ve) 378 (M+H+). 1H NMR § (CDCI3, 400MHz) 7.74 (1H, dd), 7.61 (3H, m), 7.47 (3H, m), 7.41 (1H, d), Ve 7.15 (1H, d), 6.81 (1H, d) , 6.30 (1H, s), 2.88 (1H, m), 2.23 (3H, s), 0.86 (2H, m), 0.60 (2H, m). (0 A) Example N-Cyclopropyl-4-methyl-3-[2-0x0-3-(phenylthio)-1(2H)-pyrazinyl]-benzamide “ m_l

OT B 9 70 0 \o

YAAY

- 178 m - z tetrahydrofuran? Molar of ( iso-propylmagnesium chloride a solution of : ml) was added to a stirred solution of 8 10 (eg N-cyclopropyl-4-methyl-3-(2-ox0-3-phenoxy-1) 2H)-pyrazinyl)-benzamide ml). The mixture was stirred at +,0 degrees) tetrahydrofuran s (J +,Y) benzylthiol mg) £0 ethyl solid and water and the mixture was extracted in [NHAC] room temperature for 7? hour. © was added and concentrated in vacuo. After purification with (Na2504), the acetate organic phase was dried to obtain (acetonitrile: ammonia 76.1 Gemini filter solution (MG HPLC column). A) Title compound as a solid

MS: APCI(+ve) 392 (M+H+). 1H NMR 6 (CDCI3, 300MHz) 7.72 (1H, d), 7.55 (1H, s), 7.35 (7H, m), 6.81 (1H, d), Ve 6.31 (1H, s), 4.34 (2H, m) , 2.86 (1H, m), 2.19 (3H, s), 0.83 (2H, m), 0.57 (2H, m). (YY+)s (V9) Ex. N-Cyclopropyl-4-methyl-3-[3-(4-methyl-2-phenyl-1-piperazinyl)-2-oxo-1(2H)- 119) and 3-[5-bromo-3-(4-methyl-2-phenyl-1-piperazinyl)-2- Ji«pyrazinyl]-benzamide ( 0x0-1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl -benzamide Vo

AVY (example Br to

H 0 LUN. H 0 LUN. : A mixture has been heated

YAAY

179 - — Ji) ¢3-(3,5-dibromo-2-ox0-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methyl ester ab; 110 mg); and vv) 1-methyl-3-phenyl-piperazine mg) « ; 0,1 (N,N-diisopropylethylamnie) mL (Je 1) tetrahydrofuran was microwaved for VO min at 100 °C before cooling to room temperature. The mixture was transferred to a palladium-on-carbon mixture (JV) 56 mg (1) tetrahydrofuran ml) and 1 (1,4-cyclohexadiene ml) added. The mixture was heated under nitrogen atmosphere in a microwave for 7.5 hours at 171°C. Another part of palladium was added to carbon (© mg) in (Je 1) tetrahydrofuran and the mixture was heated for an hour at 10171 m 0 after cooling ¢ (Ja ©7) amine cyclopropyl was added and that followed Addition 0 dropwise to a solution of iso-propylmagnesium chloride (?molar) in (Ja Y,0 ¢ tetrahydrofuran). The mixture was stirred for 10 minutes ¢, quenched with saturated aqueous 1111401, and extracted with ethyl acetate. The phase was dried After purification with HPLC (Gemini column, acetonitrile filtration solution: ammonia 7 0.1), the title compound was obtained: N-cyclopropyl-4-methyl-3 -(4-methyl-3'-oxo-2-phenyl-3,4,5,6-tetrahydro-2H,3'H- Vo [1,2']bipyrazinyl-4'-yl)-benzamide )£9 mg) and 3-(6'-Bromo-4-methyl-3'-0x0-2-phenyl-3,4,5,6-tetrahydro-2H,3'H-[ 1,2bipyrazinyl- 4'-yl)-N-cyclopropyl-4-methyl-benzamide A) 10 mg).

— VA. —

N-Cyclopropyl-4-methyl-3-[3-(4-methyl-2-phenyl-1-piperazinyl)-2-oxo-1(2H)- pyrazinyl]-benzamide MS: APCI(+ve) 444 (M) +H+). 1H NMR § (DMSO-d6, 400MHz) 8.45 (1H, m), 7.88-7.83 (1H, m), 7.75 and 7.71 (1H, 2 xd), 7.52 - 7.42 (3H, m), 7.37 - 7.28 (2H) , m), 7.25 — 7.16 (1H, m), 6.98 (2H, s), 6.17 and 6.07 (1H, 2 x br s), 3.27 - 3.10 (1H, m), 2.90 - 2.70 (2H, m), 2.48 - 2.37 (2H, m), 5 2.20 (3H, m), 2.15 (2H, m), 2.11 and 2.04 (3H, 2 x s), 0.69 (2H, m), 0.55 (2H, m). 3-[5-Bromo-3-(4-methyl-2-phenyl-1-piperazinyl)-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl-benzamide

MS: APCI(+ve) 522 (M+H+). 1H NMR 5 (DMSO-d6, 400MHz) 8.42 (1H, m), 7.85 (1H, m), 7.77 and 7.74 (1H, 2 xd), 0 7.52 -7.41 (3H, m), 7.37 - 7.28 (2H, m), 7.27 - 7.19 (2H, m), 6.28 and 6.16 (1H, 2 x br s), 3.29 (3H, s), 3.18 - 3.03 (1H, m), 2.89 - 2.72 (2H, m), 2.48 - 2.36 (1H, m), 2.20 (3H, m), 2.15 and 2.07 (3H, 2 x s), 0.69 (2H, m), 0.55 (2H, m). (YYY) Example N-Cyclopropyl-3-[3-[[2-(dimethylamino)ethyl](phenylmethyl)amino]-2-oxo0-1(2H)- \o pyrazinyl]-4-methyl-benzamide

Zz

ASO) 5

N YON

0 ara YAAY

— VAN -

: (1) 3-[3-[[2-(Dimethylamino)ethyl](phenylmethyl)amino]-2-oxo- 1(2H)-pyrazinyl]-4-methyl- benzoic acid, methyl ester

A mixture of: J) ¢3-(3,5-dibromo-2-oxo0-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methyl ester © cc) 74 mg) was heated; 5 N'-benzyl-N,N-dimethylethylenediamine (++ ml); and Jala (Je V) tetrahydrofuran sy (Je +,Y) N,N-diisopropylethylamnie microwaved for 11 minutes at 100°C before cooling to room temperature. The mixture was transferred to a mixture of palladium on carbon 701 (6 mg) and 1 (tetrahydrofuran mL) and NN-1 (diisopropylethylamnie 0 mL) was added. The mixture was heated in a microwave for Te min die 1171 °C before being cooled to room temperature. The mixture was filtered and the filtrate was concentrated in vacuo. After purification by HPLC (Gemini column) filtration solution (acetonitrile: ammonia 7.1), the title compound, Yo, was obtained as a solid (50 mg). (5H, 7.17 - 7.35, His ( 1H, 7.40, has 1H NMR 5 (CDCI3, 300MHz) 8.00 (1H, dd), 7.90 (1H, m), 6.96 (1H, d), 6.50 (1H, d), 5.16 (1H, d) ), 4.97 (1H, d), 3.97 - 3.84 (4H, m), 3.90 (3H, m), 3.71 (1H, m), 2.55 (2H, m), 2.22 (6H, s), 2.20 ( 3H, s).

— VAY - : (b) ‎N-Cyclopropyl-3-[3-[[2-(dimethylamino)ethyl](phenylmethyl)amino]-2-oxo-1(2H)- pyrazinyl]-4-methyl -benzamide : from ] al - - then it is reduced by -{3-[benzyl-(2-dimethylamino-ethyl)-amino]-2-oxo-2H-pyrazin-1-yl} -4-methyl-benzoic © acid, methyl at a temperature of (Je +,0) and water (Je 1 ( amine cyclopropyl 5 mg) 0 "1; (example: ammonia /+,) filter solution «Gemini (HPLC column days. After purification with 10 chambers for . mg) Yo) The title compound was obtained as a solid (acetonitrile

MS: APCI(+ve) 446 (M+H+). Ve 1H NMR 6 (DMSO-d6, 300MHz) 8.52 (1H, s), 7.85 (1H, d), 7.74 (1H, 5), 7.46 (1H, d), 7.38 - 7.19 (SH, m), 6.93 ( 1H, m), 6.86 (1H, m), 5.10 (1H, d), 4.84 (1H, d), 3.85 (1H, m), 3.58 (2H, m), 2.85 (1H, m), 2.10 (6H , s), 2.08 (3H, s), 0.69 (2H, m), 0.56 (2H, m). ( 11 ) Example 1-[3-[5-Bromo-2-0x0-3-[3-phenyl-4-[2-(1-pyrrolidinyl)ethyl]-1-piperazinyl]-1(2H) - Vo pyrazinyl]-4-methylbenzoyl]-pyrrolidine

YAAY

— VAY —

Br

A

0-07 : any [ of 0. . NEY then (ex. ¢3-(3,5-dibromo-2-oxo0-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methyl ester *,1) N,N-diisopropylethylamnie 5 ¢ mg) V+ +) phenylpiperazine=Y mg); And Yor cd): for two hours. 4d all was added at a temperature (Je 1 (tetrahydrofuran ml) © 0 mm 1171 2 hours at sad) and the mixture was heated in a microwave (Je +, Y) 1,2-Dibromoethane The reaction mixture was dried by adding 3 saturated water and extracted.

Pyrrolidine was filtered and concentrated in vacuo. “(Na2S04) was added to the organic phase after cooling and after . 1 001 min at V0 and the mixture was heated in a microwave for (Je +06) (acetonitrile : ammonia 70.1 Gemini filter solution (HPLC column purified 0.0 mg) Te ) get the address compound

MS: APCI(+ve) 619 (M+H). 1H NMR 5 (DMSO-d6, 400MHz) 7.53 (1H, dd), 7.49 and 7.45 (1H, 2 x d), 7.45 - 7.27 (6H, m), 7.22 (1H, d), 3.49 - 3.33 (8H, m) ), 3.18 (1H, m), 3.09 (1H, m), 2.83 (1H, m), 2.48 - 2.30 (6H, m), 2.24 (4H, m), 2.12 and 2.08 (3H, 5), 1.83 ( 4H, m), 1.56 (4H, m), Yo 2.06 (1H, m). : After additional filtering of the column,

YAAY

— VAL — 3-[5-bromo-2-0x0-3-[3-phenyl-4-[2-(1-pyrrolidinyl)ethyl]-1-piperazinyl]-1(2H)- pyrazinyl]-4-methyl -benzoic acid, methyl ester. (17 mg) which was used in the next step (example on )

MS: APCI(+ve) 580 (M+H+). 1H NMR 6 (DMSO-d6, 400MHz) 7.95 (1H, dd), 7.89 and 7.86 (1H, 2 x d), 7.54 (1H, f (© 7.41 - 7.26 (SH, m), 7.23 (1H, d) ), 3.86 and 3.84 (3H, 2 x 5), 3.39 - 3.27 (1H, m), 3.23 - 3.02 (2H, m), 2.83 (1H, m), 2.48 - 2.30 (6H, m), 2.24 (4H , m), 2.17 and 2.12 (3H, s), 2.06 (1H, m), 1.57 (4H, m).( VY ¥) Example N-Cyclopropyl-4-methyl-3-[2-0x0- 3-[3-phenyl-4-[2-(1-pyrrolidinyl)ethyl]-1- 01 piperazinyl]-1(2H)-pyrazinyl]-benzamide 0 7 M- A © I}

N pa 0 LN Rice is licensed: a mixture of A and then heated 3-[5-bromo-2-0x0-3-[3-phenyl-4-[2-(1-pyrrolidinyl)ethyl) [-1-piperazinyl]-1(2H)-pyrazinyl]-4-methyl-benzoic acid, methyl ester Vo

YAAY

— YAO — ) © mg) « palladium 0 (poe YYY ) ammonium formate + 73 at carbon YY) mg) (Je Y,0) ethanol s (Je +,)) N,N-diisopropylethylamnie Under a nitrogen atmosphere in a microwave for 1 min at VO 0 C the mixture was filtered and concentrated. Cyclopropyl (Je +,Y) amine and water (de 1,5) were added and the mixture was heated under nitrogen atmosphere in a microwave oven for hours at 100°C and concentrated in vacuo. After Purification by HPLC (Gemini column filtrate) + 7 acetonitrile : ammonia (title compound obtained in mg) MS: APCI(+ve) 527 (M+H+). 1H NMR 6 (CDCI3, 300MHz) 8.04 and 7.88 (1H, d), 7.73 (1H, d), 7.64 - 7.33 (6H, m), (1H, m), 6.64 (1H, m), 6.34 (1H, s), 5.06 - 4.65 (2H, m), 3.78 (1H, m), 3.58 - 2.64 7.02 (13H, m), 2.20 and 2.17 (3H, 2 x s), 2.00 (4H, m), 0.86 ( 2H, m), 0.60 (2H, m).01 ( YY ¢ ) Example 3-[3-[[[3-(Aminomethyl)phenyl]methyl]amino]-2-oxo-1(2H) -pyrazinyl]-N-cyclopropyl- 4-methyl-benzamide a “=

AN “7

DOH

: a mixture of lds \o [[3-[[[4-[5-[(cyclopropylamino)carbonyl]-2-methylphenyl]-3,4-dihydro-3- oxopyrazinylJamino]methyl phenyl] methyl] -carbamic acid Expensive

- VAT - +0 (eg) 0 50 (Je Y) dichloromethane (poe) and (Je +,0) trifluoroacetic acid at room temperature for Ye min. The mixture was concentrated in an incubator medium. After purification B HPLC (Column “Gemini” acetonitrile filtration solution: ammonia 70.1) The title compound (pe YY) was obtained as a solid.

MS: APCI(+ve) 404 (M+H+) ° 1H NMR 5 (DMSO-d6, 400MHz) 8.43 (1H, d), 7.86 (2H, m), 7.75 (1H, s), 7.49 (1H, d ), 7.29 (1H, s), 7.27 - 7.13 (3H, m), 6.83 (1H, d), 6.70 (1H, d), 4.58 (1H, dd), 4.47 (1H, dd), 3.69 (2H, s), 3.29 (2H, 5), 2.84 (1H, m), 2.11 (3H, 5), 0.68 (2H, m), 0.55 (2H, m). ( VY 0) Example 3-[3-[[[4-(Aminomethyl)phenyl|methylJamino]-2-oxo- 1 (2H)-pyrazinyl]-N-cyclopropyl- Ye 4-methyl-benzamide 0 27- °N

N m (VE ) and then prepare the title compound from Example 4© using the method described in Example

MS: APCI(+ve) 404 (M+H+). 1H NMR § (DMSO-d6, 400MHz) 8.43 (1H, d), 7.87 (2H, m), 7.75 (1H, s), 7.49 (1H, d), Vo 7.26 (4H, s), 6.82 (1H, d), 6.69 (1H, d), 4.55 (1H, dd), 4.45 (1H, dd), 3.67 (2H, s), 2.84 (1H, m), 2.11 (3H, s), 0.69 (2H, m ), 0.54 (2H, m). Expensive

VAY - — Example (VY) and Example (VYV) N-Methoxy-4-methyl-3-[2-0x0-3-(3-phenyl-1-piperazinyl)-1(2H)- pyrazinyl]-benzamide )example and 3-(3-cyclopentyl-2-oxo-1(2H)-pyrazinyl)-N-methoxy-4-methyl- )126 benzamide °N 0 =~ ° N =” 0 0 0 0 N 1 y N N y 1 0 no 0 A mixture of: 3-(3,5-dibromo-2-ox0-2H-pyrazin-1-yl)-4 was stirred -methyl-benzoic acid, methyl ester (example) ab; 71 g); 5 “(Ja +,¥) N,N-diisopropylethylamnie and +,VY) phenylpiperazine=Y g) (Je 1( tetrahydrofuran) at room temperature for 2 hours. Y) 0 ethanol was added ml) then palladium 1/7 hydrated carbon (© mg) ammonium formate (°£, + g). The mixture was stirred under nitrogen atmosphere at VO C for FO min. The mixture was filtered through the sealite filling. The filtrate was concentrated in vacuo. The residue was treated with 081 (O-methylhydroxylamine hydrochloride mg) addition of 1 (tetrahydrofuran ml) followed by addition of Y) cyclopentylmagnesium bromide in diethyl ether; 18 ml). 10 the mixture was stirred for 0 minutes; And quenching it by adding [NHAC] saturated and extracting it in ethyl acetate. The organic phase was concentrated in vacuo. After purification by HPLC (Column “Gemini” filter solution (acetonitrile: ammonia Lo), the title compound consisting of the compound: YAAY was obtained.

- 1 pm

N-methoxy-4-methyl-3-[2-0x0-3-(3-phenyl-1-piperazinyl)-1(2H)-pyrazinyl]-benzamide trifluoroacetate : mg) and compound 04) 3-(3- cyclopentyl-2-oxo-2H-pyrazin-1-yl)-N-methoxy-4-methyl-benzamide trifluoroacetate©. mg) 1 v)

N-Methoxy-4-methyl-3-[2-0x0-3-(3-phenyl-1-piperazinyl)-1(2H)-pyrazinyl]-benzamide, trifluoroacetate MS: APCI(+ve) 420 (M+H+ ). 1H NMR 6 (DMSO-d6, 400MHz) 11.81 (1H, s), 7.77 (1H, dd), 7.66 and 7.63 (1H, 2 x d), 7.54 - 7.46 (3H, m), 7.45 - 7.32 (3H, m) ), 7.08 - 7.03 (2H, m), 4.83 - 4.62 (2H, m), 01 4.24 (1H, s), 3.71 and 3.70 (3H, 2 x 5), 3.21 - 2.99 (4H, m), 2.13 and 2.10 3H, 2 x 5). 3-(3-Cyclopentyl-2-ox0-2H-pyrazin-1-yl)-N-methoxy-4-methyl-benzamide, trifluoroacetate MS: APCl(+ve) 328 (M+H+). 1H NMR 6 (DMSO0-d6, 400MHz) 11.80 (1H, s), 7.79 (1H, dd), 7.67 (1H, d), 7.52 (1H, d), 7.44 (1H, d), 7.32 (1H, d) ), 3.88 (1H, s), 3.70 (3H, ,l 3.49 (1H, quintet), 2.09 (3H, s), Vo 2.00 - 1.86 (2H, m), 1.84 - 1.54 (6H, m).

YAAY

— 189 (VY A) eg N-Cyclopropyl-4-methyl-3-[3-[[[[2-(methylthio)phenylJmethyl]amino]-2-ox0-1(2H)- ‎pyrazinyl]-benzamide 0 ZN 82 belongs to 4-Methyl-3-(2-oxo0-3-phenoxy-1(2H)-pyrazinyl)-benzoic acid, methyl ester : (") © : a mixture of va) heated (Ex. 3-(3,5-dibromo-2-0x0-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methyl ester (J— +t ) N,N-diisopropylethylamnie 5 mg) £0 (phenol « mg) 0 °C before being microwaved to 171 °C for 2 hours at Jala (Ja 7 (tetrahydrofuran s mg) YA LN 0) on palladium carbon at room temperature. The mixture was transferred to a Ve mixture and the mixture was heated in an atmosphere (da Y) 1,4-Cyclohexadiene (Je 1) tetrahydrofuran was added for 1 min at 960 °C before being cooled to room temperature.11 in a microwave nitrogen from the crude product which is then used in the next step without J and then filtered out of the mixture and concentrated to obtain (B): 10

N-Cyclopropyl-4-methyl-3-[3-[[[2-(methylthio)phenylJmethyl]amino]-2-ox0-1(2H)- pyrazinyl]-benzamide

1011 — then heating a mixture of: 4-methyl-3-(2-0x0-3-phenoxy-2H-pyrazin-1-yl)-benzoic acid, methyl ester (ex. 11 mg each); 2-(methylthio)-benzenemethanamine )+ » } mg) (Je 1) tetrahydrofuran g was microwaved for © hours at 171 °C before being cooled to room temperature. (Je +,Y)amine cyclopropyl © was added and then 1 (mM cyclopentylmagnesium bromide in 1.8 « diethyl ether mL] was added. The mixture was stirred for 0 minutes; And quenching by adding saturated 1411401 and extracting it in ethyl acetate. The organic phase was concentrated in vacuo. After purification by HPLC (Gemini column: acetonitrile filtration solution: ammonia Zo,) . mg) Ya) the title compound as a solid

MS: APCI(+ve) 421 (M+H+). Ye 1H NMR 5 (DMSO0-d6, 300MHz) 8.45 (1H, d), 7.88 (1H, dd), 7.80 - 7.73 (2H, m), 7.50 (1H, d), 7.33 - 7.22 (2H, m), 7.19 - 7.08 (2H, m), 6.81 (1H, d), 6.72 (1H, d), 4.57 (1H, dd), 4.46 (1H, dd), 2.91 - 2.80 (1H, m), 2.51 (3H, 5), 2.13 3H, 5), 0.70 (2H, m), 0.57 (ZH, m). (1Y4) Example Ve 3-[3-[[(2-Chlorophenyl)methyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl-benzamide 27- ° NCl

AL 0 B OLY 0 YAAY

- 191 - : The title compound was prepared from { (Example: 4-methyl-3-(2-ox0-3-phenoxy-1(2H)-pyrazinyl)-benzoic acid, methyl ester (VY YA) The method described in the example of aladiuly 2-chlorobenzenemethanamine and MS: APCI(+ve) 409 (M+H+).1H NMR 6 (DMSO-d6, 400MHz) 8.45 (1H, d), 7.92 (1H, t) , 7.88 (1H, dd), 7.78 (1H, d), 7.50 ° (1H, d), 7.45 (1H, m), 7.34 - 7.24 (3H, m), 6.81 (1H, d), 6.74 (1H, d), 4.65 (1H, dd), 4.55 (1H, dd), 2.86 (1H, m), 2.14 (3H, s), 0.70 (2H, m), 0.56 (2H, m).(9) Example 3-[3-[[(3-Chlorophenyl)methyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl- benzamide 01 0 20 aN b CI 0

H CC o M J : The title compound was prepared from ( (ex. 4-methyl-3-(2-0x0-3-phenoxy-1(2H)-pyrazinyl)-benzoic acid, methyl ester (VYYA) Using the method described in example 3-chlorobenzenemethanamine, MS: APCI(+ve) 409 (M+H+).

- Yay - 1H NMR 5 001150-06, 400MHz) 8.43 (1H, d), 8.03 (1H, t), 7.87 (1H, dd), 7.76 (1H, d), 7.49 (1H, d), 7.39 - 7.36 (1H, m), 7.34 (1H, d), 7.32 - 7.26 (2H, m), 6.82 (1H, d), 6.72 (1H, d), 4.58 (1H, dd), 4.48 (1H, dd), 2.85 (1H, m), 2.11 (3H, 5), 0.69 (2H, m), 0.55 (2H, m). (1) Example ©

N-Cyclopropyl-4-methyl-3-[3-[[(1R)-3-(4-methyl-1-piperazinyl)-3-oxo-1- phenylpropyl]amino]-2-oxo-1(2H) -pyrazinyl]-benzamide ] L Pp 2 AS _ (1 ] 1

N > loves N

H | H © tetrahydrofuran molar in ¥ ( iso-propylmagnesium chloride) represents the addition of a solution of : to a stirred mixture of (da) TY Ve (OR)-0-[[4-[5-[(cyclopropylamino)carbonyl] -2-methylphenyl]-3,4-dihydro-3- oxopyrazinylJamino]-benzenepropanoic acid, 1,1-dimethylethyl ester ml). Y) tetrahydrofuran y (Je +,Y) 1-methylpiperazine mg) and 100 (AY) (eg) pre-cooled to a temperature of Te min at 10 0. The reaction mixture was heated in a microwave for The chamber was concentrated ethyl acetate and quenched by adding saturated aqueous 2111401. The mixture was extracted in Ve 701 Gemini filter solution (organic HPLC column in hatchery medium. After purification with shal acetonitrile: ammonia) Obtaining the title compound as a solid (10 mg).

- 197 -

MS: APCI(+ve) 415 (M+H+). 1H NMR 6 (DMSO-d6, 400MHz) 8.44 and 8.39 (1H, 2 x d), 7.91 - 7.83 (2H, m), 7.74 and 7.72 (1H, 2 x d), 7.49 and 7.48 (1H, 2 x d), 7.43 - 7.36 (2H, m), 7.31 and 7.30 (2H, 2 xt), 7.25 - 7.18 (1H, m), 6.797 and 6.794 (1H, 2 x d), 6.683 and 6.679 (1H, 2 x d), 5.47 (1H , m), 3.45 - 3.30 (8H, m), 3.19 (1H, dd), 2.88 - 2.80 (1H, m), 2.76 (1H, dd), 2.13, © 2.11, 2.10, 2.08 (6H, 4 x s) , 0.68 (2H, m), 0.55 (2H, m). (Y¥Y) Example N-Methoxy-4-methyl-3-[2-0x0-3-(1-pyrrolidinyl)-1(2H)-pyrazinyl]-benzamide 2 1 _ This is SOS [A Lo A: The title compound was prepared from 0 3-(3,5-dibromo-2-oxo0-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methyl ester using (YY) the method described in an example

MS: APCI(+ve) 329 (M+H+). 1H NMR 5 (DMSO-d6, 400MHz) 11.81 (1H, s), 7.76 (1H, d), 7.64 (1H, s), 7.50 (1H, d), 6.84 (1H, d), 6.78 (1H, d) ), 3.91 - 3.72 (4H, m), 3.70 (3H, 5), 2.15 (3H, 5), 1.96 - 1.82 Yo (4H, m). a qt —

( 1 ¥Y) Ex. N-Cyclopropyl-4-methyl-3-[2-o0x0-3-[[2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl] ethyl]amino] -1(2H)-pyrazinyl]-benzamide

OL ~ N lm 7 0 no to cake AS SE N = N H i “ Oo© to a stirred solution of : 3-(3,5-dibromo-2-0x0-2H-pyrazin -1-yl)-4-methyl-benzoic acid, methyl ester (Example Ab)”+ g) in (Ja ¥) tetrahydrofuran (de +,VV) triethylamine and (YE) 4-( 2-aminoethyl)-phenol mg). The reaction mixture was stirred for VY h and added: (VY +) 1-(2-chloroethyl)-pyrrolidine hydrochloride mg) Cesium carbonate (0 5 mg) Y)NN-dimethylformamide s ml). The mixture was heated in a microwave at 100°C for 100 minutes. The reaction solution was then cooled to room temperature and quenched by addition of saturated NaHCO3. The mixture was extracted with dichloromethane. The combined organic layers were jue with brine; dried (Na2S04), filtered, and removed solvent. The product was taken in tetrahydrofuran (¥ ml) and then added +,V© (amine cyclopropyl ml) and cyclopentylmagnesium bromide © (¥ molar) in diethyl ether; (Ja +,YO part by part. The reaction mixture was stirred under nitrogen for 1 hour before adding (Y)ethanol (ml) for ammonium (Ye + (mg) formate) and 1107 palladium on carbon (Yo) mg). The reaction mixture was heated in a microwave at 100 °C for Te min. It was filtered and washed with ethanol, and the filtrate was concentrated (YAAY).

— 1090© — : ammonia / +,) Gemini filter solution (HPLC column in vacuo. After purification in mg). 01 (title compound) acetonitrile was obtained

MS: APCI(+ve) 502 (M+HH+). 1H NMR 6 (DMSO-d6, 400MHz) 8.43 (1H, d), 7.86 (1H, dd), 7.73 (1H, d), 7.48 (1H, d), 7.29 (1H, 1), 7.17 - 7.12 (2H) , m), 6.89 - 6.84 (3H, m), 6.68 (1H, d), 4.02 (2H, 1), 3.60 - 3.44 ° (2H, m), 2.88 - 2.78 (3H, m), 2.76 (2H, t), 2.54 - 2.46 (4H, m), 2.09 (3H, 5), 1.71 - 1.65 (4H, m), 0.71 - 0.66 (2H, m), 0.58 - 0.53 (2H, m). (114) Example N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[2-(1-pyrrolidinyl) ethoxy]phenyl] ethylJamino]-2-oxo- 1(2H)-pyrazinyl]-benzamide 001 0 2- M OH

A la oe

N N

H H

0 a, a-Dimethyl-2-(phenylmethoxy)-benzenemethanamine (00 ml) (01 anhydrous tetrahydrofuran g) in 1 (anhydrous) cerium chloride A suspension of M. M. was stirred. A solution of VA=min was added and then cooled to 0” for nitrogen in an atmosphere of 0*1 M?mL) and the reaction mixture was stirred for V1 (diethyl ether in methyllithium Vo g) At +,¥) 2-(phenylmethoxy)-benzonitrile min. A solution of -M was added and cooled to Yoo ml. The reaction mixture was stirred and gradually warmed to Y)tetrahydrofuran

YAAY

-197- Hours and his nomination VY Center. The mixture was stirred for ammonia period and quenched by adding VA solution. The organic phase was separated and the phase was extracted. ethyl acetate and the solid was washed with the combined organic layers were washed with brine. aqueous ethyl acetate twice using SCX, filtered, and the solvent removed. After purification using chromatography (Na2S04) and drying. (pe 0 ) Obtaining compound © subtitle : (b) N-Cyclopropyl-3-[3-[[1-(2-hydroxyphenyl)-1-methylethylJamino]-2-ox0-1(2H) )- pyrazinyl]-4-methyl-benzamide : to a stirred solution of (example 3-(3,5-dibromo-2-ox0-2H-pyrazin-1-yl)-4-methyl- benzoic acid, methyl ester Ve : Microwave vial added Jala (Je ¥) tetrahydrofuran g) in 4 µL) and 001(NN-diisopropylethylamnie 0 mg) Ya) o,a mixture heated -dimethyl-2-(phenylmethoxy)-benzenemethanamine m. The reaction mixture was cooled to a temperature of 170 minutes at 10 minutes of reaction in a microwave for a solution of Az (ml). Chamber +,°) amine cyclopropyl and add Ve drop by drop. (Je "¢ diethyl ether molar in Y)cyclopentylmagnesium bromide (ml) and saturated aqueous 1111401 were stirred and ethanol extracted (7 min. Yo) was added to the reaction mixture for 10 minutes using ethyl acetate.

YAAY

1997 - The collected organic layers were washed with brine; and dried (0782504), filtered, solvent removed. The remaining 3a was removed in (Je ¥) ethanol and ammonium formate (¥, + g) and 1107 palladium added to carbon (£4 mg). The reaction mixture was heated in a microwave for Ye min at 100 °C and then 90 min at Te °C before being cooled to ambient temperature; It was filtered and washed with © 08001. The filtrate was concentrated in vacuo. After meeting with HPLC (Gemini column, acetonitrile filtration solution: ammonia 701), the title compound was obtained as a solid (YY. mg). MS: APCI(+ve) 419 (M+H+). 1H NMR § (DMSO-d6, 400MHz) 9.50 (1H, s), 8.43 (1H, d), 7.86 (1H, dd), 7.73 ( 1H, d), (1H, d), 7.24 (1H, dd), 7.06 - 7.01 (1H, m), 6.99 - 6.97 (1H, m), 6.79 - 6.72 (2H, 01 7.48 m) , 6.70 (1H, d), 6.64 (1H, d), 2.89 - 2.81 (1H, m), 2.10 (3H, s), 1.85 3H, s), 1.82 (3H, s), 0.71 - 0.66 ( 2H, m), 0.57 - 0.53 (2H, m) (Yre) Example N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[2-1 - ‎pyrrolidinyl)ethoxy[phenyl]ethylJamino]-2-oxo-1(2H)-pyrazinyl]-benzamide Yo ; [0 0 ZN 0

A mk <>

N N

H H

0

YAAY

- 18: to a stirred solution of

N-cyclopropyl-3-(3-(2-(2-hydroxyphenyl)propan-2-ylamino)-2-oxopyrazin-1(2H)-yl)-4- methylbenzamide and ¢(Je ¥) NN-dimethylformamide In (p > 1.1 74 Jb) +,£Y) Cesium carbonate y g) +,1Y) N-(2-chloroethyl)-pyrrolidine, hydrochloride 6 h. It took place for 10 hours and then at 0 C for 10 C. (sad) 100 g) the reaction mixture was stirred at and the mixture was washed with water and brine. The organic phase, ethyl acetate, was dried by adding Gemini solution (HPLC column), filtered, and concentrated in an incubator medium. After purification with (Na2S04) 3 4), the title compound was obtained as a solid (acetonitrile: ammonia). 70.1 mg filtration).

MS: APCI(+ve) 516 (M+H+). 1H NMR 6 (DMSO-d6, 400MHz) 8.42 (1H, d), 7.86 (1H, dd), 7.72 (1H, d), 7.48 (1H, d), 7.32 (1H, dd), 7.21 - 7.16 (1H , m), 6.98 (1H, d), 6.92 - 6.86 (2H, m), 6.65 (1H, d), 6.62 (1H, d), 4.06 - 3.94 (2H, m), 2.88 - 2.80 (1H, m) ), 2.79 (2H, 1), 2.52 - 2.43 (4H, m), 2.09 (3H, s), 1.83 (6H, 5), 1.69 - 1.61 (4H, m), 0.72 - 0.66 (2H, m), 0.57 - 0.51 (2H, m). \o (0 15 ) Example N-Cyclopropyl-3-[3-[[(1R,2R)-3-hydroxy-2-methyl-1-phenylpropyl]amino}-2-oxo- 1(2H) )-pyrazinyl]-4-methyl-benzamide All

M ~ 0 A CO : . = 0 (1) : (2S)-3-[[(1,1-Dimethylethyl)diphenylsilylJoxy]-N-methoxy-N,2-dimethyl-propanamide solution added of Y) iso-propylmagnesium chloride molar in YA¢ tetrahydrofuran (da©) dropwise into a stirred solution of: (2S)-3-(tert-butyl-diphenyl-silanyloxy)-2-methyl-propionic acid , methyl ester (Eur. J. Org. Chem. 2006, 3645, 7.5 g), O,N-dimethylhydroxylamine hydrochloride (Y,00) g) (Ja 10) tetrahydrofuran at 0 mm. after completion; The mixture was quenched by adding saturated aqueous 111140 and extracted in ethyl acetate. The organic phase (Na2S04)Vo was dried, filtered, and concentrated in jie medium & to yield the crude product as a solid (AY (g). 1H NMR 6 (CDCI3, 400MHz) 7.72 - 7.62 (4H, m), 7.45 - 7.34 (6H, m), 3.93 (1H, dd), 3.66 (3H, s), 3.59 (1H, dd), 3.20 (3H , 5), 3.26 - 3.14 (1H, m), 1.08 (3H, ,l 1.03 (9H, s) (b): (R)-N-[(1R,2R)-3-[[( 1,1-Dimethylethyl)diphenylsilylJoxy]-2-methyl-1-phenylpropyl]-2- methyl-2-propanesulfinamide Yo A solution of diisobutylaluminium hydride was added in (1 mol tetrahydrofuran ov mL) dropwise to a stirred solution of:

YAAY

“Yee (25)-3-[[(1,1-dimethylethyl)diphenylsilyl]Joxy]-N-methoxy-N,2-dimethyl-propanamide ? 1 and the mixture was stirred for 1 0 sia at ( Jo £4) tetrahydrofuran g) in 7 dyes (ex. 001 (001 molar ¥ hydrochloric v. (Ja YO) ethyl acetate min) poured onto a mixture of ml). The organic phase was washed with a solution Brine, dry it (0482504, filter it and concentrate it in medium (Je ¥'+) tetrahydrofuran was added. crude aldehyde empty to get crude aldehyde © titanium ethoxide 3 g) 1,1( (R)-(+)- 2-methyl-2-propanesulfinamide and then ethyl acetate (ml) was added. The mixture was stirred at room temperature for 90 minutes and then diluted (01 ml). The mixture was stirred for one hour. The phase was separated (001) and quenched with brine (da Yo) and filtered through a cellite bed and concentrated in vacuo to obtain organic (Na2804); dried dry (90 ml) and dichloromethane cooled over crude imine sulfide; which was dissolved at 0 A solution of -0 © M. ml) VY « ¥ 5a (? diethyl ether in phenylmagnesium bromide) was added dropwise and the reaction mixture was warmed to zero within ¥ hours; It was quenched by adding 1111401 aqueous “((Na2S04) organic shall) and extracted at 010010:00:60080. Saturated (Je 10+) was dried, filtered and concentrated in vacuo. VO ethyl acetate : iso-hexane The residue was purified (5:02 chromatography and filtered using 7100 to obtain the subtitle compound.) - (zero IH NMR 5 (CDCI3, 400MHz) 7.66 - 7.62 (3H, m), 7.59 - 7.55 (3H, m), 7.45 - 7.22 (14H, m), 4.59 (1H, dd), 3.87 (1H, d), 3.55 (1H, dd), 3.40 (1H, dd), 2.23 (1H, m), 1.16 (9H , s), 1.06 (9H, s), 0.88 (3H, d).Ye

YAAY

— YY —

(c) 3-[3-[[(1R,2R)-3-Hydroxy-2-methyl-1-phenylpropyl|]amino]-2-oxo-1(2H)-pyrazinyl]-4- methyl-benzoic acid, methyl ester

Then _0 reduces to 1 from: (R)-N-[(1R,2R)-3-[[(1,1-dimethylethyl)diphenylsilyljoxy]-2-methyl-1-phenylpropyl]-2- © methyl-2-propanesulfinamide (ex. 177b;©,Y g) (Ja Y©) methanol and a solution of hydrogen chloride in:

1,4-dioxane (£ mol) Ja YO at 00 C for 1 hour and left at room temperature for 1 hour. The mixture was concentrated in vacuo and the residue was washed with ether to obtain

: g). Y) added dry amine hydrochloride 0 (example 3-(3,5-dibromo-2-ox0-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methyl ester ml) . ©+) tetrahydrofuran s (Je ¢) N,N-diisopropylethylamnic was then added (aa) 8 h. After cooling to room temperature; Saturated aqueous. The organic phase (Ja 001) ethyl acetate was dried in an atmosphere of (Je 51) ethanol, filtered and concentrated in vacuo. “(Na2804) 0 ammonium formate 5” (axe YYV ZV +) was added Hydrated on palladium carbon then added nitrogen for 2 h 1 Ve ml. The mixture was stirred at 7 (N,N-diisopropylethylamnie s (p > ¥) and cooled to room temperature; filtered through a filler of celite Focusing on a vicious medium

‎YAAY

— YY — and washed it with water. The organic phase (Jo Yoo) ethyl acetate was dried, the residue was diluted, filtered, and concentrated in vacuo to yield the title compound (7.0 g). ), 7.91 and 7.88 (1H, 2 x d), 7.84 and 7.79 (1H, 2 x d), 7.58 and 7.56 (1H, 2 x d), 7.43 - 7.36 (2H, m), 7.31 (2H, 1), 7.25 - 7.19 (1H, m), 6.76 and 6.755 (1H, 2 x d), 6.662 and 6.657 (1H, 2 x d), 5.02 (1H, dd), 4.77 (1H, d), © 3.86 and 3.84 (3H, 2 x 5), 3.22 - 3.14 (2H, m), 2.29 - 2.13 (1H, m), 2.16 and 2.09 (3H, 2 x s), 0.87 (3H, d). (3)

N-Cyclopropyl-3-[3-[[(1R,2R)-3-hydroxy-2-methyl-1-phenylpropyl]amino]-2-oxo- 1(2H)-pyrazinyl]-4-methyl-benzamide « tetrahydrofuran 7 mol in ( iso-propylmagnesium chloride) a solution of : ml) was added dropwise to a stirred mixture of 0,0 3-[3-[[(1R,2R)-3-hydroxy-2-methyl -1-phenylpropyl[amino]-2-oxo-1(2H)-pyrazinyl]-4- methyl-benzoic acid, methyl ester at (Ja Y+) tetrahydrofuran s (Js +,Y) amine cyclopropyl «(ase 500 zx 1 Jie) | 0 done. ethyl acetate, aqueous saturated in NHAC] safram. After 10 minutes, the reaction was quenched by adding, filtering and concentrating in vacuo to obtain the product “(Na2S04) drying the organic phase

Ze) Gemini filter solution (mg HPLC column). After purification with 0Y0) the raw title, the title compound was obtained. ) acetonitrile: ammonia

YAAY

—- YY 1H NMR 6 (DMSO-d6, 400MHz) 8.45 and 8.38 (1H, 2 x d), 7.97 - 7.83 (2H, m), 7.75 and 7.70 (1H, 2 x d), 7.49 and 7.47 (2H, 2 x d) ), 7.44 - 7.20 (5H, m), 6.77 and 6.76 (1H, 2 x d), 6.65 and 6.64 (1H, 2 x d), 5.05 - 4.99 (1H, m), 4.80 and 4.74 (1H, 2 x t), 3.23 - 3.12 (2H, m), 2.90 - 2.79 (1H, m), 2.30 - 2.13 (1H, m), 2.12 and 2.05 (3H, 2 x 5), 0.87 (3H, d), 0.72 - 0.63 (2H , m), 0.60 - 0.50 (2H, m). © (YYV) Example N-Cyclopropyl-3-[3-[[(1R,2R)-3-hydroxy-2-methyl-1-(1-naphthalenyl)propyl]amino]-2- ox0- 1(2H)-pyrazinyl]-4-methyl-benzamide ‎0 7 °N

A 2 CO) ; be. ! i : (0 Ye 3-[3-[[(1R,2R)-3-Hydroxy-2-methyl-1-(1-naphthalenyl)propyl]Jamino]-2-oxo-1(2H)- pyrazinyl]- 4-methyl-benzoic acid, methyl ester : The title compound was prepared from (25)-3-[[(1,1-dimethylethyl)diphenylsilyl Joxy]-N-methoxy-N,2-dimethyl-propanamide { 171) Using the methods described in Example 1-naphthalenylmagnesium { 111 (Ex. 0 Ba1g)s

YAAY

1H NMR 6 (DMSO-d6, 400MHz) 8.34 and 8.33 (1H, 2 x d), 8.05 (1H, d), 7.98 and 7.84 (1H, 2 x d), 7.88 (1H, d), 7.80 (1H, t) , 7.61 (1H, 1), 7.56 - 7.37 (4H, m), 7.16 (1H, d), 6.90 (1H, d), 6.54 - 6.46 (1H, m), 6.45 and 6.44 (1H, 2 x d), 3.93 and 3.88 (3H, 2 x 5), 3.71 - 3.63 (1H, m), 3.49 - 3.40 (1H, m), 2.55 - 2.38 (1H, m), 2.31 and 2.17 (3H, 2 x 5), 0.76 and 0.75 3H, 2 x d). © : (b) N-Cyclopropyl-3-[3-[[(1R,2R)-3-hydroxy-2-methyl-1-(1-naphthalenyl)propylJamino]-2- oxo0-1) 2H)-pyrazinyl]-4-methyl-benzamide : the title compound was prepared from 3-[3-((1R,2R)-3-hydroxy-2-methyl-1-naphthalen-1-yl-propylamino) -2-oxo-2H-pyrazin- 01 1-yl]-4-methyl-benzoic acid, methyl ester (C1176) using the method described in Example (11 YY) (Example MS: APCI(+ve) ) 483 (M+H+).1H NMR 6 (DMSO-d6, 400MHz) 8.47 - 8.36 (2H, m), 7.95 (1H, d), 7.87 (1H, d), 7.82 (1H, d), 7.77 and 7.71 (1H, 2 x d), 7.65 - 7.45 (6H, m), 6.73 and 6.72 (1H, 2 x d), 6.67 Vo and 6.67 (1H, 2 x d), 6.08 (1H, dd), 4.87 and 4.83 (1H , 2 x t), 3.35 - 3.26 (2H, m), 2.90 - 2.78 (1H, m), 2.41 - 2.30 (1H, m), 2.15 and 2.06 (3H, 2 x 5), 0.87 (3H, d), 0.73 - 0.63 (2H, m), 0.60 - 0.50 (2H, m).

11 © — for example (18) N-Cyclopropyl-4-methyl-3-[3-[[(1R,2S)-2-methyl-3-(4-morpholinyl)-1- phenylpropyl[amino]-2-oxo-1(2H)-pyrazinyl]-benzamide M-27 0 ~ 1 0 nM N NY 8 L_o 0 0 (): N-Cyclopropyl-4- methyl-3-[3-[[(1R,2R)-2-methyl-3-0x0-1-phenylpropyl]Jamino]-2-oxo- 1(2H)-pyrazinyl]-benzamide solution added of Dess-Martin Periodinane )+ + mg) in (Je ¥) dichloromethane drip to a solution of : N-cyclopropyl-3-(3-((1R,2R)-3-hydroxy-2-methyl- 1 -phenylpropylamino)-2-oxopyrazin- Ye 1(2H)-yl)-4-methylbenzamide (ex. ¥1) 5006 mg) in (Ja ¢) dichloromethane at Yo 5.0 Stirring the resulting mixture at 5m for Vo min. The reaction mixture was quenched by adding 11625203 saturated water (V mL) and 11011003 saturated water. The mixture was stirred for 10 min and extracted in dichloromethane Vo. The organic phase (Na2S04) was dried, filtered and evaporated to yield the crude product (dl mg) which was used in the next step without purification. YAAY

7.91 : (b) N-Cyclopropyl-4-methyl-3-[3-[[(1R,2S)-2-methyl-3-(4-morpholinyl)-1- phenylpropyljamino]-2-oxo -1(2H)-pyrazinyl]-benzamide : to a solution of

N-cyclopropyl-4-methyl-3-[3-((1R,2R)-2-methyl-3-0x0-1-phenyl-propylamino)-2-oxo-©2H-pyrazin-1-yl]-benzamide (ds +,Y) morpholine mL); £) dichloromethane mg) was added in 0 AIPA (eg mg). The reaction mixture was stirred at (V+) sodium triacetoxyborohydride, then added 1 h and quenched by adding 3 aqueous solution. The mixture was stirred for 10 minutes 11 minutes at room temperature. The organic phase was concentrated in vacuo. After purification b. dichloromethane and extracted it in Ye (acetonitrile: ammonia 7 0.1) filter solution “Gemini” (HPLC column title compound $0 mg) was obtained.

MS: APCI(+ve) 502 1317 1H NMR 56 (DMSO-d6, 400MHz) 9.23 and 9.08 (1H, 2 x d), 8.45 and 8.41 (1H, 2 x d), 7.87 (1H, dd), 7.74 and 7.70 ( 1H, 2 x d), 7.49 and 7.48 (1H, 2 x d), 7.38 - 7.21 (SH, m), ~~ © 6.732 and 6.73 (1H, 2 x d), 6.64 (1H, d), 5.07 (1H, dd ), 3.79 - 3.58 (4H, m), 2.89 - 2.79 (1H, m), 2.37 - 2.21 (3H, m), 2.14 (1H, m), 2.11 and 2.06 (3H, 2 x 5), 2.02 - 1.94 (2H, m), 0.79 and 0.78 (3H, 2 x d), 0.73 - 0.63 (2H, m), 0.59 - 0.51 (2H, m).

YAAY

YY

Using amines g corresponding alcohols (Table ¥) from 4-7-01 and then preparing the following examples (in some reactions a mixture of (<= YA) was obtained General procedure described in example Preparative HPLC by Isomers Separated 0 ) diasteroisomers diastereomers 1191 Example N-Cyclopropyl-4-methyl-3-[3-[[(1R,2S)-2-methyl) -3-(4-methyl-1-piperazinyl)-1- © phenylpropyl}amino]-2-oxo-1(2H)-pyrazinyl}-benzamide 1000 Example 3-[3-[[(1R,2S) )-3-(4-Acetyl-1-piperazinyl)-2-methyl-1-phenylpropylJamino}-2-oxo- ‎1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl-benzamide

Vey example Vo

N-Cyclopropyl-4-methyl-3-[3-[[(1R,2S)-2-methyl-1-phenyl-3-(1- piperidinyl)propyl]amino]-2-oxo-1(2H)- pyrazinyl]-benzamide 107 Example N-Cyclopropyl-4-methyl-3-[3-[[(1R,2S)-2-methyl-1-phenyl-3-(1- pyrrolidinyl)propyl]amino] -2-oxo-1(2H)-pyrazinyl]-benzamide Vo 127 Example N-Cyclopropyl-3-[3-[[(1R,2S)-3-(dimethylamino)-2-methyl-1-phenylpropyl [Jamino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

71 m

Ved example N-Cyclopropyl-4-methyl-3-[3-[[(1R,2S)-2-methyl-1-(1-naphthalenyl)-3-(1- pyrrolidinyl)propyl]amino} -2-oxo-1(2H)-pyrazinyl]-benzamide

Yeo Example N-Cyclopropyl-4-methyl-3-[3-[[(1R,2S)-2-methyl-3-(4-morpholinyl)-1-(1- 5 naphthalenyl)propyl]amino] -2-oxo-1(2H)-pyrazinyl]-benzamide 16 Example N-cyclopropyl-3-[3-[[(1R,2S)-3-(diethylamino)-2-methyl- 1 -phenylpropyl] amino]-2-oxo- 1(2H)-pyrazinyl]-4-methyl-benzamide 10497 Example Vo

N-Cyclopropyl-3-[3-[[(1R,2S)-3-[(2R)-2-(methoxymethyl)-1-pyrrolidinyl]-2-methyl-1- phenylpropyl]amino]-2-oxo- 1(2H)-pyrazinyl]-4-methyl-benzamide

YEA Example N-Cyclopropyl-3-[3-[[(1R,2R)-3-[(2R)-2-(methoxymethyl)- 1 -pyrrolidinyl]-2-methyl-1- phenylpropyl]amino] -2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide 'oe 19 Example N-Cyclopropyl-3-[3-[[(1R,2S)-3-[(2S)-2 -(methoxymethyl)-1-pyrrolidinyl]-2-methyl-1- phenylpropyl[amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

YAAY

7.9

Yoo Example N-Cyclopropyl-3-[3-[[(1R,2R)-3-[(2S)-2-(methoxymethyl)-1-pyrrolidinyl]-2-methyl-1- phenylpropyl]amino ]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide 101 Example N-Cyclopropyl-3-[3-[[(1R,2S)-3-[4-(hydroxymethyl) -1-piperidinyl]-2-methyl-1- 5 phenylpropyl[amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide 1017 Example N-Cyclopropyl-3-[3-[ [(1R,2S)-3-(4-hydroxy-1-piperidinyl)-2-methyl-1- phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide ‎Yor Jl. 0

N-Cyclopropyl-3-[3-[[(1R,2S)-3-[(1,1-dimethylethyl)amino}-2-methyl-1- phenylpropyl]amino]-2-oxo-1(2H)- pyrazinyl]-4-methyl-benzamide

Yoi Example N-Cyclopropyl-3-[3-[[(1R,25)-3-[(1,]1-dimethylethyl)methylamino]-2-methyl-1- phenylpropyl]amino]-2- oxo-1(2H)-pyrazinyl]-4-methyl-benzamide Vo

Yoo Jl.

N-Cyclopropyl-3-[3-[[(1R,2S)-3-[[2-(dimethylamino)ethyl]amino]-2-methyl-1- phenylpropyl]amino]-2-oxo-1(2H) -pyrazinyl]-4-methyl-benzamide

YAAY

You Example N-Cyclopropyl-3-[3-[[(1R,2S)-3-[[2-(dimethylamino)ethy]]methylamino]-2-methyl-1- phenylpropyl]amino]-2 -oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Yov Example N-Cyclopropyl-3-[3-[[(1R,2S)-3-[(2,2-dimethylpropyl)amino]-2-methyl-1- © phenylpropyl]amino]-2-oxo -1(2H)-pyrazinyl]-4-methyl-benzamide (Y) Table 0 20

N ; R 8 E (CY MS 1H NMR. § (DMSO-d6) [M+H]+ R| example m/z 8.78 and 8.69 (1H, 2 x d), 8.45 and 515 ya 8.40 (1H, 2 x d), 7.86 (1H, dd), 7.74 and 7.70 (1H, 2 x d), 7.48 and 7.47 0 (111,2* d), 7.38 - 7.29 (5H, m), 7.27 “NN N ><

VoL -7.21 (2H, m), 6.75 and 6.74 (1H, 2 > x d), 6.641 and 6.635 (1H, 2 x d), 5.03 (1H, m), 2.90 - 2.79 (1H, m), VoL

2.46 - 2.29 (2H, m), 2.20 - 2.13 (8H, m), 2.11 - 2.06 (2H, m), 2.11 and 2.05 (3H, 2 x 5), 1.93 - 1.83 (1H, m), 0.80 (3H) , d), 0.73 - 0.63 (2H, m), 0.60 - 0.50 (2H, m) 9.32 and 9.17 (1H, 2 x d), 8.45 and 543 Yeu 8.40 (1H, 2 x , has 7.86 (1H, dd) ), 7.74 and 7.70 (1H, 2 x d), 7.49 and 7.47 (1H, 2 x d), 7.38 - 7.21 (SH, m), 6.735 and 6.73 (1H, 2 x d), 6.64 (1H, d), 5.08 ( 1H, dd), 3.67 - 3.43 (5H, -

NT NT m), 2.90 - 2.78 (1H, m), 2.37 - 2.13 Heo I 0 (SH, m), 2.11 and 2.05 (3H, 2 x 5), 2.01 - 1.94 (1H, m), 1.96 and 1.955 (3H, 2 x 5), 0.79 and 0.78 (3H, 2 x d), 0.72 - 0.64 (2H, m), 0.59 - 0.51 (2H, m 9.32 and 9.21 (1H, 2 x d), 8.45 and 500 AA 8.41 (1H, 2 x d), 7.87 (1H, dd), 7.74 NSPE and 7.71 (1H, 2 x d), 7.49 and 7.48 N ©

YAAY

(1H, 2 x d), 7.38 - 7.20 (SH, m), 6.71 (1H, d), 6.62 (1H, d), 5.06 (1H, dd), 2.89 - 2.80 (1H, m), 2.58 - 2.41 ( 1H, m), 2.30 - 2.16 (2H, m), 2.16 - 2.02 (1H, m), 2.11 and 2.05 (3H, 2 x 5), 1.95 - 1.86 (1H, m), 1.75 - 1.63 (2H, m) ), 1.64 - 1.51 (2H, m), 1.44 - 1.31 (2H, m), 0.77 and 0.76 (3H, 2 x d), 0.73 - 0.64 (2H, m), 0.60 - 0.51 (2H, m 9.17 and 9.00 ( 1H, 2 x d), 8.45 and 486 VEY 8.40 (1H, 2 x d), 7.86 (1H, d), 7.74 and 7.69 (1H, 2 x d), 7.48 and 7 (1H, 2 x d), 7.38 - 7.28 (4H , m), 7.28 -7.21 (1H, m), 6.73 and 6.72 (1H, 2 x d), 6.62 (1H, d), 5.10 - 5.02 (1H, -

YN m), 2.89 - 2.79 (2H, m), 2.61 - 2.30 Ho (4H, m), 2.11 and 2.04 (3H, 2 x 5), 2.05 - 1.99 (1H, m), 1.82 - 1.64 (4H, m ), 0.83 - 0.76 (3H, m), 0.73 - 0.63 (3H, m), 0.60 - 0.50 (2H, m)

YAAY

- 11 - 8.80 and 8.62 (1H, 2 x d), 8.45 and 460 Vey 8.40 (1H, 2 x d), 7.86 (1H, d), 7.74 and 7.70 (1H, 2 x d), 7.49 and 7.48 (1H, 2 x d) ), 7.37 - 7.20 (SH, m), 6.735 and 6.73 (1H, 2 x d), 6.63 (1H, © d), 5.10 - 5.03 (1H, m), 2.89 - 2.80 ™ N : v7

Noi (1H, m), 2.49 - 2.32 (2H, m), 2.15 - 2.04 (9H, m), 1.97 - 1.90 (1H, m), 0.81 and 0.79 (3H, 2 x d), 0.72 - 0.64 2H, m ), 0.59 - 0.51 (2H, m 8.49 and 8.26 (1H, 2 x d), 8.46 and 536 148 8.41 (1H, 2 x d), 8.39 (1H, d), 7.94 (1H, dt), 7.86 (1H, d) ), 7.77 and 7.69 (1H, 2 x d), 7.63 - 7.45 (SH, m), 6.71 Cr and 6.69 (1H, 2 x d), 6.64 and 6.63 Cr (1H, 2 x d), 6.12 (1H, m), 2.59 - 2.38 ™ N™ 3 i (6H, m), 2.23 - 2.15 (1H, m), 2.13 0" and 2.04 (3H, 2 x 5), 1.82 - 1.68 (4H, m), 0.82 in 0.80 (3H, 2 x d), 0.73 - 0.63 (2H, m), 0.60 - 0.50 (2H, m)

YAAY

8.49 - 8.18 (3H, m), 7.95 and 7 552 ) to (1H, 2 x d), 7.83 (1H, d), 7.77 and 7.70 (1H, 2 x d), 7.63 - 7.45 (SH, m), 6.71 and 6.70 (1H, 2 x d), 6.65 and (CC 6.64 (1H, 2 x d), 6.21 - 6.11 (1H, m), (= ~ 3.77 - 3.58 (SH, m), 2.91 - 2.78 (1H, NT NT)

IE m), 2.41 - 2.24 (SH, m), 2.16 - 2.07 (1H, m), 2.13 and 2.05 (3H, 2 x 5), 0.80 and 0.78 (3H, 2 x d), 0.73 - 0.63 2H, m) , 0.59 - 0.50 (2H, m 8.69 and 8.63 (1H, 2 x d), 8.45 and 488 143 8.41 (1H, 2 x d), 7.86 (1H, dd), 7.73 and 7.72 (1H, 2 x d), 7.49 and 7.48 (1H, 2 x d), 7.36 - 7.28 (4H, m), 7.27 -7.19 (1H, m), 6.732 and 6.727 (1H, 2 ha 2 2.7 0(, 6.64 (1H, d), 5.11 - 5.01 (1H) , A : L m), 2.90 - 2.79 (1H, m), 2.64 - 2.30 (SH, m), 2.28 - 2.13 (1H, m), 2.12 - 2.04 (1H, m), 2.10 and 2.05 3H, 2 x ), 0.99 - 0.90 (6H, m), 0.81 (3H, 1),

YAAY a m 9.00 and 8.97 (1H, 2 x d), 8.47 and 530 0 8.42 (1H, 2 x d), 7.86 and 7.72 (1H, 2x d), 7.71 and 7.49 (1H, 2 x d), 7.38 - 7.30 (4H, m), 7.28 - 7.21 (1H, m), 6.72 and 6.71 (1H, 2 x d), 6.63 and 6.62 (1H, 2 x d), 5.20 - 5.11 (1H, m), 3.44 - 3.37 (1H, m), 3.27 - 3.19 J (1H, m), 3.22 and 3.21 3H, 2 x 5), “_ \ A 2.92 - 2.80 (2H, m), 2.58 - 2.31 (3H, Hoo m), 2.16 - 2.04 (1H, m) ), 2.11 and 2.07 (3H, 2 x 5), 2.00 (1H, d), 1.88 - 1.70 (2H, m), 1.69 - 1.57 (1H, m), 1.54 - 1.42 (1H, m), 0.74 (3H , d), 0.72 - 0.65 (2H, m), 0.59 - 0.52 (2H, m 8.44 and 8.37 (1H, 2 x d), 8.31 and 530 [YEA 0 8.13 (1H, 2 x d), 7.86 (1H, 2 x d) dt), b A 7.75 and 7.70 (1H, 2 x d), 7.48 and )

YAAY

7.47 (1H, 2 x d), 7.44 - 7.37 (2H, m), 7.35 - 7.28 (2H, m), 7.25 - 7.18 (1H, m), 6.77 and 6.75 (1H, 2 x d), 6.65 and 6.63 (1H , 2 x d), 4.80 - 4.70 (1H, m), 3.34 - 3.27 (1H, m), 3.20 and 3.20 (3H, 2 x 5), 3.17 - 3.10 (1H, m), 3.06 - 2.99 (1H, m) ), 2.90 - 2.80 (1H, m), 2.66 - 2.54 (1H, m), 2.30 - 2.10 (2H, m), 2.12 and 2.05 (3H, 2 x 5), 1.85 - 1.73 (1H, m), 1.70 - 1.58 (2H, m), 1.51 - 1.39 (1H, m), 0.744 and 0.734 (3H, 2 x d), 0.71 - 0.63 (2H, m), 0.59 - 0.50 (2H, m) 8.45 and 8.39 (1H, 2 x 5), 8.18 and 530 V4 7.94 (1H, 2 x d), 7.87 (1H, d), 7.76 and 7.70 (1H, 2 x 5), 7.52 - 7.45 (1H, m), 7.43 - 7.29 (4H, m), 7.27 - 7.18 2 m m), 3.20 3H, 5), 3.18 - 3.08 (1H, m), 2.99 - 2.90 (1H, m), 2.89 - 2.80 (1H,

YAAY

11 - m), 2.60 - 2.34 (4H, m), 2.21 - 1.96 (2H, m), 2.13 and 2.05 3H, 2 x 5), 1.86 - 1.71 (1H, m), 1.69 - 1.56 (2H, m) , 1.53 - 1.40 (1H, m), 0.90 3H, 5), 0.74 - 0.64 (2H, m), 0.60 - 0.50 (2H, m) 9.02 - 8.95 (1H, m), 8.50 - 8.35 (1H, 530 Vou m), 7.90 - 7.83 (1H, m), 7.74 - 7.66 (1H, m), 7.53 - 7.44 (1H, m), 7.44 - 7.16 (5H, m), 6.76 - 6.58 (2H, m), 4.73 and 4.58 (1H, 2 x m), 3.43 - 7 0 3.31 (1H, m), 3.26 - 3.11 (4H, m), 3s 3.08 - 2.97 (1H, m), 2.93 - 2.79 (1H, .m) , 2.6 - 2.4 (2H, m), 2.30 - 2.02 (5H, m), 1.88 - 1.59 (3H, m), 1.52 - 1.38 (1H, m), 0.78 - 0.62 (SH, m), 0.61 - 0.48 ( 2H, m) 9.08 and 8.87 (1H, 2 x d), 8.45 and 530 ¢ 61 8.40 (1H, 2 x d), 7.86 (1H, dd), 7.74 5 lb and 7.70 (1H, 2 x d), 7.49 and 7.48 on

YAAY

- 1 - )111, 2x d), 7.37 - 7.21 (5H, m), 2 (1H, d), 6.62 (1H, d), 5.10 - 5.02 (1H, m), 4.36 (1H, t), 3.18 (2H, 1), 3.14 - 3.00 (1H, m), 2.89 - 2.79 (1H, m), 2.78 - 2.69 (1H, m), 2.12 and 2.05 (3H, 2 x 5), 1.96 - 1.84 (2H, m), 1.80 - 1.70 (1H, m), 1.69 - 1.54 (2H, m), 1.50 - 1.37 (1H, m), 1.36 - 1.21 (2H, m), 0.80 and 0.78 (3H, 2 x d), 0.72 - 0.64 (2H, m), 0.59 - 0.51 (2H, m 9.18 and 9.06 (1H, 2 x d), 8.45 and 516 0 8.40 (1H, 2 x d), 7.86 (1H, dd), 7.74 and 7.70 (1H, 2 x , has 7.49 and 7.47 (1H, 2 x d), 7.38 - 7.21 (5H, m), 6.72 (1H, d), 6.62 (1H, d), 5.06 (1H, dd), ¢ SN Y N™ 4.49 (1H, d), 3.52 - 3.41 (1H, m), for ©

Oh

2.93 - 2.78 (2H, m), 2.62 - 2.37 (2H, m), 2.25 - 2.00 (1H, m), 2.11 and 2.05 (3H, 2 x 5), 1.98 - 1.45 (6H, m), 0.78 and 0.77 (3H, 2 x d), 0.72 - 0.64

YAAY nmososionm 9.14 and 9.09 (1H, 2 x d), 8.45 and 488 Vor 8.40 (1H, 2 x d), 7.86 (1H, d), 7.72 (1H, d), 7.48 and 7.48 (1H, 2 x d), 7.40 - 7.27 (4H, m), 7.26 - 7.19 (1H, m), 6.74 - 6.68 (1H, m), 6.63 - 6.58 2 (1H, m), 5.11 - 5.02 (1H, m), 2.89 - - Le vor 2.79 (1H, m), 2.40 - 2.27 (2H, m), H 5: H 2.25 - 2.13 (1H, m), 2.10 and 2.06 (3H, 2x 5), 1.01 (9H, s), 0.83 and 0.82 (3H , 2 x d), 0.72 - 0.64 (2H, m), 0.59 - 0.51 (2H, m) 8.47 and 8.41 (1H, 2 x d), 8.08, 7.83 502 vot and 7.87 (2H, 3 xd), 7.75 and 7.73 ( 1H, 2 x 5), 7.49 and 7.48 (1H, 2 x d), 7.38 - 7.28 (4H, m), 7.26 - 7.18 0 (1H, m), 6.75 (1H, d), 6.66 and 6.65 ™ N° y hoi (1H, 2 x d), 5.14 and 5.05 (1H, 2 x dd), 2.90 - 2.79 (1H, m), 2.41 - 2.20 2H, m), 2.14, 2.11, 2.09 and 2.07

YAAY

(6H, 4 x 5), 2.04 - 1.95 (1H, m), 0.96 and 0.94 (9H, 2 x 5), 0.84 and 0.81 (3H, 2 x d), 0.73 - 0.64 (2H, m), 0.59 - 0.51 (2H, m) 8.69 and 8.54 (1H, 2 x d), 8.44 and 503 Yoo 8.38 (1H, 2 x d), 7.86 (1H, d), 7.74 and 7.70 (1H, 2 x d), 7.49 and 7.47 (2xd, J=7.9Hz, 1H), 7.41 - 7.28 (4H, m), 7.26 - 7.19 (1H, m), 6.75 ¢ and 6.74 (1H, 2 x d), 6.63 and 6.62 NN PN

H = H (1H, 2 x d), 5.03 (1H, dd), 2.90 - 2.78 (1H, m), 2.42 - 2.22 (7H, m), 2.12 and 2.05 (3H, 2 x 5), 2.09 (6H, 5), 0.84 (3H, d), 0.73 - 0.64 (2H, m), 0.59 - 0.50 (2H, m 8.59 and 8.55 (1H, 2 x d), 8.46 and 517 yor 8.40 (1H, 2 x d), 7.87 ( 1H, d), 7.74 and 7.72 (1H, 2 x d), 7.50 and 7.48 0 (1H, 2 x d), 7.40 - 7.29 (5H, m), 7.28 ; NT -7.20 (1H, m), 6.751 and 6.747 ( 1H, 2 x d), 6.65 (1H, d), 5.11 - 5.03 (1H,

YAAY m), 2.90 - 2.80 (1H, m), 2.45 - 2.28 (6H, m), 2.20, 2.18,2.13,2.11, 2.10 and 2.07 (12H, 6 x 5), 2.04 - 1.96 (1H, m), 0.81 (3H, d), 0.74 - 0.64 2H, m), 0.59 - 0.51 2H, m 8.48 - 8.36 (2H, m), 7.86 (1H, dd), 502 yov 7.74 and 7.70 (1H, 2 x d), 7.49 and 7. (1H, 2 x d), 7.40 - 7.28 (4H, m), 7.26 - 7.18 (1H, m), 6.74 (1H, d), 6.63 and 6.62 (1H, 2 xd), 5.11 - 5.03 (1H , ~

VY TVR m), 2.91 - 2.78 (1H, m), 2.41 - 2.02 H : H (5H, m), 2.11 and 2.05 3H, 2 x 5), 0.88 (9H, s), 0.85 (3H, d), 0.74 - 0.63 2H, m), 0.59 - 0.50 (2H, m) (Yeh) Example N-Methoxy-4-methyl-3-[3-[[(1R,2S)-2-methyl-1- (1-naphthalenyl)-3-(1- pyrrolidinyl)propyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide 0 ~ no; 2: - “7°N N: N

H by 8 l o

YAAY

4-Methyl-3-[3-[[(1R,2R)-2-methyl-1-(1-naphthalenyl)-3-oxopropyl]Jamino]-2-oxo- 1(2H)-pyrazinyl]-benzoic acid , methyl ester : the subtitle compound was prepared from 3-[3-[[(1R,2R)-3-hydroxy-2-methyl-1-(1-naphthalenyl)propylJamino]-2-oxo-1(2H) )- © pyrazinyl]-4-methyl-benzoic acid, methyl ester (VFA) using the method described in the NYY example (example: (b) 4-Methyl-3-[3-[[( 1R,2S)-2-methyl-1-(1-naphthalenyl)-3-(1-pyrrolidinyl)propyl[Jamino]- 2-o0x0-1(2H)-pyrazinyl]-benzoic acid, methyl ester Yo was prepared Subtitle compound of: 4-methyl-3-[3-[[(1R,2R)-2-methyl-1-(1-naphthalenyl)-3-oxopropyl]amino]-2-oxo-1(2H) - pyrazinyl]-benzoic acid, methyl ester (VTA) using the method described in Example TY 0A (Example MS: APCI(+ve) 511 (M+H+). Vo 1H NMR E (DMSO0-d6, 400MHz) 8.53 - 8.21 (2H, m), 8.03 - 7.75 (4H, m), 7.66 - 7.43 (6H, m), 6.75 - 6.57 (2H, m), 6.19 - 6.04 (1H, m) ), 3.87 and 3.84 3H, s), 2.50 - 2.39 (6H,

YAAY m), 2.29 - 2.18 (1H, m), 2.17 and 2.08 (3H, 2 x s), 2.50 - 2.39 (6H, m), 1.82 - 1.68 (4H, m), 0.82 and 0.80 (3H, 2 x d) . (c) N-Methoxy-4-methyl-3-[3-[[(1R,2S)-2-methyl-1-(1-naphthalenyl)-3-(1-pyrrolidinyl) propyl] amino]-2-oxo-1(2H)-pyrazinyl]-benzamide © 0.1 ¢ diethyl ether in J¥ go Y) iso-propylmagnesium chloride A solution of : was added dropwise to a stirred solution of ( Ja 4-methyl-3-[3-[[(1R,2S)-2-methyl-1-(1-naphthalenyl)-3-(1-pyrrolidinyl)propyl]Jamino]- 2-0x0-1(2H) -pyrazinyl]-benzoic acid, methyl ester stereo) 10) O-methylhydroxylamine hydrochloride 5 mg) 4 + VOA (ex. 0 at room temperature. After 10 min the reaction was quenched by adding (Je Y ) tetrahydrofuran (Na2S04) The organic phase was dried, saturated aqueous ethyl acetate, extracted in NH4CI filter solution “Gemini” (HPLC column), filtered and concentrated in vacuo. After purification B, the title compound was obtained as a substance Solid (10 mg). (acetonitrile: ammonia +)

MS: APCI(+ve) 526 (M+H+). Vo 1H NMR 6 (DMSO-d6, 400MHz) 11.81 and 11.75 (1H, 2 x s), 8.40 (1H, dd), 8.57 - 8.18 (1H, m), 7.95 (1H, d), 7.83 (1H, d) , 7.79 (1H, dd), 7.70 - 7.48 (6H, m), 6.72 and 6.70 (1H, 2 x d), 6.66 - 6.63 (1H, m), 6.16 - 6.06 (1H, m), 3.71 and 3.68 (3H , 2 x 5), 2.64 -

YAAY

2.40 (4H, br), 2.27 - 2.11 (1H, br), 2.14 and 2.05 (3H, 2 x s), 1.82 - 1.68 (4H, br), 0.89 - 0.77 (3H, br). (VT J) corresponding alcohols (Table 11-44) The following examples (VOA) were prepared using the method described in Example 1(a) (ed) Jaa ©

N-Methoxy-4-methyl-3-[3-[[(1R,2S)-2-methyl-1-phenyl-3-(1- pyrrolidinyl)propyl]amino]-2-oxo-1(2H)- pyrazinyl]-benzamide ( "0 ) Example N-Methoxy-4-methyl-3-[3-[[(1R,2S)-2-methyl-3-(4-morpholinyl)-1- phenylpropyl] amino]-2-oxo-1(2H)-pyrazinyl]-benzamide Vo (example) O

N-Methoxy-4-methyl-3-[3-[[(1R,2S)-2-methyl-3-(4-morpholinyl)-1-(1-naphthalenyl)propyl]amino]-2-oxo-1 (2H)-pyrazinyl]-benzamide

YAAY

YYo of Table (4) ZY 0 OC 0 ~"°N R H 0 MS Example 1H NMR. § (DMSO-d6) [M-+H]+ R m/z and 11.76 (1H, 2 x 5), 9.46 - 476 01 11.84 (1H, m), 7.79 (1H, d), 7.69 and 9.29 (1H, 2 x 5), 7.60 - 7.22 (SH, m), 7.64 and 6.83 (1H, 2 x d), 6.76 and 6.84 (1H, 2 x d), 5.23 - 5.09 (1H, m), 6.75 “>” b and 3.68 (3H, 2 x 5), 3.64 - 3.48 N° 3.71 H = (2H, m), 3.19 - 2.77 (3H, m), 2.65 - (1H, m), 2.16 and 2.08 ( B d), 7.65 and 7.61 (1H, 2 x d), 7.52 and 1 (1H, 2 x d), 7.38 - 7.21 (6H, m), H (Lo 7.51 YAAY

6.73 (1H, d), 6.643 and 6.639 (1H, 2 x d), 5.07 (1H, dd), 3.81 - 3.59 (4H, m), 3.71 and 3.69 (3H, 2 x 5), 2.35 2.22 (3H, m ), 2.21 - 2.09 (1H, m), 2.12 and 2.07 (3H, 2 x 5), 1.98 (1H, dd), 0.79 and 0.78 (3H, 2 x d) 11.81 and 11.75 (1H, 2 x 5), 8.49 - 542 11 8.18 (2H, m), 7.95 (1H, d), 7.83 (1H, d), 7.79 (1H, dd), 7.70 - 7.48 (6H, m), 6.72 and 6.70 (1H, 2 x d), 6.65 and CC 6.645 (1H, 2 x d), 6.21 - 6.13 (1H, m), (fe 3.75 - 3.60 (4H, m), 3.71 and (3H, 2 x 7 a : 3 5), 2.61 - 2.42 (4H, m), 2.42 - 2.26 (2H, m), 2.14 and 2.06 (3H, 2 x s), 2.07 (1H, m), 0.80 and 0.78 (3H, 2 x d

YAAY

—YYV-

(0131) Example 3-[3-[[(1R,2R)-3-Hydroxy-2-methyl-1-phenylpropyl]Jamino]-2-oxo-1(2H)-pyrazinyl]-N- methoxy-4-methyl-benzamide, trifluoroacetate

Ym-27b JA: “ONY NY oH Ho J : © A solution of Y) iso-propylmagnesium chloride M tetrahydrofuran ¢ 0,0 mL) was added dropwise to a stirred mixture of:

3-[3-((1R,2R)-3-hydroxy-2-methyl-1-phenyl-propylamino)-2-oxo-2H-pyrazin-1-yl]-4- methyl-benzoic acid, methyl ester mg) Y ++) O-methylhydroxylamine hydrochloride 5 sg) TV E C 11 (ex. min. The reaction was quenched by adding 111141 aqueous V0 after 0 ml) at 0 °C) tetrahydrofuran 0 and filtering Its concentration was in (Na2S04) and the organic phase was dried. ethyl acetate and its extraction in

Gemini acetonitrile filtration solution: ammonia Ze) The title compound was obtained. (M+H+) 423 (H“-)01 tm MS: 1H NMR 5 014180-06, 400MHz) 11.77 (1H, m), 7.78 (1H, d), 7.68 and 7.62 (1H, 2) xs), 0 (1H, t), 7.42 (2H, 1), 7.33 (2H, t), 7.24 (1H, 0. 6.80 - 6.75 (1H, m), 6.71 - 6.66 (1H, 7.51 agagh) m), 5.04 - 4.97 (1H, m), 3.71 and 3.68 (3H, 2 x 5), 3.23 - 3.12 (2H, m), 2.31 - 2.20 (1H, m), 2.14 and 2.07 (3H, 2 x s) , 0.88 (3H, d).(VY) Example N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[2-(methylamino)ethoxy]phenyl Jethyl [amino]-2-oxo0-1(2H)-pyrazinyl]-benzamide 5

N

0 ZN grit > 0 mL (0)

N N

H H

0 to (Je +,Y) 1-bromo-2-chloroethane mg) and ¥'¥'+) potassium carbonate was added : a stirred solution of

N-cyclopropyl-3-(3-(2-(2-hydroxyphenyl)propan-2-ylamino)-2-oxopyrazin-1(2H)-yl)-4- methylbenzamide Ye nitrogen mL). The reaction mixture was stirred in an atmosphere of (acetonitrile (gm)) for 151 174 hours (eg) and then concentrated in vacuo. The residue was treated with water and extracted 16 at 87 °C for a period of time and filtered (Na2SO4) The organic phase was brine and dried Jue at 010010:010601806. It was in amine methyl 777 mg (using VY +) and concentrated in vacuo. The remaining minutes were processed. The mixture was concentrated in Te for 5 001 and heated in a microwave at (Je) (? ethanol YO: ammonia 761 Gemini filter solution (HPLC column — vacuo). After purification. Obtaining the title compound as a solid (10 mg) acetonitrile in bulk

MS: APCI(+ve) 476 (M+H+). 1H NMR 5 (DMSO-d6, 400MHz) 8.43 (1H, d), 7.86 (1H, dd), 7.72 (1H, d), 7.48 (1H, d), 7.35 (1H, dd), 7.22 - 7.17 (1H , m), 6.97 (1H, d), 6.94 - 6.85 (2H, m), 6.67 (1H, d), 6.63 (1H, d), 4.04 - 3.92 (2H, m), 2.89 - 2.80 (3H, m) ), 2.28 (3H, 5), 2.09 (3H, 5), 1.83 (6H, 5), 0.71 - 0.66 (2H, m), 0.57 - 0.52 (2H, m). ° (V1€) Joe

N-Cyclopropyl-4-methyl-3-[3-[[ 1-methyl-1-[2-[3-(methylamino)propoxy]phenyl]ethyl] amino]-2-oxo-1(2H)-pyrazinyl] -benzamide 0 SN a ad

A © : " t] 17

H H

0 = : the address complex was prepared from 0

N-cyclopropyl-3-(3-(2-(2-hydroxyphenyl)propan-2-ylamino)-2-oxopyrazin-1(2H)-yl)-4- methylbenzamide (V7) using the method described in Example 1 -bromo-3-chloropropane (example (;1) and

MS: APCI(+ve) 490 (M+H+). 1H NMR § (DMSO-d6, 400MHz) 8.43 (1H, d), 7.86 (1H, dd), 7.73 (1H, d), 7.48 (1H, d), Vo 7.35 (1H, dd), 7.23 - 7.17 ( 1H, m), 6.98 - 6.88 (3H, m), 6.67 (1H, d), 6.64 (1H, d), 4.05 -

YAAY

YY. —

3.93 (2H, m), 2.88 - 2.39 (2H, m), 2.34 (3H, s), 2.10 (3H, 5), 2.00 - 1.91 (2H, m), 1.85 (3H, 5), 1.83 (311, 5), 0.72 - 0.67 (2H, m), 0.57 - 0.53 (2H, m).

( 1+5 eg N-Cyclopropyl-4-methyl-3-[2-0x0-3-[[(1R)-1-[2-[2-(1-pyrrolidinyl)ethoxy]phenyl propyl] amino]-1(2H)-pyrazinyl]-benzamide 5

oT button ZN 0 "1 Lmca A N N COLT VD 0 (1)

(S)-2-Methyl-N-[(1R)-1-[2-(2-hydroxyethoxy)pheny!]propyl]-2-propanesulfinamide and (S)-2-methyl-N-[(1S)- 1-[2-(2-hydroxyethoxy)phenyl]propyl]-2-propanesul finamide anhydrous copper(I) 5 mg) ¥4A) (S)-2-Methyl-2-propanesulfinamide Ve g added ) +,©) 2-(2-hydroxyethoxy)-benzaldehyde to a stirred solution of (a>0.001) sulphate (a>0.001 h) then filtered and concentrated in VY ml. The reaction mixture was stirred for 0 ) dichloromethane in . . VA= and cooled to (Ja YO) dichloromethane in vacuo. The residue was treated with (Je 4,8 mol Y) tetrahydrofuran in ethylmagnesium chloride solution of M was added for 2 hours; Then vem for 1 hour and allowed to warm up to 5 YA= drop by drop. The mixture was stirred when VO “dichloromethane” was quenched by adding saturated solution 1411401. The mixture was extracted using, filtered, solvent removed (Na2S04) and dried by washing the collected organic layers with a solution of

Done ) acetonitrile : ammonia 7.01 dias Gemini solution (HPLC column — after purification from (S)-2-Methyl-N-[(1R)-1-[2-(2-hydroxyethoxy) phenyl]propyl]-2-propanesulfinamide 111 11111 6 (DMSO-d6, 400MHz) 7.29 (1H, dd), 7.20 - 7.15 (1H, m), 6.96 - 6.88 (2H, m), 5.17 (1H, d), 4.90 (1H, t), 4.53 (1H, d), 4.04 - 3.93 (2H, m), 3.73 (2H, q), 1.86 - 1.67 © (2H, m), 1.05 (9H, s), 0.82 (3H , t).(S)-2-Methyl-N-[(1S)-1-[2-(2-hydroxyethoxy)phenyl]propyl]-2-propanesulfinamide mg) 1 4 0 )

IHNMR (DMSO-d6, 400MHz) 7.32 (1H, dd), 7.21 - 7.16 (1H, m), 6.97 - 6.87 (2H, m), 5.35 (1H, d), 4.92 (1H, t), 4.43 - 4.37 (1H, m), 4.06 - 3.95 (2H, m), 3.73 (2H, q), Vo 1.81-1.62 (2H, m), 1.11 (9H, s), 0.82 (3H, t): b -4-methyl-benzamide. A mixture of \o (S)-2-methyl-N-[(1R)-1-[2-(2-hydroxyethoxy)phenyl]propyl]-2-propanesulfinamide was simulated.

YAAY

(example) dissolving 01) methanol (pe YY ml) and a solution of hydrogen chloride in 1 4 ;- dioxane (; molar; ; (Je) at room temperature for VY hour. The concentration was mixture in the center

discharger. The residue was treated with: 3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methyl ester eg (ab; ©£0 mg) tetrahydrofuran (Je +,4Y) triethylamine (© ml). The mixture was stirred at room temperature for #0 days before adding (J—= +,©) cyclopropyl amine 1(m) cyclopentylmagnesium bromide in diethyl ether; © (Je) dropwise. The mixture was stirred for 11 minutes, quenching it by adding a saturated 1111401 solution and extracting it in ethyl acetate, then drying the organic phase (Na2S04), filtering it and concentrating it in vacuo, then treating the remaining 0 with ethanol (© ml) and this was followed Addition of +,¢Y) ammonium formate g) ARE palladium to carbon 01 (mg). The reaction mixture was heated in a microwave for 2 hours at Yoo C before being cooled to room temperature, filtered, and washed with ethanol. The filtrate was concentrated in vacuo. The residue was treated with dichloromethane, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to yield the crude product 40 (mg)

0 which was used in the next step without further purification.

(c) N-Cyclopropyl-4-methyl-3-[2-0x0-3-[[(1R)-1-[2-[2-(1-pyrrolidinyl)ethoxy]phenyl] propyl [amino]-1(2H)-pyrazinyl]-benzamide

(Je oY)) methanesulfonyl chloride was added to a stirred solution of: YAAY

N-cyclopropyl-3-[3-[[(1R)-1-[2-(2-hydroxyethoxy)phenyl]propyl]amino]-2-0xo0-1(2H)- pyrazinyl]-4-methyl -benzamide (+ £1 mg) 5 (Je +,0) triethylamine in (Je V+) dichloromethane at 0 0 5 The reaction mixture was stirred for 1 hour at 0 C and 1 hour at room temperature. © water was added and the organic phase separated; It was dried (Na2S04), filtered and concentrated in an incubator medium. The remaining dallas was represented with (Je +,VY) Pyrrolidine s (Je ) +) dichloromethane and the mixture was stirred at room temperature for YE 1 h. The mixture was concentrated in vacuo. After securing by HPLC (Gemini column acetonitrile filtration solution: ammonia 76.1), . (pe Y¢ Y) alia the title compound as substance

MS: APCI(+ve) 516 (M+H+). Ye 1H NMR § (DMSO-d6, 400MHz) 8.44 (0.5H, d), 8.40 (0.5H, d), 7.88 - 7.84 (1H, m), 7.77 (0.5H, d), 7.71 (0.5H, d) ), 7.51 - 7.46 (1H, m), 7.40 - 7.35 (1H, m), 7.31 - 7.25 (1H, m), 7.23 - 7.17 (1H, m), 7.03 - 6.98 (1H, m), 6.92 - 6.86 (1H, m), 6.81 - 6.78 (1H, m), 6.69 - 6.65 (1H, m), 5.26 - 5.19 (1H, m), 4.15 - 4.08 (2H, m), 2.88 - 2.80 (3H, m) , 2.60 - 2.52 (4H, m), 2.13 (1.5H, s), 2.07 (1.5H.8( 1.90 - 1.79 (2H, m), 1.71 - 1.65 (4H, m), Yo 0.89 - 0.82 (3H, m), 0.72 - 0.64 (2H, m), 0.58 - 0.51 (2H, m).(17) Example N-Cyclopropyl-4-methyl-3-[2-ox0-3-[[(1S) -1-[2-[2-(1- pyrrolidinyl)ethoxy]phenyl]propyl]Jamino]-1(2H)-pyrazinyl]-benzamide ‎YAAY

A

Rice 0 ZN 07

A © 0 8 0 : The title compound was prepared from (S)-2-methyl-N-[(1S)-1-[2-(2-hydroxyethoxy)phenyl]|propyl]-2-propanesulfinamide 2110) 5 (@V 10) using the method described in Example IY 10 (Example MS: APCI(+ve) 516 (M+H+). ©

IH NMR 6 (DMSO-d6, 400MHz) 8.44 (0.5H, d), 8.40 (0.5H, d), 7.88 - 7.84 (1H, m), 7.77 (0.5H, d), 7.71 (0.5H, d) , 7.51 - 7.46 (1H, m), 7.40 - 7.35 (1H, m), 7.31 - 7.25 (1H, m), 7.23 - 7.17 (1H, m), 7.03 - 6.98 (1H, m), 6.92 - 6.86 ( 1H, m), 6.80 (1H, t), 6.67 (1H, dd), 5.26 - 5.18 (1H, m), 4.16 - 4.08 (2H, m), 2.89 - 2.79 (3H, m), 2.61 - 2.52 ( 4H, m), 2.13 (1.5H, 5), 2.07 (1.5H, 5), 1.90 - 1.78 (2H, m), 1.72 - 1.64 (4H, m), 0.89 - 0.82 (3H, Ye m), 0.72 - 0.64 (2H, m), 0.59 - 0.51 (2H, m). (YTV) Example N-Cyclopropyl-4-methyl-3-[3-[[1-[2-[2-(methylamino)ethoxy]phenyl] cyclopropyl] amino|-2-oxo-1(2H) -pyrazinyl]-benzamide

N

0 = N fortress ~~

A 0 \

CCT

H | H0

Yo

YAAY

E79 -

1-(2-(Benzyloxy)phenyl)cyclopropanamine (0) Titanium(IV) isopropoxide was added to a stirred solution of : 2-(benzyloxy)benzonitrile 0.0© g) in YO) diethyl ether ml) and cooled to -8 °C under N2 and then add ¥,1V) ethylmagnesium bromide ml of a solution of 3M in diethyl ether). The resulting © mixture was stirred at -8 °C for 10 minutes and then warmed to room temperature for 1 hour. (Je V,YY) Boron trifluoride diethyl etherate was added dropwise and the mixture was stirred for 1 hour. ales) the reaction was carried out using 1 M HCI (Yo) mL). (Ja ¥'+) diethyl ether was added and the organic layer was separated. To the aqueous layer, 701 aqueous NaOH (+© ml) diethyl ethers was added, and this was filtered through Celite to remove the solids (which were washed with (diethyl ether). 0 This mixture was extracted — V+ » Y) diethyl ether mL) 5 (V+) dichloromethane mL). All organic layers were collected, dried (0482504) and solvent removed in vacuo. The residue was dissolved in dichloromethane and Cad was collected in a 01 g SCX column. Impurities were juiced thoroughly with (Je© +) methanol and Cad after eluting with methanolic ammonia 7 N (Je YO) and evaporation the subtitle compound was obtained as brown oil

0 (175, .. g). NMR 6 (CDCI3) 7.47 (d, 2H), 7.40 (t, 2H), 7.33 (t, 1H), 7.26 - 7.20 (m, 2H), 6.95 111 (d, 1H), 6.90 (td, 1H), 5.18 (s, 2H), 1.07 (dd, 2H), 0.89 (dd, 3H) (b): Methyl 3-(3-(1-(2-(benzyloxy)phenyl)cyclopropylamino)-5 -bromo-2-oxopyrazin-1(2H)- yl)-4-methylbenzoate Ye YAAY

: to (example ab; 3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methyl ester (ex. 1-(2- (Benzyloxy)phenyl)cyclopropanamine: (Jo (? THE no g) was added in ml) and the reaction was heated within (0 ¥) N,N-diisopropylamine g) Ave a closed ml 10 minutes in a microwave bottle Av M for YY. At “CEM Discover microwave” © lock. after cooling to room temperature; The organic layers were washed with water; dried, 0-85, filtered with 5:02 Gil a slay KS) and filtered and purified the crude product (Na2S04) to obtain the subtitle product as foam (iso-hexane in dichloromethane Tyee (p > 0,17) Orange 1H NMR 5 (DMSO0-d6) 7.94 (dd, 1H), 7.85 (d, 1H), 7.55 - 7.51 (m, SH), 7.35 (t, 2H), 01 7.29 (t, 1H), 7.20 (td, 1H), 7.03 (d, 1H), 7.01 (s, 1H), 6.89 (td, 1H), 5.22 (s, 2H), 3.83 (s, 3H), 2.12 (s, 3H), 1.27 - 1.08 (m, 4H).: (c) Methyl 3-(3-(1-(2-hydroxyphenyl)cyclopropylamino)-2-oxopyrazin-1(2H)-yl)-4- methylbenzoate Yo : to Methyl 3-(3-(1-(2-(benzyloxy)phenyl)cyclopropylamino)-5-bromo-2-oxopyrazin-1(2H)-yl)-4-methylbenzoate

YAAY

No (eg (VV 6 e mg) in (Ja Yo ) ethanol Ao °) ammonium formate mg) and PAC (1071 01 mg) were added and the reaction was heated at VO C for 1 hour. The mixture was filtered through Celite and the solids were washed with Atta 100. The filtrate and de-volatiles were collected in vacuo to yield a pale yellow solid. Dichloromethane and © water were added and the organic layer was separated. The aqueous layer was again extracted with dichloromethane ethyl acetate The combined organic extract (Na2804) was dried and the solvent was eluted in vacuo to yield the title product Al = 77 off-white foam (DMSO0-d6) 11.26 (s, 1H), 8.45 (s, 1H), 7.95 (d, 1H), 7.85 (s, 1H), 7.56 (d, 6 11112 111 1H), 7.45 (d, 1H), 7.11 (t , 1H), 6.88 (d, 1H), 6.80 - 6.73 (m, 3H), 3.84 (s, 3H), 3.31 (s, Ye 2H), 2.12 (s, 3H), 1.11 - 1.03 (m, 2H), 1.30 - 1.22 (m, 2H). : (d) -cyclopropyl-3-(3-(1-(2-hydroxyphenyl)cyclopropylamino)-2-oxopyrazin-1(2H)-yl) -4- methylbenzamide : mmol) MET Ja +, 0) cyclopropyl amine to 0

Methyl 3-(3-(1-(2-hydroxyphenyl)cyclopropylamino)-2-oxopyrazin-1(2H)-yl)-4- methylbenzoate at room temperature e.g. THF (fere g) in ' = Vy (Ex. drip. Molar THF was stirred in 1 ml of isopropylmagnesium chloride, A0+) solution.

YAAY

-YYA-

The reaction mixture was for 1 hour and then (+,A0) isopropylmagnesium chloride mL of solution was added

? molar in (THF) and the reaction mixture was stirred for 1 hour. Water and aqueous 1101 were carefully added

JY se ¥ and the aqueous layer was extracted using dichloromethane (twice). The combined organic layers (Na2S04) were dried and solvent removed in vacuo to obtain the subtitle product.

© YET yellow solid (g).

1H NMR 5 (DMSO-d6) 11.15 (s, 1H), 8.47 (s, 1H), 8.36 (d, 1H), 7.85 (dd, 1H), 7.71 (d,

1H), 7.47 (d, 1H), 7.46 (dd, 1H), 7.11 (dt, 1H), 6.89 (d, 1H), 6.80 - 6.73 (m, 3H), 2.87 -

2.79 (m, 1H), 2.09 (s, 3H), 1.30 - 1.21 (m, 2H), 1.14 - 1.04 (m, 2H), 0.70 - 0.64 (m, 2H), 0.55- 0.51 (m, 2H) .

: (—2) 001 3-(3-(1-(2-(2-Chloroethoxy)phenyl)cyclopropylamino)-2-oxopyrazin-1(2H)-yl)-N-cyclopropyl-4-methylbenzamide

to : -cyclopropyl-3-(3-(1-(2-hydroxyphenyl)cyclopropylamino)-2-oxopyrazin-1(2H)-yl)-4- methylbenzamide Yo (ex. OYE avy g) In acetonitrile (° ml) under nitrogen, potassium (aa V,) ¥) carbonate was added, followed by the addition of (Je 0,7 *) 1-bromo-2-chloroethane, and the mixture was heated at 40 m for 11 h. After cooling to room temperature, the mixture was filtered through a cellite, and the Jue stiffened with more acetonitrile. The filtrate was collected

‎YAAY

The solvent was degassed in vacuo to obtain the subtitle product as an orange-tipped solid

to brown 0.777 (g). 1H NMR 6 (DMSO-d6) 8.35 (d, 1H), 7.84 (dd, 1H), 7.67 (d, 1H), 7.52 (dd, 1H), 7.46 (d, 1H), 7.25 (s, 1H), 7.21 (dt, 1H), 6.97 (d, 1H), 6.90 (t, 1H), 6.87 (d, 1H), 6.71 (d, 1H), (t, 2H), 4.00 (t, 2H), 2.86 - 2.78 (m, 1H), 2.05 (s, 3H), 1.26 - 1.06 (m, 4H), 0.69 - e 4.31 (m, 2H), 0.55 - 0.50 (m, 2H). 0.64

(9) : N-Cyclopropyl-4-methyl-3-(3-(1-(2-(2-(methylamino)ethoxy) phenyl)cyclopropyla- mino)-2-oxopyrazin-1(2H)- yl)benzamide 0 to: 3-(3-(1-(2-(2-Chloroethoxy)phenyl)cyclopropylamino)-2-oxopyrazin-1(2H)-yl)-N- cyclopropyl-4 TY Jha (2001)-methylbenzamide (200 mg) in a 10 ml microwave vial added (Y) amine methyl 777 ml solution in ethanol the yield was sealed and heated Jala microwave CEM Discover VO for 0 min at 100 C. The volatiles were removed in vacuo and the residue was removed in methanol 430 by preparative HPLC (ACE column (ACE) 7001 acetonitrile filtration: TFA) to obtain a compound Title 0 product dissolved in acetonitrile, filtered through SCX resin, filtered with methanol s acetonitrile (excluded) and then with 111113N in YAAY

And 7144 methanol. Basal fractions and volatiles were extracted in vacuo. After crushing with diethyl ether the title product was obtained as a white solid (£7 mg). MS: APCI(+ve) 474 (M+H)+.1H NMR 6 (DMSO-d6) 8.35 (d, 1H), 7.84 (dd, 1H), 7.68 (d, 1H), 7.53 - 7.49 (m, 2H), (d, 1H), 7.19 (id, 1H), 6.96 (d, 1H), 6.86 (t, 1H), 6.86 (d, 1H), 6.69 (d, 1H), 4.08 (t, 6 7.46 2H), 2.95 (t, 2H), 2.86 - 2.79 (m, 1H), 2.39 (s, 3H), 2.06 (s, 3H), 1.20 - 1.01 (m, 4H), (m, 2H), 0.55 - 0.50 (m, 2H). 0.64 - 0.69 Example A) 5 ( N-Cyclopropyl-4-methyl-3-[3-[[ 1-[2-[2 -(ethylamino)ethoxy]phenyl]cyclopropyl]amino]- 2-o0x0-1(2H)-pyrazinyl]-benzamide Ye Ne ZN 0 0 AL Ig N =X N H | H 0 = the title product was prepared from: 3-(3-(1-(2-(2-chloroethoxy)phenyl)cyclopropylamino)-2-oxopyrazin-1(2H)-yl)-N- cyclopropyl- 4-methylbenzamide amine ethyl y (—)1Y Jia) 0 7170 in water) in ethanol as a co-solvent using a method similar to that described in Example 1 and v) 1. YAAY

MS: APCI(+ve) 488 (M+H)+. 1H NMR 5 (DMSO-d6) 8.35 (d, 1H), 7.84 (d, 1H), 7.68 (s, 1H), 7.50 - 7.41 (m, 3H), 7.19 (t, 1H), 6.95 (d, 1H) ), 6.88 - 6.83 (m, 2H), 6.70 (d, 1H), 4.05 (t, 2H), 2.94 (t, 2H), 2.88 - 2.77 (m, 1H), 2.62 (q, 2H), 2.06 ( s, 3H), 1.22 - 0.97 (m, 4H), 0.99 (t, 3H), 0.70 - 0.64 (m, 2H), 0.54 - 0.49 (m, 2H). ° ( 114 ) Example N-Cyclopropyl-3-fluoro-4-methyl-5-[3-[[1-methyl-1-[2-[2- (methylamino)ethoxy]phenyl]ethyl]Jamino [-2-oxo-1(2H)-pyrazinyl]-benzamide

N

1” 9 ZN oT

N N

H H

0

F

3-Fluoro-4-methyl-5-nitro-benzoic acid, ethyl ester (1) Ye solid (ax © «J. Chem. Soc. 1960, 672-6) ethyl 3-amino-4-methyl-5 -nitrobenzoate to slowly ((de Yo) aqueous repellent 48 7 ice-cooled tetrafluoroboric acid at 0 m g) was added and sodium nitrite (1,19) was stirred for heat) and the mixture was stirred for © minutes. ml added). After one hour, V0) was quenched again with tetrafluoroboric acid for an hour, then added to obtain diethyl ethers. Separation of the precipitate by filtration (caution - possibly an explosive substance); And washed it with water Vo m for an hour 111 g). The product was diluted with solid sand and heated at 1, TY) over dichloromethane solid (gases are observed). after cooling to room temperature; has been added

YAAY

Ya ) ml) and then separate the solids by filtration. Then collect the filtrate, Ps, in the solvent in vacuo to obtain the crude product as oil. The product was combined with the crude product from the Jan reaction performed in half-band and purified (chromatography 2 and filtered with iso-hexane to yield the subtitle product as a 90 g yellow solid) IH NMR 5 (CDCI3) 8.37 (s). , 1H), 7.94 (dd, 1H), 4.43 (q, 2H), 2.53 (d, 3H), 1.42 (t, 3H) © (b) 3-Amino-5-fluoro-4-methyl-benzoic acid, ethyl ester 3-Fluoro-4-methyl-5-nitro-benzoic acid, ethyl ester (eg 4 7 g) in (Je 71) ethanol was pumped continuously through the PA/C cartridge for Hs of hydrogen The solvent was removed to yield 0.7 (g) subtitle product as a solid. (CDCI3) 7.15 (s, 1H), 7.13 (d, 1H), 4.34 (q, 2H), 3.81 (5, 2H), 2.10 (d, 3H), V+ 5 1111/18 (t, 3H). 1.37 3-[(Cyanomethyl)amino]-5-fluoro-4-methyl- benzoic acid, ethyl ester 0 (z) to a stirred solution of: 3-amino-5-fluoro-4-methyl-benzoic acid, ethyl ester (Ex. 19 Aug.) (a > 0.7 in THF (da 01( VO) at room temperature (de V,YA) N-ethyldiisopropylamine was added, followed by the addition of 0,+ (Je) 500086610010716) and the reaction mixture was heated on reflux for 14 hours . Additional acetonitrile gbromo (Jo +,YV) was added and the mixture was heated on reflux for 7 hours. Another amount of (Je +, YY) bromoacetonitrile was added and heating continued YAAY

for another VY hour. After cooling to room temperature the reaction mixture was concentrated. Aqueous HCI 1 “Ja 1 (Nm) Yo) ethyl acetates mL) was added. The layers were separated, the organic molecule “(Na2SO4) was dried, filtered and concentrated to obtain the subtitle product (1.8 g) as 1H NMR 5 (CDCI3) 7.30 (d, 1H), 7.17 (s, 1H), 4.38 (q , 2H), 4.24 (s, 2H), 4.03 (s, 1H), ° (s, 3H), 1.40 (t, 3H). 2.12 (9) : 3-(3,5-Dibromo- 2-oxo-1(2H)-pyrazinyl)-5-fluoro-4-methyl-benzoic acid, ethyl ester to a suspension of: 3-[(cyanomethyl)amino]-5-fluoro-4-methyl-benzoic acid , ethyl ester 0 (ex. VEY production g) in (Je VY) dichloromethane in a nitrogen atmosphere at room temperature to which y, Y) oxalyl bromide s (Ja o,f ) DMF was added ml) dropwise over the course of minutes. After stirring at room temperature for 7 hours another amount of (A0)+ oxalyl bromide 150 lb) DMF (Je ml) was added and the reaction was stirred for VE hour. The mixture was concentrated in vacuo (VO (volatile substances containing bromide Alaah alert«0). The residue was purified (chromatograph 5:02) and filtered with dichloromethane to yield a subtitle product (0.77 (g). NMR 6 (DMSO-d6) 8.11 (s, 1H), 7.93 (s, 111), 7.84 (dd, 1H), 4.34 (q, 2H), 2.10 (d, 111 3H), 1.32 (t, 3H). YAAY

(e): 3-[5-Bromo-3-[[1-methyl-1-[2-(phenylmethoxy)phenyl]ethyl]amino]-2-oxo-1(2H)- pyrazinyl]-5 -fluoro-4-methyl-benzoic acid, ethyl ester

Dissolved: 3-(3,5-Dibromo-2-oxo-1(2H)-pyrazinyl)-5-fluoro-4-methyl-benzoic acid, ethyl ester 8 (ex. mol) in 0.001 dioxane (ml) 0. Added: o,0-dimethyl-2-(phenylmethoxy)-benzenemethanamine (ex. Jive 7; g) and 1 “Ja +,7V) ethyldiisopropylamine 7.97 mmol) in a nitrogen atmosphere, and the resulting solution was stirred at 100°C for 10 hours. The reaction mixture was diluted with water (+0 (Je) and extracted (001) ethyl acetate 0 ml X 7). The collected organic materials “(MgSO04) were dried, filtered and evaporated to obtain the crude product 0 and then the product was evaporated by chromatograph 2 and filtered with dichloromethane to obtain the subtitle product (1.00 g). 1-methyl-1-[2-(phenylmethoxy)phenyl]ethyl]Jamino]-2-o0x0-1(2H)- Vo pyrazinyl]-N-cyclopropyl-5-fluoro-4-methyl-benzamide Add (Je V,A) cyclopropyl amine to: YAAY

— 0m - 3-[5-bromo-3-[[1-methyl-1-[2-(phenylmethoxy)phenyl]ethyl}amino]-2-oxo-1(2H)- pyrazinyl}-5 fluoro-4-methyl-benzoic acid, ethyl ester (eg 1.1 a 164 g) in THF (YE) ml) in nitrogen atmosphere at room temperature and then A) isopropylmagnesium chloride was added 57 ml of a 1 M solution in THF© (THF) was dripped for 10 minutes. The reaction solution was stirred at VO C for 11 hours. After cooling to room temperature, the solution was acidified by adding Y HCI 3 Lr and extracted in dichloromethane The organic parts were concentrated in vacuo to obtain the title compound

sub (7.; g). 1H NMR 6 (DMSO-d6) 8.51 (d, 1H), 7.74 (d, 1H), 7.67 (s, 1H), 7.43 (dd, 2H), 7.37 - (m, 4H), 7.26 - 7.21 (m, 1H), 7.15 (s, 1H), 7.08 (d, 1H), 6.99 (s, 1H), 6.95 (t, 1H), Yo 7.29 (s, 2H), 2.90 - 2.81 (m, 1H), 1.97 (d, 3H), 1.84 (s, 6H), 0.76 - 0.67 (m, 2H), 0.58 - 5.13 (m, 2H). 0.53 MS: APCI(+ve) 605 (M +H)+.(g): N-cyclopropyl-3-fluoro-5-[3-[[1-(2-hydroxyphenyl)-1-methylethyl]Jamino]-2-oxo-1(2H)- Yo ‎pyrazinyl]-4-methyl-benzamide The title product was prepared from: YAAY

3-[5-bromo-3-[[1-methyl-1-[2-(phenylmethoxy)phenyl]ethyl]Jamino]-2-oxo-1(2H)- pyrazinyl]-N-cyclopropyl-5-fluoro- 4-methyl-benzamide (example 14 lyoY g) using a hydrogenation method similar to that described in example fd 5 V). MS: APCI(+ve) 437 (M+H)+.(h): 3-[3-[[1-[2-(2-Chloroethoxy)phenyl]-1-methylethyl]amino]-2 -oxo-1(2H)-pyrazinyl]-N- cyclopropyl-5-fluoro-4-methyl-benzamide The title product was prepared from: N-cyclopropyl-3-fluoro-5-[3-[[1 -(2-hydroxyphenyl)-1-methylethylJamino]-2-oxo-1(2H)- pyrazinyl]-4-methyl-benzamide Ve (ex. 169 g 0.77 g) 5 1-bromo-2- chloroethane using a method similar to that described in Example (171e). MS: APCI(+ve) 500 (M+H)+. : (i) N-Cyclopropyl-3-fluoro-4-methyl-5-[3-[[ 1-methyl-1-[ 2-[2-(methylamino)ethoxy] Yo phenyl]ethyl] amino]-2-oxo-1(2H)-pyrazinyl]-benzamide The title product is prepared from:

YAAY

— A 3-[3-[[1-[2-(2-chloroethoxy)phenyl]-1-methylethylJamino]-2-o0xo-1(2H)-pyrazinyl]-N-cyclopropyl-5-fluoro- 4-methyl-benzamide (Ex. 2119) amine methyl using a method similar to that described in Example CTY (Phenominex) on a MeCM / ammonia %+,Y) RPHPLC gradient. Purification was with 1H NMR 6. (DMSO-d6) 8.52 (d, 1H), 7.75 (d, 1H), 7.64 (s, 1H), 7.34 (d, 1H), 7.34 (dd, © 1H), 7.19 (t, 1H), 6.98 - 6.87 (m, 3H), 6.68 (s, 2H), 4.03 - 3.89 (m, 2H), 2.90 - 2.79 (m, 3H), 2.26 (s, 3H), 1.99 (d, 3H), 1.83 (s, 6H), 0.73 - 0.67 (m, 2H), 0.58 - 0.52 (m, 2H).

MS: APCI(+ve) 494 (M+H)+. amine 5 (VY) analogues (eg alcohol (© table) from 1597-16) The following examples were prepared. (YA) using the methods described in Example - 0 ( VV ) Example N-Cyclopropyl- 4-methyl-3-[3-[[(1R,2S)-2-methyl-3-(4-methyl-1-piperidinyl)-1- phenylpropyl]Jamino]-2-oxo-1(2H)- pyrazinyl]-benzamide () VY) Example: N-Cyclopropyl-4-methyl-3-[3-[[(1R,2S)-2-methyl-3-[4-(1-methylethyl)-1) -piperazinyl]-1- 0 phenylpropyl]amino}-2-oxo-1(2H)-pyrazinyl]-benzamide ( 1 ) Example N-Cyclopropyl-4-methyl-3-[3-[[(1R, 2S)-2-methyl-1-phenyl-3-(1-piperazinyl) propyl]amino] -2-oxo-1(2H)-pyrazinyl]-benzamide High

— M74 - ( VV 9 Ex. N-Cyclopropyl-3-[3-[[(1R,2S)-3-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)-2 -methyl- 1-phenylpropyl[amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide (VV) Example N-Cyclopropyl-3-[3-[[(1R,2S) Example )-3-(4-fluoro-1-piperidinyl)-2-methyl-1-© phenylpropyl[amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide (YYo) N-Cyclopropyl-3-[3-[[(1R,2S)-3-(4,4-difluoro-1-piperidinyl)-2-methyl-1- phenylpropyl]amino]-2-oxo-1(2H )-pyrazinyl]-4-methyl-benzamide ( 1/1 ) Example 0

N-Cyclopropyl-3-[3-[[(1R,2S)-3-[4-(dimethylamino)- 1-piperidinyl]-2-methyl-1- phenylpropyl]amino]-2-oxo-1(2H) -pyrazinyl]-4-methyl-benzamide (YVv ) Example N-Cyclopropyl-4-methyl-3-[3-[[(1R,2S)-2-methyl- 1 -phenyl-3-[4- (trifluoromethyl)-1- piperidinyl[propyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide Yo ( VA ) Example N-Cyclopropyl-4-methyl-3-[3-[[( 1R,2S)-2-methyl-3-(3-0x0-1-piperazinyl)-1- ‎phenylpropyl[amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

— Yea — (Yva ) Example N-Cyclopropyl-3-[3-[[(1R,2S)-3-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-2 -methyl-1- phenylpropyl[amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl- benzamide ( VA) Example N-Cyclopropyl-4-methyl-3-[3-[[ (1R,2S)-2-methyl-3-[(3R)-3-methyl-1-piperazinyl]-1- © phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide (YAY) Example N-Cyclopropyl-4-methyl-3-[3-[[(1R,2S)-2-methyl-3-[(3S)-3-methyl-1-piperazinyl]-1- phenylpropyl} amino]-2-oxo-1(2H)-pyrazinyl]-benzamide (VAY) Example

N-Cyclopropyl-4-methyl-3-[3-[[(1R,2S)-2-methyl-3-[(2-methylpropyl)amino]-1- phenylpropyl]amino]-2-oxo-1(2H) )-pyrazinyl]-benzamide (YAY) Example N-Cyclopropyl-3-[3-[[(1R,2S)-3-(cyclopropylamino)-2-methyl-1-phenylpropyl]amino]- 2- 0x0-1(2H)-pyrazinyl]-4-methyl-benzamide Yo (YAE) Joe

N-Cyclopropyl-4-methyl-3-[3-[[(1R,2S)-2-methyl-3-[(2R)-2-methyl-1-pyrrolidinyl]-1- phenylpropyl]amino]-2- oxo-1(2H)-pyrazinyl]-benzamide

YAAY

Yo. — Eh ( \ Ao ) Example N-Cyclopropyl-3-[3-[[(1R,2S)-3-[(3S)-3-hydroxy- 1-piperidinyl]-2-methyl-1 - phenylpropyl[amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl- benzamide ( YAR ) Example N-Cyclopropyl-3-[3-[[(1R,2S)-3- Example [(3R)-3-hydroxy-1-piperidinyl]-2-methyl-1- 5 phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl|-4-methyl-benzamide (YAY) N-Cyclopropyl-4-methyl-3-[3-[[(1R,2S)-2-methyl-3-[(2R)-2-methyl-1-piperazinyl}-1- phenylpropyl]amino]- 2-oxo-1(2H)-pyrazinyl]- benzamide (VAA) Example

N-Cyclopropyl-3-[3-[[(1R,2S)-3-(2,7-diazaspiro[3,5]non-7-yl)-2-methyl-1- phenylpropyl]amino]-2-oxo0- 1(2H)-pyrazinyl]-4-methyl- benzamide (YA) Example N-Cyclopropyl-4-methyl-3-[3-[[(1R,2S)-2-methyl-1-phenyl- 3-(4- thiomorpholinyl)propyl]amino]-2-oxo-1(2H)-pyrazinyl]- benzamide Yo ( V4 . ) Example N-Cyclopropyl-3-[3-[[(1R, 2S)-3-[(3S)-3-hydroxy-1-pyrrolidinyl]-2-methyl-1- phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

( Yay) Example N-Cyclopropyl-4-methyl-3-[3-[[(1R,2S)-2-methyl-1-phenyl-3-[4-(tetrahydro-1,1- dioxido) -3-thienyl)-1-piperazinyl[propyl]amino]-2-oxo-1(2H)-pyrazinyl]- benzamide ( 7 ) Example 1-[(2S,3R)-3-[[4- [5-[(cyclopropylamino)carbonyl]-2-methylphenyl]-3,4-dihydro-3- © oxopyrazinylJamino]-2-methyl-3-phenylpropyl]- 4-piperidinecarboxamide ( Yay) Example N-Cyclopropyl- 3-[3-[[(1R,2S)-3-[(2-hydroxy-1,1-dimethylethyl)amino]-2-methyl-1- phenylpropyl]lamino]-2-oxo-1(2H) -pyrazinyl]-4-methyl-benzamide ( V4¢ ) Jae Vo

N-Cyclopropyl-3-[3-[[(1R,2S)-3-[(3R,5S)-3,5-dimethyl-1-piperazinyl}-2-methyl-1- phenylpropyl]amino]-2- oxo-1(2H)-pyrazinyl]-4-methyl- benzamide ( 15 ) Example N-Cyclopropyl-4-methyl-3-[3-[[(1R,2S)-2-methyl-1-phenyl -3-(4- ‎piperidinylamino)propyl[amino]-2-oxo-1(2H)-pyrazinyl]- benzamide Yo ( 141 ) Example N-Cyclopropyl-4-methyl-3-[3-[[ (1R,2S)-2-methyl-3-(5-methyl-2,5- ‎diazabicyclo[2.2.1]hept-2-yl)-1-phenylpropyl]amino]-2-oxo-1(2H) -pyrazinyl]- benzamide ( yay ) eg Yo

N-Cyclopropyl-3-[3-[[(1R,2S)-3-(2,2-dimethyl-1-pyrrolidinyl)-2-methyl-1- phenylpropyl]amino]-2-o0xo0-1(2H) -pyrazinyl]-4-methyl-benzamide Agala

7e Table (0) Em- ~= 0 Mb ~~ N R H 0 MS ee m/z 9.09 and 8.87 (1H, 2 x d), 8.45 and 514 Ye 8.40 (1H , 2 x d), 7.88 - 7.84 (1H, m), 7.74 and 7.70 (1H, 2 x d), 7.49 and 7.48 (1H, 2 x d), 7.37 - 7.20 (5H, m), ~ 6.72 (1H, d) , 6.62 (1H, d), 5.10 - 5.03 NT TL (1H, m), 3.10 - 2.96 (1H, m), 2.89 - 7 "2.79 (1H, m), 2.75 - 2.66 (1H, m), 2.53 - 2.40 (1H, m), 2.16 - 2.02 (1H, m), 2.12 and 2.06 (3H, s), 1.96 - 1.84 (2H, m), 1.81 - 1.72 (1H, m), 1.63 - 1.42 (3H, m) ), 1.39 - 1.25 (2H, m), 0.85 (3H, d), 0.79 and 0.78 (3H, 2 x d), 0.72 - 0.64 (2H, m), 0.59 - 0.51 2H, m 8.90 and 8.65 (1H, 2 x d), 8.44 and 543 Mm YY) 7.21 (5H, m), TYTN 6.73 (1H, d), 6.64 and 6.63 (1H, d), 1 “ra 5.10 - 5.02 (1H, m), 2.89 - 2.79 (1H, Y m), 2.64 - 2.19 (7H, m), 2.36-2.20 (2H, br m), 2.17 - 2.03 (1H, m), 2.13 and 2.06 (3H, 2 xs), 1.98 - 1.90 (1H, m), 0.92 (6H, d ), 0.81 and 0.79 (3H, 2 x d), 0.72 - 0.64 (2H, m), 0.59 - 0.50 2H, m 9.32 and 9.19 (1H, 2 x d), 8.45 and 501 b" t 8.41 (1H, 2 x d), 7.86 (1H, dd), 7.74 and 7.70 (1H, 2 x d), 7.49 and 7.48 Z (1H, 2 x d), 7.39 - 7.20 (5H, m), 6.72 0 and 6.71 (1H, 2 x d) , 6.62 (1H, d), Nn NY 5.07 (1H, dd), 2.91 - 2.69 (m, 5H), : 2.25 - 2.04 (3H, m), 2.11 and 2.05 H NE (3H, 2x 5), 1.95 - 1.88 (1H, m), 0.78 and 0.76 (3H, 2 x d), 0.72 - 0.64 (2H, m), 0.59 - 0.51 (2H, m)

YAAY

017 — 8.89 and 8.72 (1H, 2 x d), 8.45 and 506 \ VY 8.40 (1H, 2 x d), 7.86 (1H, dd), 7.74 and 7.71 (1H, 2 x d), 7.49 and 7.48 (1H, 2 x d) ), 7.38 - 7.20 (5H, m), 6.735 - and 6.73 (1H, 2 x d), 6.63 (1H, d), NT TT 5.13 - 5.04 (1H, m), 2.90 - 2.79 (1H, H a m), 2.75 — 2.50 (7H, m), 2.43-2.31 —N, (2H, m), 2.27 - 2.04 (2H, m), 2.22 (3H, 5), 2.12 and 2.06 (3H, 2 x 5 ), 1.84 - 1.71 (2H, m), 0.79 and 0.77 (3H, 2 x d), 0.72 - 0.65 (2H, m), 0.59 - 0.51 2H, m 9.31 and 9.19 (1H, 2 x d), 8.45 and 518 RW 8.40 (1H, 2 x d), 7.86 (1H, d), 7.74 © and 7.70 (1H, 2 x d), 7.49 and 7.48 ¢ (1H, 2 x d), 7.39 - 7.21 (5H, m), 6.72 ~~ ( 1H, d), 6.63 (1H, d), 5.10 - 5.04 (1H, the TL m), 4.71 (1H, d), 2.91 - 2.78 (1H, m), Ho = 2.73 - 1.71 (11H, m) ), 2.11 and 2.05 (3H, 5), 0.78 and 0.77 (3H, 2 x d), 0.72 - 0.64 (2H, m), 0.59 - 0.51 (2H, m) 9.25 and 9.08 (1H, 2 x d), 8.45 and 536 \Vo 8.40 (1H, 2 x d), 7.86 (1H, d), 7.74 | z and 7.70 (1H, 2 x d), 7.49 and 7.48 (1H, 2 x d), 7.39 - 7.22 (5H, m), 6.74 h” (1H, d), 6.64 (1H, d) , 5.11 - 5.04 (1H, m) for m), 2.89 - 2.79 (1H, m), 2.76 — 1.95 (11H, m), 2.11 and 2.05 (3H, 2 x 5), 0.79 and 0.78 (3H) , 2 x d), 0.73 - 0.64 (2H, m), 0.59 - 0.51 (2H, m 9.21 and 9.01 (1H, d), 8.44 and 8.39 543 17 (1H, 2 x d), 7.88 - 7.82 (1H, m) , 7.74 and 7.69 (1H, 2 x d), 7.48 and 7.46 (1H, 2 x d), 7.38 - 7.20 (5H, m), 6.72 & |NN (1H, d), 6.63 (1H, d), 5.10 - 5.02 (1H, ho LL P m), 3.16 - 3.01 (1H, m), 2.89 - 2.71 N (m, 2H), 2.12, 2.10, 2.10 and 2.06 (9H, 4 x 5), 2.19 — 1.49 (10H, m ), 0.78 and 0.77 (3H, 2 x d), 0.71 - 0.64 (2H, m), 0.59 - 0.51 (2H, m 8.95 and 8.67 (1H, 2 x d), 8.44 and 568 VY 8.39 (1H, 2 x d), 7.85 (1H, dd), 7.74 and 7.69 (1H, 2 x d), 7.48 and 7.47 ¢ (1H, 2 x d), 7.38 - 7.21 (5H, m), 6.73 SNS (1H, d), 6.64 (1H, d) ), 5.11 - 5.01 (1H, Nod for "m), 3.23 - 3.08 (1H, m), 2.89 2.78 F (2H, m), 2.57 - 1.54 (10H, m), 2.12 F

YAAY

— Yo§ — and 2.06 (3H, 2 x s), 0.82 and 0.79 (31, 2 x d), 0.72 - 0.64 (2H, m), 0.59 - 0.50 (2H, m 8.69 and 8.53 (1H, 2 x d), 8.46 and 515 \VA 8.40 (1H, 2 x d), 7.85 (1H, d), 7.75 - © 7.68 (2H, m), 7.48 and 7.47 (1H, 2 x d), 7.39 - 7.22 (5H, m), 6.75 and 6.74 (1H, 2 x d), 6.65 and 6.64 (1H, 2 x d), ™ 5.11-5.03 (1H, m), 3.46 - 3.34 (1H, a for m), 3.21 - 3.10 ( 1H, m), 3.00 - 2.70 (4H, m), 2.44 - 2.29 (1H, m), 2.22 - 0 2.09 (1H, m), 2.11 and 2.04 (3H, 2 x s), 2.08 - 2.00 (1H, m) ), 0.83 and 0.82 (3H, 2 x d), 0.72 - 0.64 (2H, m), 0.59 - 0.51 (2H, m) 9.34 and 9.22 (1H, 2 x d), 8.45 and 558 - va 8.41 (1H, 2 x d) ), 7.87 (1H, dd), 7.73 and 7.70 (1H, 2 x d), 7.49 and 7.48 (1H, 2 x d), 7.38 - 7.21 (5H, m), 6.715 NTN Tr and 6.713 (1H, 2 x d), 6.62 (1H, d), 1 0 5.07 (1H, dd), 3.82 (4H, d), 2.89 - 3) 2.78 (1H, m), 2.71 - 2.54 (1H, m), 2.42 - 2.25 ( 2H, m), 2.23 - 2.08 (1H, m), 2.11 and 2.05 (3H, 2 x 5), 1.98 - 1.91 (1H, m), 1.88 - 1.77 (3H, m), 1.75 - 1.64 (3H, m), 0.77 and 0.76 (3H, 2 x d), 0.72 - 0.64 (2H, m), 0.59 -0.51 (2H, m) i 9.30 and 9.20 (1H, 2 x d), 8.45 and 515 YA 8.41 (1H, 2) x d), 7.86 (1H, dd), 7.74 and 7.69 (1H, 2 x d), 7.49 and 7.48 (1H, 2 x d), 7.38 - 7.20 (5H, m), 6.715 and 6.711 (1H, 2 x d), 6.62 (1H, d), 0 5.10 - 5.02 (1H, m), 3.08 - 2.71 (4H, m), 2.64 - 2.55 (1H, m), 2.19 - 2.08 NTN NY (1H, m), 2.11 and 2.05 3H, 2 x 5), hob Lom 1.94 - 1.78 (4H, m), 1.46 - 1.36 (1H, m), 0.88 and 0.87 (3H, 2 x d), 0.78 and 0.76 (3H, 2 x d), 0.72 - 0.64 (2H) , m), 0.58 - 0.51 2H, m 9.30 and 9.20 (1H, 2 x d), 8.45 and 515 yA 8.41 (1H, 2 x d), 7.86 (1H, dd), 7.74 and 7.69 (1H, 2 x d), 7.49 and 7.48 (1H, 2 x d), 7.38 - 7.20 (5H, m), 6.715 and 6.711 (1H, 2 x d), 6.62 (1H, d), 5.10 - 5.02 (1H, m), 3.08 - 2.71 (4H, m), 2.64 - 2.55 (1H, m), 2.19 - 2.08 (1H, m), 2.11 and 2.05 3H, 2 x 5), 0 YAAY

{ — Yoo — 1.94 - 1.8 (3H, m), 1.46 - 1.36 (1H, m), 1.46 - 1.36 (1H, m), 0.88 and 0.87 (3H, 2 x d), 0.78 and 0.76 (3H, 2 x d) , 0.72 - 0.64 (2H, m), 0.58 - 0.51 (2H, “NN m) I 1 ” | 0 L_NH 8.61 and 8.52 (1H, 2 x d), 8.45 and 488 VAY 8.39 (1H, 2 x d) ), 7.86 (1H, dd), 7.74 and 7.70 (1H, 2 x d), 7.49 and 7.47 (1H, 2 x d), 7.40 - 7.19 (5H, m), 6.74 and 6.73 (1H, 2 x d), 6.63 and 6.62 (1H, 2 x d), 5.09 - 5.02 (1H, m), 2.91 - 2.78 (1H, m), 2.35 - 2.13 (5H, m), ~\ 1 2.11 and 2.05 (3H, 2 x 99, 1.81 - 1.59 Lo NY (2H, m), 0.90 - 0.81 (9H, m), 0.73 - 0.63 (2H, m), 0.59 - 0.50 (2H, m 8.46 and 8.39 (1H, 2 x d), 7.86 (1H, 2 472 \AY xd), 7.75 and 7.70 (1H, 2 x d), 7.49 and 7.48 (1H, 2 x d), 7.46-7.21 (5H, m), 6.78 and 6.77 (1H, 2 x d), 6.68 and 6.67 (1H, 2 x d), 5.09 - 5.01 (1H, - A m), 2.90 - 2.79 (1H, m), 2.67 - 2.57 μm) (1H, m), 2.53 - 2.2 (3H, m), 2.13 and H 2.06 (3H, 2 x 5), 0.99 - 0.89 (3H, m), 0.74 - 0.63 (2H, m), 0.61 - 0.41 (6H, m 8.46 - 8.36 (m, 1H), 8.29 - 8.07 (m, 500 VAS 1H), 7.88 - 7.83 (m, 1H), 7.76 - 7.68 (m, 1H), 7.50 - 7.45 (m, 1H), 7.41 - = 7.35 (m, 2H), 7.34 - 7.30 (m, 2H) , | _ 7.24 - 7.20 (m, 1H), 6.78 - 6.74 (m, 1H), 6.66 - 6.62 (m, 1H), 4.96 - 4.88 + (m, 1H), 2.94 - 2.88 (m, 1H), 2.87 - NT B 2.79 (m, 1H), 2.40 - 2.20 (m, 3H), Ho: 2.08 (d, 3H), 2.03 - 1.98 (m, 1H), 1.97 - 1.91 (m, 1H), 1.90 - 1.78 (m, 1H), 1.68 - 1.55 (m, 2H), 1.34 - 1.25 (m, 1H), 0.95 (t, 3H), 0.92 - 0.89 (m, 3H), 0.72 - 0.64 (m, 2H), 0.58 - 0.50 (m, 2H) 9.39 - 9.30 (m, 1H), 8.44 (dd, 1H), 516 \ Ao 7.87 (d, 1H), 7.72 (d, 1H), 7.49 (1, 1H), 7.36 - 7.31 (m, 2H), 7.29 - 7.22 (m, 3H), 6.74 - 6.71 (m, 1H), 6.64 - 6.61 (m, 1H), 5.08 - 5.04 (m, 1H), , 4.52 (t, 1H), 3.80 - 3.71 (m, 1H), 3.08 - 2.91 (m, 1H), 2.88 - 2.80 (m, 1H), 2.55 - 2.45 (m, 2H), 2.21 - 2.13 (m,

YAAY

~ You — 1H), 2.08 (d, 3H), 2.03 - 1.96 (m, N 1H), 1.95 - 1.89 (m, 1H), 1.79 - 1.71 (m, 1H), 1.71 - 1.63 (m, 2H), 1.63 - 1.54 (m, 1H), 1.15 - 1.05 (m, 1H), NN 0.79 - 0.74 (m, 3H), 0.72 - 0.65 (m, bo © 2H), 0.58 - 0.51 (m, 2H) r

Oh

9.26 (dd, 1H), 8.47 - 8.39 (m, 1H), 516 YAY 7.87 (d, 1H), 7.72 (d, 1H), 7.51 - 7.45 (m, 1H), 7.38 - 7.31 (m, 2H), 7.31 - 7.22 (m, 3H), 6.72 (d, 1H), 6.62 (d, 1H), 5.08 - 5.02 (m, 1H), 3.70 - 3.59 - (m, 1H), 2.99 - 2.91 (m, 1H) , 2.89 - NT NY 2.73 (m, 2H), 2.19 - 2.07 (m, 1H), Ho | 2.07 (d, 3H), 1.98 - 1.92 (m, 1H), 1.85 - 1.63 (m, 4H), 1.61 - 1.49 (m, 1H), OH 1.10 - 0.97 (m, 1H), 0.80 - 0.73 (m, 3H), 0.72 - 0.64 (m, 2H), 0.60 - 0.51 m, 2H 8.47 - 8.38 (m, 1H), 7.88 - 7.84 (m, 515 YAY 1H), 7.76 - 7.70 (m, 1H), 7.51 - 7.46 (m, 1H), 7.36 - 7.28 (m, 4H), 7.27 - 7.20 (m, 1H), 6.75 - 6.72 (m, 1H), } 6.65 - 6.62 (m, 1H), 5.05 - 4.98 (m, : 1H), 2.90 - 2.78 (m, 3H), 2.69 - 2.62 NTN NY (m, 1H), 2.47 - 2.31 (m, 4H), 2.27 - A L 2.16 (m, 2H), 2.06 (d, 3H) ), 1.96 - 1.82 “H (m, 1H), 0.92 - 0.87 (m, 3H), 0.86 - 0.80 (m, 3H), 0.72 - 0.64 (m, 2H), 0.59 - 0.51 (m, 2H 9.05 - 8.57 (m, 2H), 8.51 - 8.36 (m, 541 \ AA 1H), 7.89 - 7.84 (m, 1H), 7.76 - 7.69 (m.1H), 7.66 - 7.20 (m, 7H), 7.11 - rr 6.94 ( m, 1H), 6.86 - 6.72 (m, 2H), 7 5.20 - 5.04 (m, 1H), 3.73 (s, 4H), 3.05 ~~ - 2.60 (m, 4H), 2.18 - 2.04 (m, 5H) , 0" ml" | 2.03 - 1.79 (m, 3H), 1.10 - 0.97 (m, N 2H), 0.75 - 0.63 (m, 2H), 0.59 - 0.49 (m, 2H (CD30D) 7.86 - 7.80 (m, 1H), 7.76 518 YAR -7.67 (m, 1H), 7.52 - 7.36 (m, SH), 7.34 - 7.28 (m, 1H), 6.94 (dd, 1H), 6.71 (dd, 1H), 5.34 - 5.26 (m, 1H), 3.72 - 3.34 (m, 3H), 3.20 - 3.10 (m, ~ 2H), 3.09 - 2.89 (m, 4H), 2.87 - 2.73 iodine (m, 2H), 2.19 (d, 3H), 1.08 - 0.99 (m, "3 Sha | 3H), 0.83 - 0.75 (m, 2H), 0.65 - 0.55 (m, 2H

YAAY k—YoVv — 9.18 (m, 1H), 8.43 (m, 1H), 7.86 (dd, 502 7 1H), 7.72 (dd, 1H), 7.49 (d, 1H), 7.37 - 7.28 (m, 4H) , 7.27 - 7.22 (m, 1H), 6.74 (dd, 1H), 6.63 (dd, 1H), 5.04 (m,

1H), 4.60 - 4.55 (m, 1H), 4.27 - 4.18

(m, 1H), 2.90 - 2.79 (m, 2H), 2.69 - ISNT 2.59 (m, 1H), 2.48 - 2.42 (m, 1H), L > 2.41 -2.31 (m, 2H), 2.28 - 2.21 (m, i» 1H), 2.13 - 1.97 (m, 5H), 1.62 - 1.53 (m, 1H), 0.78 (d, 3H), 0.72 - 0.64 (m, 2H), 0.59 - 0.51 (m, 2H i 5 (CD30D) 7.87 - 7.81 (m, 1H), 7.72 619 Ya)

-7.65 (m, 1H), 7.51 - 7.45 (m, 1H), 7.34 - 7.27 (m, 4H), 7.26 - 7.22 (m, 1H), 6.76 - 6.73 (m, 1H), 6.54 - 6.51

(m, 1H), 5.12 - 5.07 (m, 1H), 3.26 - 3.11 (m, 2H), 3.07 - 2.94 (m, 2H), 2.87 - 2.60 (m, 7H), 2.59 - 2.24 (m, SYN

6H), 2.22 - 2.12 (m, 3H), 2.10 - 1.96 of 1 L

E (m, 2H), 0.87 - 0.82 (m, 3H), 0.81 - To

0.74 (m, 2H), 0.64 - 0.57 (m, 2H 5

(m, 1H), 8.45 - 8.36 (mm, 543 yay 8.56 - 8.78 y 1H), 7.84 - 7.80 (m, 1H), 7.71 - 7.65

| (m, 1H), 7.47 - 7.42 (m, 1H), 7.34 - CJ

| 7.25 (m, 4H), 7.24 - 7.18 (m, 1H), 7

7.11 - 7.07 (m, 1H), 6.72 - 6.70 (m, ~

| 1H), 6.64 - 6.58 (m, 2H), 5.06 - 5.01 Lo SU (m, 1H), 3.05 - 2.94 (m, 1H), 2.86 - :

| 2.76 (m, 1H), 2.75 - 2.62 (m, 1H), ©

2.46 - 2.34 (m, 1H), 2.11 - 1.96 (m,

| SH), 1.94 - 1.84 (m, 2H), 1.83 - 1.73

(m, 2H), 1.72 - 1.60 (m, 3H), 0.82 -

| 0.74 (m, 3H), 0.69 - 0.61 (m, 2H),

,! 0.56 - 0.48 (m, 2H

9.09 - 8.94 (m, 1H), 8.45 - 8.36 (m, 504 and 4H)

| 1H), 7.86 - 7.82 (m, 1H), 7.72 - 7.68 P

(m, 1H), 7.48 - 7.43 (m, 1H), 7.36 -

| 7.26 (m.4H), 7.23 - 7.17 (m, 1H), 8 0 >on

‎: 6.71 - 6.68 (m, 1H), 6.60 - 6.57 (m, ron)

1H), 5.07 - 5.01 (m, 1H), 4.53 - 4.41 Ro ~- H

| (m, 1H), 3.30 - 3.29 (m, 2H), 2.85 -

| 2.78 (m, 1H), 2.35 - 2.28 (m, 2H),

‎; 2.21 -2.11 (m, 1H), 2.09 - 2.02 (m,

| 3H), 0.91 - 0.89 (m, 3H), 0.89 - 0.87

i (m, 3H), 0.82 - 0.78 (m, 3H), 0.70 -

‎0.62 (m, 2H), 0.56 - 0.49 (m, 2H)

‎§

| YAAY

º — YONA — 9.44 - 8.84 (m, 1H), 8.41 (d, 1H), 8.24 529 Yat - 8.13 (m, 1H), 7.86 (dd, 1H), 7.72 (dd, 1H), 7.51 - 7.47 (m , 1H), 7.39 - 7.22 (m, 4H), 7.03 (d, 1H), 6.76 (dd, 1H), 6.67 (d, 1H), 5.12 - 5.06 (m, - 1H), 3.46 - 3.26 (m, 3H), 3.02 - 2.95 7m NTT (m, 1H), 2.89 - 2.79 (m, 1H), 2.35 - Ho: Ne 2.22 (m, 1H), 2.14 - 1.98 (m, 4H), B H 1.90 - 1.81 (m, 1H), 1.26 - 1.12 (m, 6H), 0.79 - 0.74 (m, 3H), 0.73 - 0.65 (m, 2H), 0.58 - 0.51 (m, 2H ! 8 (CD30D) 7.87 - 7.81 (m, 1H), 7.72 515 "6 )0, J = 26.7 Hz, 1H), 7.52 - 7.46 (m, 1H), 7.45 - 7.34 (m, 4H), 7.31 - 7.26 2 (m, 1H), 6.94 - 6.88 (m, 1H), 6.69 - 6.64 (m, 1H), 5.32 - 5.21 (m, 1H), 1 3.55 - 3.46 (m, 2H), 3.23 - 2.99 (m, SSNS 3H), 2.92 - 2.78 (m, 3H), 2.59 - 2.44 m for (m, 1H), 2.31 - 2.13 (m, 511(, 1.91 - “H 1.75 (m, 2H), 1.04 - 0.96 (m, 3H), 0.83 - 0.74 (m, 2H), 0.66 - 0.57 (m, 2H 9.61 - 9.15 (m, 1H), 8.46 - 8.39 (m, 527 Y aq 1H), 7.84 (dd, 1H), 7.74 - 7.62 (m, ¢ i 1H), 7.48 - 7.43 (m, 1H), 7.36 - 7.15 (m, 5H), 6.70 - 6.67 (m, 1H), 6.61 - AEN 72 6.56 (m, 1H), 5.06 - 4.86 (m, 1H), Lo 3.19 - 3.16 (m, 1H), 3.09 - 3.02 (m, 1H), 2.90 - 2.56 (m, SH), 2.45 - 2.37 (m, 1H), 2.37 - 2.31 (m, 1H), 2.20 - 2.19 ( m, 3H), 2.05 (d, J = 20.5 Hz, 3H), 1.82 - 1.67 (m, 1H), 1.60 - 1.51 (m, 1H), 0.98 - 0.92 (m, 1H), 0.77 - 0.73 (m, 2H), 0.70 - 0.62 (m, 2H), 0.57 - 0.49 (m, 2H) 9.06 - 8.52 (m, 1H), 8.46 - 8.33 (m, 1 514 1H), 7.86 - 7.81 (m, 1H), 7.72 - 7.63 (m, 1H), 7.48 - 7.43 (m, 1H), 7.38 - 7.24 (m, 4H), 7.24 - 7.15 (m, 1H), 6.71 - 6.64 (m, 1H), 6.62 - 6.56 (m, 8 S 1H), 5.15 - 4.50 (m, 1H), 2.87 - 2.77 A B No (m, 1H), 2.45 - 2.35 (m, 2H), 2.35 - Hof 2.20 (m, 1H) ), 2.08 - 2.01 (m, 4H), 2.00 - 1.92 (m, 1H), 1.74 - 1.57 (m, 3H), 1.56 - 1.46 (m, 1H), 1.03 - 0.62 : (m, 11H), 0.57 - 0.48 (m, 2H) 1 i

YAAYi

1

i 1 #9 — (149A) Example iN-Cyclopropyl-3-[3-[[1-[2-[2-(ethylamino)ethoxy]phenyl]-1-methylethylJamino]-2-oxo-

: 1(2H)-pyrazinyl]-4-methyl-benzamide.

1 i 0 2: oN

iNCh z

‎N N

i H H

i 0

| 3,3-Dimethyl-2(3H)-benzofuranone (0 °

3

A solution of benzofuran (HY) Y=-En (g) dissolved in (J— You) DMF {

Using siodo methane (£) (Ja YY, at 0 C before adding 1” 4 ( potassium carbonate g) part by part for 0 minutes in a nitrogen atmosphere the resulting suspension was stirred at Yo .for 1 days .i£

The mixture was filtered and the solids were washed with ethyl acetate. The filtrate was diluted by adding

i

Hydrochloric acid Ye? molar; And extract it using ethyl acetate. The organic layer was dried

(MgSO4), filtered and evaporated to obtain the crude product. The crude product was purified (chromatograph 5102 and filtered with dichloromethane LY in iso-hexane). has been fumigated

the purified parts to dryness to obtain the subtitle compound (YAY) g).

,

| 1H NMR 5 (CDCI3) 7.32 - 7.08 (m, 4H), 1.53 (s, 6H).

: 2-Hydroxy-a, a -dimethyl-benzeneacetamide (b) 0

V ammonia in (p>17) (eg brain) 3,3-Dimethylbenzofuran-2(3H)-one soluble

Standard in (Je©) methanol in an atmosphere of «0100860. The resulting solution was stirred at Yom for t

‎:

i

‎YAAY

:

b

;

;

i i

; 71.

an hour. The reaction mixture was evaporated to obtain a crude product. The solid was pulverized with VT {

diethyl ether and filtered to obtain the subtitle compound (10.78 g). 1

‎ 1H NMR 6 (DMSO-d6) 7.18 (d, 1H), 7.07 - 7.00 (m, 1H), 6.78 - 6.71 (m, 2H), 6.63 (s,

| 1H), 6.38 (s, 1H), 3.35 (s, 1H), 1.43 (s, 6H).

i

a, © -Dimethyl-2-(phenylmethoxy)-benzeneacetamide () © | Ab 58 JL) 2-hydroxy- a, a -dimethyl-benzeneacetamide A solution of i was treated

| g)Y),AY) potassium carbonate using (J— Vou ) DMF dissolved in (p>104 m for Yo ml) in an atmosphere of “010086. The resulting mixture was stirred at (Y+,YA) benzyl bromide 1

1 hour. The reaction mixture was diluted by adding water (00 Jo) and stirred for Ye min. The 0 solid was separated by filtration, washed with water, and dried in vacuo to yield the subtitle compound (1, 45 g). 1 ‏

,!

MS: APCI(+ve) 270 (M+H)+

| a, a -Dimethyl-2-(phenylmethoxy)- benzenemethanamine ( J) (example a, » -dimethyl-2-(phenylmethoxy)-benzeneacetamide solution of dallas tamm | ml) with Yoo (ml) and water (You) acetonitrile dissolved in PEN V4 , {o Jd Y4A Yo:

| The nitrogen solution was stirred under an atmosphere of (p>VV.) (Bis(trifluoroacetoxy)iodo)benzene ml); And extract it by Yor) an hour. The reaction mixture was diluted with water, Te, for 10 minutes, obtained at M Y NaOH, then the aqueous layer was acidified at 0 m using a solution. diethyl ether ‎ ‎ YAAY

E: A E g 711 - -— and extracted it using ethyl acetate. The organic layer (MgS04) was dried, filtered and evaporated to obtain the subtitle compound (YY, YR g). Z 1H NMR 6 (DMSO0-d6) 7.54 - 7.29 (m, 6H), 7.22 - 7.13 (m, 1H), 7.07 (d, 1H), 6.93 - (m, 1H), 5.20 (s, 2H) ), 2.21 (s, 2H), 1.46 (s, 6H). 6.84 © (e): 3-[3-[[1-[2-(2-Chloroethoxy)phenyl]-1-methylethylJamino]-2 -oxo0-1(2H)-pyrazinyl]-N- cyclopropyl-4-methyl-benzamide The subtitle compound was prepared using: o,a-dimethyl-2-(phenylmethoxy)-benzenemethanamine (Ex. 8 1d) Using the Ye methods described in Example 1 to obtain: N-cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[2-(1-pyrrolidinyl)ethoxy] ] phenyl[ethylJamino]-2-oxo-1(2H)-pyrazinyl]-benzamide whose alkyldh was treated with 1-bromo-2-chloroethane as described in Example (179e) to obtain on the subtitle product.MS: APCI(+ve) 481 (M+H)+ Yo (and): YAAY [E]

i t b - yay - m a N-Cyclopropyl-3-[3-[[1-[2-[2-(ethylamino)ethoxy]phenyl]-1-methylethyl J]amino]-2-oxo- 1(2H)- pyrazinyl]-4-methyl-benzamide 1 The subtitle compound was prepared using: 3-[3-[[1-[2-(2-Chloroethoxy)phenyl]-1-methylethylJamino]-2-oxo-1(2H) -pyrazinyl]-N- { cyclopropyl-4-methyl-benzamide ° i (Example 9A (2—) and 7970 amine ethyl in water using the example i method. 0.171 1 º MS: APCI (+ve) 490 (M+H)+.i : 111 NMR 6 (DMSO-d6) 8.42 (d, 1H), 7.85 (d, 1H), 7.74 (s, 1H), 7.47 (d, 1H), 7.34 (d, 1H), 7.23 - 7.14 (m, 1H), 6.99 - 6.87 (m, 3H), 6.69 - 6.59 (m, 2H), 4.01 - 3.89 (m, 2H), i 2.90 -2.78 (m, 3H), 2.54 - 2.44 (m, 2H), 2.06 (s, 3H), 1.80 (s, 6H), 0.92 - 0.78 (m, 3H), Ve { 0.73 - 0.64 (m, 2H), 0.59 - 0.50 ( m, 2H) i } The following examples (49 (YT) (Table 1) were prepared in a manner similar to example (194) i (Y49). Example N-Cyclopropyl-4-methyl-3- [3-[[1-methyl-1-[2-[2-(1-piperazinyl)ethoxy]phenyl]ethyl] amino]-2-oxo-1(2H)-pyrazinyl]- benzamide Vo(Yer) Example ,

N-Cyclopropyl-3-[3-[[1-[2-[2-(diethylamino)ethoxy]phenyl]-1-methylethyl]amino]-2- ! 0x0-1(2H)-pyrazinyl]-4-methyl-benzamide { {YAAYX

- 717 Z Example (010) º N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[2-(1- piperidinyl)ethoxy]phenyl]ethyl [amino]-2-oxo-1(2H)-pyrazinyl]-benzamide m N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[2-4] Example : -methyl-1- 6 piperazinyl)ethoxy[phenyl]ethyl]amino]-2-oxo0-1(2H)-pyrazinyl]-benzamide (Y+¥)

N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[2-(4- morpholinyl)ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)- pyrazinyl]-benzamide (Y+¢ ) Jee Ve 1 N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[4- §# (methylamino)butoxy]phenyl]ethyl]amino Example [-2-oxo-1(2H)-pyrazinyl]-benzamide (Yeo)

N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[4-[(2,2,2- trifluoroethyl)aminobutoxy]phenyl]ethyl]amino]-2-oxo- 1(2H)-pyrazinyl]-benzamide Yo (001 ie) N-Cyclopropyl-4-methyl-3-[3-[[ 1-methyl-1-[2-[4-(4-methyl) -1- piperazinyl)butoxy]phenyl]ethyl]Jamino]-2-oxo-1(2H)-pyrazinyl]-benzamide (Y+V) Example | N-Cyclopropyl-4-methyl-3-[3- [[ 1 -methyl-1-[2-[3-[(2,2,2- Ye ! trifluoroethyl)amino]propoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

YAAY

;

i i i

!

64

a

Example (Y+A) N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[3-(4-methy]-1- : piperazinyl)propoxy [phenyl]ethylJamino]-2-oxo-1(2H)-pyrazinyl]-benzamide

:

! Yq) Example (v+9)d N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[1-methyl-2-(4-methyl-1) - © 1

) piperazinyl)ethoxy[phenyl]ethylJamino]-2-oxo0-1(2H)-pyrazinyl]-benzamide

!

(YY +) Example:

]N-Cyclopropyl-3-[3-[[1-[2-[2-[(2-methoxyethyl)amino]ethoxy]phenyl]-1

;

methylethyl[amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide (Y1Y) Example Ve ; N-Cyclopropyl-3-[3-[[1-[2-[2-[(2-hydroxyethyl)amino]ethoxy]phenyl]-1-

{

{

methylethyl[amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide i (YVY) Example | N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[2-[(1-

l methylethyl)amino]ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide Yo (YY) Example | N-Cyclopropyl-3-[3-[[1-[2-[2-[[(25)-2-hydroxypropyl]amino]ethoxy]phenyl]-1-

i methylethyl[amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-6-benzamide

I i .YAAY i

A Yeo — — B Table (7) E _R ] 0 : 2 0 Solve “ > N N ' º H H 0 1 y 1 Example 1H NMR. (DMSO0-d6) MS R E [M+H]+ y!m/z 1 (d, 1H), 7.85 (d, 1H), 7.75 (s, 531 Yad 8.43 0 1H), 7.47 ( d, 1H), 7.32 (d, 1H), (m, 1H), 6.99 - 6.83 (m, H 7.14 - 7.22 1 for 3H), 6.68 - 6.58 (m, 2H), 4.06 - C (m, 2H), 2.90 - 2.78 (m, 1H), N 3.91 (m, 6H), 2.39 - 2.28 (m, | 2.58 - 2.69 4H), 2.11 (s, 3H), 1.87 ( s, 6H), (m, 2H), 0.60 - 0.50 (m, 0.63 - 0.73 2H (m, 1H), 7.91 - 7.81 (m, 517 0 0 Yeo 8.38 - 8.47 N 1H), 7.77 (s, 1H), 7.45 (d, 1H), : (d, 1H), 7.23 - 7.13 (m, 1H), 7.32 YAAY I

7.02 - 6.92 (m, 1H), 6.93 - 6.83 (m, z 2H), 6.68 - 6.58 (m, 2H), 3.98 - 3.85 (m, 2H), 2.86 - 2.70 (m, 3H), 2.53 - 2.46 (m, 4H), 2.11 (s, 3H), 1.87 (s, 6H), 0.92 (t, 6H), 0.72 - 0.65 (m, 2H), 0.59 - 0.52 (m, 2H 8.43 (d, 1H) , 7.86 (d, 1H), 7.77 (s, 530 vel ] 1H), 7.48 (d, 1H), 7.32 (d, 1H), 7.22 - 7.14 (m, 1H), 7.00 - 6.84 (m, 3H), 6.68 - 6.57 (m, 2H), 4.06 - © e 3.90 (m, 2H), 2.89 - 2.78 (m, 1H), ' j 2.70 - 2.58 (m, 2H), 2.44 - 2.32 (m, 4H) , 2.02 (s, 3H), 1.79 (s, 6H), 1.52 - 1.28 (m, 6H), 0.74 - 0.64 (m, 2H), 0.60 - 0.51 (m, 2H 8.44 - 8.36 (m, 1H), 7.84 (d, 1H), 545 | vey 7.73 (s, 1H), 7.46 (d, 1H), 7.30 (d, 0 1H), 7.19 - 7.12 (m, 1H), 6.97 - N 6.84 (m, 3H), 6.67 - 6.56 (m, 2H), 39 4.00 - 3.89 (m, 2H), 2.87 - 2.76 (m,

YAAY

{ — 71 — 1H), 2.69 - 2.58 (m, 2H), 2.45 - 2.17 (m, 8H), 2.13 - 2.03 (m, 6H), 1.76 (s, 6H), 0.68 - 0.62 (m, 2H), 0.56 - 0.49 ( 2H) 8.44 (d, 1H), 7.88 (d, 1H), 7.76 (s, 532 Yo 1H), 7.50 (d, 1H), 7.34 (d, 1H), 7.23 - 7.17 (m, 1H) ), 7.01 - 6.85 (m, ] 3H), 6.69 - 6.60 (m, 2H), 4.06 - C )

N

3.97 (m, 2H), 3.58 - 3.49 (m, 4H), | 81 2.90 - 2.81 (m, 1H), 2.72 - 2.63 (m, 2H), 2.47 - 2.40 (m, 4H), 2.13 (s, 3H), 1.88 (s, 6H), 0.73 - 0.66 (m, 2H) , 0.60 - 0.53 (m, 2H 8.53 - 8.44 (m, 1H), 7.89 (d, 1H), 504 Vet 7.78 (s, 1H), 7.53 (d, 1H), 7.35 (4, i Sn ! 1H), 7.20 (¢, 1H), 7.01 - 6.86 (m, 3H), 6.74 - 6.59 (m, 2H), 4.01 - J 3.86 (m, 2H), 2.94 - 2.81 (m, 1H), 2.50 - 2.43 (m, 2H), 2.26 (s, 3H), 2.15 (s, 3H), 1.91 (s, 6H), 1.80 -

YAAY

— YA - 1.70 (m, 2H), 1.61 - 1.51 (m, 2H), 0.75 - 0.65 (m, 2H), 0.61 - 0.51 (m, 0-0 8.48 - 8.39 (m, 1H), 7.87 (d, 1H), i.0 7.76 (s, 1H), 7.48 (d, 1H), 7.31 (4, 1H), 7.23 - 7.11 (m, 2H), 6.99 - 6.85 (m, 3H), 6.71 - 6.57 (m , 2H),

He F 4.00 - 3.86 (m, 2H), 3.27 - 3.14 (m, 6d ' 2H), 2.90 - 2.77 (m, 1H), 2.60 - 0 A 2.56 (m, 2H), 2.01 (s , 3H), 1.78 (5, to 6H), 1.78 - 1.68 (m, 2H), 1.61 - : 1.51 (m, 2H), 0.74 - 0.64 (m, 2H), 0.58 - 0.48 (m, 2H ° ' 8.50 - 8.42 (m, 1H), 7.89 (d, 1H), 573 You 7.79 (s, 1H), 7.55 - 7.46 (m, 1H), 7.34 (d, 1H), 7.25 - 7.17 (m, 1H) , 7.02 - 6.87 (m, 3H), 6.75 - 6.60 (m, by 2H), 4.03 - 3.88 (m, 2H), 2.94 - 2.79 (m, 1H), 2.36 - 2.21 (m, 10H), 2.17 - 2.09 (m, 6H), 1.89 - 1.82 (m, 6H), 1.79 - 1.72 (m, 2H), 1.62 -

YAAY i ~ Yue — em { 0.62 - 0.53 (m, 2H 8.48 - 8.38 (m, 1H), 7.86 (d, 1H), ov 558 ! 7.78 (s, 1H), 7.48 (d, 1H), 7.32 (d , 1H), 7.23 - 7.12 (m, 1H), 6.97 - 6.87 (m, 3H), 6.71 - 6.60 (m, 2H), Wor ;

N.K

4.02 - 3.91 (m, 2H), 3.20 - 3.10 (m, 1 2H), 2.89 - 2.70 (m, 3H), 2.39 - 2.29 (m, 1H), 2.13 (s, 3H), 1.79 (s, 7H) , 0.74 - 0.63 (m, 2H), 0.58 - 0.47 (m, 2H) 8.44 - 8.37 (m, 1H), 7.85 (d, 1H), YA 559 * 7.76 (s, 1H), 7.48 (d, 1H) , 7.34 (d, 1H), 7.23 - 7.16 (m, 1H), 6.99 - 6.85 (m, 3H), 6.73 - 6.59 (m, 2H), 5

N for 4.02 - 3.85 (m, 2H), 2.92 - 2.78 (m, 2 1H), 2.45 - 2.16 (m, 10H), 2.15 - 2.05 (m, 6H), 1.91 - 1.81 (m, 8H) , 0.73 - 0.63 (m, 2H), 0.58 - 0.48 (m, 2H)

YAAY

ا ا 1 YY. — — (m, 1H), 7.86 (dd, 1H), 0 8.40 - 8.45 i 559 ' i (m, 1H), 7.50 - 7.47 (m, 7.67 - 7.71 1H) , 7.34 - 7.31 (m, 1H), 7.16 - (m, 1H), 6.99 (s, 1H), 6.87 - | 7.16 N (m, 2H), 6.64 (ddd, 2H), 4.67 C ) 6.85 N b - 2.36 (m, 1H), 2.84 (d, 2H), 4.63 - (m, 6H), 2.11 (t, 6H), 2.08 (s, 2.25 2H ), 1.86 (d, 3H), 1.79 (d, 3H), (dd, 3H), 0.69 (dd, 2H), 0.56 - 1.12 (m, 2H) 0.54 (s, 1H), 7.89 (d, 1H), 7.80 (s, 8.47 Y \ 0 520 1H), 7.48 (d, 1H), 7.34 (d, 1H), (m, 1H), 6.98 - 6.87 (m , 7.14 - 7.23 dimple" 3H), 6.65 (d, 2H), 4.04 - 3.89 (m, 2H), 3.34 - 3.26 (m, 2H), 3.19 s, C 3H), 2.92 - 2.82 (m, 3H), 2.71 - (m, 2H), 2.15 (s, 3H), 1.89 )8, 2.60 6H), 0.74 - 0.63 (m, 2H), 0.60 - (m, 2H ) 0.49 (m, 1H), 7.86 (d, 1H), 8.39 - 8.45 711 He OH 506 (s, 1H), 7.48 (d, 1H), 7.31 (d, NT 7.75 1H), 7.22 - 7.16 (m, 1H), 6.99 - [ (m, 3H), 6.69 - 6.59 (m, 2H), 6.85 YAAY

: 1 i { : - 11 - : : 4.40 - 4.29 (m, 1H), 4.01 - 3.90 (m, 2H), 3.45 - 3.35 (m, 2H), 2.93 - : 2.83 (m, 3H), 2.65 - 2.54 (m, 2H), 2.13 (s, 3H), 1.83 (d, 6H), 0.74 - 0.63 (m, 2H), 0.61 - 0.50 (m, 2H) 8.44 - 8.40 (m, 1H), 7.85 (d, 1H), 504 NY 7.74 (s, 1H), 7.47 (d, 1H), 7.34 (d, 1H), 7.22 - 7.17 (m, 1H), 6.99 - 6.87 (m, 3H), 6.69 - 6.60 (m, 2H), 1 J

SN

4.02 - 3.89 (m, 2H), 2.90 - 2.80 (m, 3H), 2.73 - 2.65 (m, 1H), 2.12 (s, 3H), 1.87 - 1.80 (m, 6H), 0.89 (d, 6H), 0.72 - 0.66 (m, 2H), 0.57 - 0.52 (m, 2H) 8.48 (s, 1H), 7.87 (d, 1H), 7.79 (s, 1H), 7.48 (d, 1H), 7.34 (d, 1H) ), 7.24 - 7.14 (m, 1H), 7.00 - 6.85 (m, 3H), 6.64 (d, 2H), 4.40 - 4.26 (m, - ) ( ) (m H fortress i 1H), 4.03 - 3.89 (m, 2H), 3.67 - 39 OH 3.53 (m, 1H), 2.95 - 2.81 (m, 3H), 2.47 - 2.39 (m, 2H), 2.12 (s, 3H), 1.87 (s, 6H), 0.97 (d, 3H), 0.73 - 0.64 (m, 2H), 0.59 - 0.51 (m, 2H)

YAAY

§ —-YVY — Example : (Y1) N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1- [2-(4-piperidinylmethoxy)phenyl] ethylJamino] -2-oxo-1(2H)-pyrazinyl]- benzamide H (J ZN 0 0 IN LF <5 z N “a 0 Cs N-Cyclopropyl-3- (3-(2-(2-hydroxyphenyl)propan-2-ylamino)-2-oxopyrazin-1(2H)-yl)-4- methylbenzamide (ex. 4 Ala (a > 11 £) potassium carbonate (pa and (p>++)€) tert-butyl 4-(bromomethyl)piperidine-1-carboxylate together in acetonitrile Vo (10mL) on reflux overnight. The cooled reaction solution was evaporated Until dry and divide the residue between 10 (ethyl acetate mL) and Yo water (mL). Lad The separated aqueous layer was extracted to a 10 XY (ethyl acetate mL); The combined organic layers (MgS04) were dried and evaporated. The residue was dissolved in 01 (dichloromethane ml) and treated with 1 1 (trifluoroacetic acid) 0 after stirring at room temperature for 1 hour; Then the solvent was evaporated to leave the crude product 0 after 1 preparative HPLC purification (Gemini column - mobile phase 1 [acetonitrile / ammonia (to obtain the title compound as a solid)© mg). YAAY a

! !—~ YVY-

MS: APCI(+ve) 516 (M+H)+ 01H NMR 5 (DMSO-d6) 8.44 (s, 1H), 7.86 (d, 1H), 7.72 (s, 1H), 7.49 (d, 1H), 7.32 (d, 1H), 7.19 (t, 1H), 6.96 (d, 1H), 6.89 ( 1H), 6.81 (s, 1H), 6.64 (q, 2H), 3.80 - 3.69 (m, 2H), 2.95 - 2.78 (m, 2H), 2.46 - 2.33 (m, 2H), 2.10 (s, 3H), 1.83 (s, 6H), 1.74 - 1.62 (m, 2H), 1.25 - 1.01 (m, 4H), 0.76 - 0.45 (m, 4H). © The following examples (719-7159) (Table V) have been prepared in a manner similar to example (716) AE (119) diN-Cyclopropyl-4-methyl-3-[3-[[1-methyl). -1-[2-(3-pyrrolidinyloxy)phenyl] ethylJamino]- 2-0x0-1(2H)-pyrazinyl]-benzamide D 1 | (V1) Jie Ne

N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-(3-pyrrolidinyloxy)phenyl]ethylJamino]- | 2-oxo-1(2H)-pyrazinyl]-benzamide f | (YVV) Example | N-Cyclopropyl-4-methyl-3-[3-[[ 1-methyl-1-[2-[2-(4- ‎| piperidinyl)ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H )-pyrazinyl]-benzamide Yo ‎| (YVA) Example N-Cyclopropyl-4-methyl-3-[3-[[ 1-methyl-1-[2-(3-piperidinylmethoxy) phenyl]ethyl] | amino]-2-oxo-1(2H)-pyrazinyl]-benzamide ‎ ‎ ‎ ‎ ‎ ‎ | YAAY

i 6 no 1(Y)4) Example | N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1- [2-(4-piperidinyloxy)phenyl]ethyl Jamino]-2- oxo-1(2H)-pyrazinyl]-benzamide (V ) table_R 0 2 0

A N

{ N N i H H 0 1 ° t } 1H NMR. § (DMSO-d6) MS R Example [MH] m/z 8.49 - 8.41 (m, 1H), 7.87 (d, 1H), 474 Vie i 7.76 (s, 1H), 7.48 (d, 1H), 7.34 (d, 1H), 7.18 - 7.12 (m, 1H), 6.93 - 6.87 1/E (m, 2H), 6.67 - 6.61 (m, 3H), 4.95 - 84.89 (m, 1H), 3.73 - 3.64 ( m, 2H), 3.50 - 3.36 (m, 3H), 2.88 - 2.79 (m,1H), 2.14 (s, 3H), 1.88 (s, 6H), 0.73 - 0.64 (m, 2H), 0.59 - 0.50 ( m, 2H i :

YAAY

{ . - TVe -

(m, 1H), 7.93 - 7.80 (m, 488 1711 8.42 - 8.55 s 1H), 7.69 (d, 1H), 7.48 (d, 1H), 7.35 | (d, 1H), 7.22 - 7.13 (m, 1H), 6.93 - ;

And

(m, 3H), 6.68 - 6.60 (m, 2H), {6.85 A

‎4.89 - 4.80 (m, 1H), 3.03 - 2.59 (m,

| 4H), 2.05 (5, 3H), 2.05 - 1.92 (m,

‎1H), 1.87 - 1.57 (m, 8H), 0.74 - 0.64

(m, 2H), 0.58 - 0.48 (m, 2H).

8.49 - 8.42 (m, 1H), 7.89 - 7.82 (m, 530 ARR ] 1H), 7.71 (s, 1H), 7.48 - 7.42 (m,

| 1H), 7.31 (d, 1H), 7.20 - 7.14 (m,

,! 111(, 6.96 (d, 1H), 6.89 - 6.83 (m, , 2H), 6.67 - 6.56 (m, 2H), 3.98 - 3.87

(m, 2H), 2.88 - 2.77 (m, 3H), 2.37 -

, 2.27 (m, 2H), 2.10 (s, 3H), 1.84 (s,

| 6H), 1.65 - 1.47 (m, 6H), 1.05 - 0.88

‎(m, 2H), 0.70 - 0.61 (m, 2H), 0.57 -

‎; 0.48 (m, 2H)

‎YAAY

—- YY - 8.48 - 8.40 (m, 1H), 7.87 (d, 1H), 516 8 7.76 (s, 1H), 7.49 (d, 1H), 7.31 (d, 1H), 7.22 - 7.14 (m, 1H) ), 7.02 - 6.94 (m, 1H), 6.92 - 6.80 (m, 2H), 6.71 - 6.59 (m, 2H), 3.85 - 3.69 (m, 2H), J 3.05 - 2.99 (m, 111), 2.89 - 2.73 (m, ¢ 2H), 2.44 - 2.27 (m, 4H), 2.13 (s, 3H), 1.92 - 1.85 (m, 1H), 1.86 (s, 6H), 1.56 - 1.50 (m, 1H), 1.37 - 1.14 º ' (m, 2H), 0.72 - 0.65 (m, 2H), 0.58 - 0.51 º ' (m, 2H) : 8.46 - 8.41 (m, 1H), 7.86 (d, 1H), 502 AAR 7.73 ( s, 1H), 7.49 (d, 1H), 7.34 d, 1H), 7.18 - 7.12 (m, 1H), 6.97 (d, 1H), 6.88 - 6.83 (m, 2H), 6.69 - 6.60 b ! (m, 2H), 4.48 - 4.40 (m, 1H), 2.94 - sb 2.80 (m, 3H), 2.59 - 2.52 (m, 2H), 2.12 (s, 3H), 1.87 (8, 8H) , 1.50 - 1.38 (m, 2H), 0.72 - 0.65 (m, 2H), 0.58 - 0.51 (m, 211

YAAY

Con 1 (Y Y. ) Example | N-Ethyl-4-methyl-3-[3-[[1-methyl-1-[2- [2-(methylamino)ethoxy]phenyl]ethyl]amino]-2- ! oxo-1(2H)-pyrazinyl]-benzamide

N

NJ

HN b 0: )( oe 3-[5-Bromo-3-[[ 1-methyl-1-[2-(phenylmethoxy)phenyl]ethylJamino]-2-oxo- 1(2H)- pyrazinyl] -4-methyl-benzoic acid methyl ester (eg a,0-dimethyl-2-(phenylmethoxy)-benzenemethanamine A solution of : ml) was treated with (7) dioxane g) dissolved in 0.8 Ed 4 7,449 Ab JL) methyl 3-(3,5-dibromo-2-oxopyrazin-1(2H)-yl)-4-methylbenzoate Ve The resulting solution was stirred at . nitrogen under (de0 AY) N-ethyldiisopropylamine and (a>h). After cooling to room temperature, the reaction mixture was diluted with water 10 for 0 m (MgSO4) and the organic layer was dried. (Y X ml 001 (ethyl acetate) and extracted (Ja 0 ) for iso-hexane in diethyl ether 756, filtered and evaporated. The crude product was crushed using 60) hours. The solid was separated by filtration to obtain on the subtitle compound yo

MS: APCI(+ve) 563 (M+H)+..(a>i tel)

i i k YVA — (b) : 3-[3-[[1-(2-Hydroxyphenyl)-1-methylethylJamino]-2-oxo-1 (2H)-pyrazinyl ]-4-methyl- benzoic acid methyl ester to: 3-[5-bromo-3-[[1-methyl-1-[2-(phenylmethoxy)phenyl]ethyl]amino]-2-oxo- 1(2H)- ° pyrazinyl]-4-methyl-benzoic acid, methyl ester (ex. (a> ¥ dYY in (Je ©+) ethanol ammonium formate )¢ ),¥ g) and 0 7 20/0 FVA) + g) and the reaction mixture was heated at Vo C for 1 hour. The reaction mixture was filtered through a celite and the filtrate was concentrated in vacuo. The resulting mixture was diluted with water (Jo Yo. ) 01 and extracted with (Ja You ) dichloromethane. The organic layer (048504) was dried, filtered, and concentrated in vacuo to yield the subtitle compound (1.61 g). MS: APCI(+ve) 394 (M+H)+.(c): 4-Methyl-3-[3-[[1-methyl-1-[2-[2-[methyl[(phenylmethoxy) )carbonyl[Jamino]ethoxy] phenyl[ethyl]Jamino]-2-oxo-1(2H)-pyrazinyl]-benzoic acid methyl ester \o to: 3-[3-[[1-(2- Hydroxyphenyl)- 1-methylethyl[amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl- benzoic acid methyl ester YAAY i i { i —Yva — { potassium carbonate was added ( Je V0 +) acetonitrile in (p= Y, 890 by 701 (example | g) and 1.176 J. Med. g) and this was followed by the addition of (1992, 35 (17), 3246 given 90 05 more nitrogen was added hr in VY m for AC Heating the reaction mixture at +,Y¢) potassium carbonate 5 g) 8 A) benzyl 2-chloroethyl(methyl)carbamate from two days. The reaction mixture was cooled; evaporated to dryness, split sad g) and the reaction mixture © i was stirred, and the organic layer was separated. The aqueous layer was extracted once dichloromethane 5 ele remaining between £ (Na2S04) (twice) and the combined organic layers were further dried dichloromethane using i ( ethyl acetate JARRE) and evaporated. After purification (chromatography 2 and filtering using To get the subtitle product (1.57 g). , SH), 7.20 - 7.16 01 (m, 1H), 6.91 (t, 3H), 6.65 (d, 2H), 5.05 (s, 2H), 4.09 - 3.99 (m, 3H), 3.84 (s, 2H) , 2.92 (d, 3H), 2.13 (s, 3H), 1.99 (d, 2H), 1.80 (s, 6H) i .: (d) z i 4-Methyl-3-[3- [[1-methyl-1-[2-[2-[methyl[(phenylmethoxy)carbonylJamino]ethoxy]

I phenyl] ethyl] amino]-2-oxo-1(2H)-pyrazinyl]-benzoic acid Vo : to + 4-Methyl-3-[3-[[1-methyl-1-[2-[ 2-[methyl[(phenylmethoxy)carbonyl amino] ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzoic acid methyl ester { i YAAY a

: 1! { — YA — lithium hydroxide monohydrate (Ja 11 ) THF was added in (p= V,4Y J 00 (example: | g) in water (0.0 ml) (suspension ultrasound processor) and the reaction mixture was stirred for (127) hydrochloric hours at room temperature. Water was added and the solution was acidified by adding and evaporating 1. (MgSO4) The organic layer was dried. ethyl acetate molar was extracted * 0 1,749 ( to obtain the subtitle compound iso-hexane | diethyl ether and after technique using ©g). | MS: APCI(+ve) 571 (M+H)+. 1H NMR 5 (DMSO0-d6) 7.95 (d, 1H), 7.79 (s, 1H), 7.54 (d, 1H), 7.32 (s, 6H), 7.19 (d, 1H), 7.00 - 6.89 (m, 3H) ), 6.66 (s, 2H), 5.05 (s, 2H), 4.06 (d, 2H), 3.64 (s, 2H), 2.92 (d, 3H), 2.12 (s, 3H), 1.80 (s, 6H) . 01 (e): [2-[2-[1-[[4-[5-[(Ethylamino)carbonyl]-2-methylphenyl]-3,4-dihydro-3- oxopyrazinylJamino]-1- methylethyl]phenoxy]ethylJmethyl-carbamic acid phenylmethyl ester To : Z 0 4-methyl-3-[3-[[1-methyl-1-[2-[2-[methy][(phenylmethoxy)carbonylJamino]ethoxy] phenyl] ethyl] amino]-2-oxo-1(2H)-pyrazinyl]-benzoic acid : ml) ¥) DMF added in (p > 04 0 (Example | YAAY)

- YAY - g) and ole A) O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate followed that (Je +,YVY) N-ethyldiisopropylamine and the reaction mixture was stirred for 11 minutes. minutes before adding i hours. The reaction mixture, ¥osad, was diluted, the reaction mixture, (Jo++ TY) amine ethyl e, was stirred with water and the aqueous layer i© was extracted using ethyl acetate. The combined organic layers (Na2504) were dried and solvent removed in vacuo to yield subtitle product (VY) g). a

MS: APCI(+ve) 598 (M+H)+. (f): z

N-Ethyl-4-methyl-3-[3-[[ 1-methyl-1-[2-[2-(methylamino)ethoxy]phenyl] ethyllamino}-2- oxo-1(2H)-pyrazinyl]-benzamide Ve to : ْ [2-[2-[1-[[4-[5-[(ethylamino)carbonyl]-2-methylphenyl]-3,4-dihydro-3- oxopyrazinyl]Jamino]-1-methylethyl]phenoxy [ethyl]methyl-carbamic acid phenylmethyl ' ester : Pd/C and the product was pumped through a cartridge (Je 01 (ethanol g) 0.1 d0 was added (ex. 01 at a rate of [da 1 min. under maximum H2 at ov m on H-Cube hydrogen al se. The solvents were removed: in vacuo and the residue was taken in acetonitrile. After purification using preparative HPLC (column! SCX) and then treatment with resin ) acetonitrile :TFA 7 +,Y filter solution ACE

YAAY

A— YAY - (and filtering with methanol (excluded) and thereafter with 3 V p in methanol and collecting i basal parts) and pulverizing with diethyl ether then obtaining the title product ((pe Y .

MS: APCI(+ve) 464 (M+H)+. 1H NMR 5 (DMSO0-d6) 8.49 (s, 1H), 7.88 (d, 1H), 7.76 (s, 1H), 7.49 (d, 1H), 7.36 (d, 1H), 7.20 (t, 1H), 6.95 (m, 3H), 6.67 (d, 1H), 6.63 (d, 1H), 4.05 - 3.98 (m, 2H), 3.28 (1, ° { 2H), 2.96 (d, 2H), 2.33 (s, 3H), 2.10 (s, 3H), 1.85 (s, 3H), 1.82 (s, 3H), 1.11 (t, 3H) The following Examples 779-771 (Table A) are prepared in a manner similar to Example 7730: 1 (Y 7 ) Example | 1-[4-Methyl-3-[3-[[1-methyl-1-[2-[2-(methylamino)ethoxy]phenyl]ethylJamino]-2- oxo- { 1(2H)-pyrazinyl]benzoyl]-azetidine 01 i(YYY) Example N-Ethoxy-4-methyl-3-[3-[[1-methyl-1-[2-[2] -(methylamino)ethoxy]phenyl]ethylJamino]-2-ox0-1(2H)-pyrazinyl]-benzamide : (YY ¥) Example 4-Methyl-N-(1-methylethyl)-3-[3- [[1-methyl-1-[2-[2- Vo i (methylamino)ethoxy]phenyl]ethyl}amino]-2-oxo-1(2H)-pyrazinyl]-benzamideYAAY

— YAY — (YY¢ ) Example

N-Cyclobutyl-4-methyl-3-[3-[[1-methyl-1-[2-[2-(methylamino)ethoxy]phenyl] i ethyl]amino]-2-oxo-1(2H)-pyrazinyl ]-benzamide eg ((Yve zN-(2-Fluoroethyl)-4-methyl-3-[3-[[1-methyl-1-[2-[2-(methylamino)ethoxy]phenyl] © 0 ethyl [Jamino]-2-oxo-1(2H)-pyrazinyl]- benzamide (YT) Example | 4-Methyl-3-[3-[[1-methyl-1-[2-[2-(methylamino) (ethoxy] phenyl] ethyl[amino]-2-oxo- 1(2H)-pyrazinyl]-N-(2-methylpropyl)-benzamide Co Example (YYV) 4-Methyl-N-(1 -methylcyclopropyl)-3-[3-[[1-methyl-1-[2-[2- i | .| (methylamino)ethoxy]phenyl]ethyl]Jamino]-2-oxo-1 (2H )-pyrazinyl]-benzamide | (YYA) Example | N-(2-Hydroxyethyl)-4-methyl-3-[3-[[1-methyl-1-[2- [2-(methylamino) ethoxy]phenyl] | ethylJamino]-2-oxo-1(2H)-pyrazinyl]-benzamide Vo i (YY4) Example | 4-Methyl-3-[3-[[1-methyl-1- [2-[2-(methylamino)ethoxy]phenyl]ethyl]amino]-2-oxo- | 1(2H)-pyrazinyl]-benzamide i; !I z | YAAY {

z a | — YALE — (A) MS table | 1H NMR. § (DMSO-d6) [M-+H]+ R Example y m/z 7.64 (d, 1H), 7.48 (d, 2H), 7.35 (d, 476 77 1H), 7.19 (t, 1H), 6.98 - 6.88 (m, 3H), 6.62 (ddd, 2H), 4.33 (d, 2H), 8

N

4.06 - 3.93 (m, 3H), 3.44 (gq, 2H), l y 2.83 (1, 2H), 2.27 - 2.25 (m, 3H), 2.11 - 2.06 (m, 3H), 1.83 (s , 6H), 1.06 (td, 2H) 7.78 (d, 1H), 7.71 (s, 1H), 7.52 (d, 480 7 ) 1H), 7.42 (d, 1H), 7.26 (m, 1H), 7.24 ( t, 1H), 7.01 - 6.96 (m, 2H), 6.70 (d, He 1H), 6.63 (d, 1H), 4.26 - 4.09 (m, ), 6.63 (d, 1H) ( Sha | 2H ), 3.92 (q, 2H), 3.40 - 3.23 (m, 2H), 2.52 (5, 3H), 2.11 (s, 3H), 1.89 s, 3H), 1.80 (s, 3H), 1.21 (t, 3H)

YAAY

ْ i i — YAo — Lal ‎| 8.23 (d, 1H), 7.89 (dd, 1H), 7.81 (d, 478

1H), 7.49 (d, 1H), 7.38 (dd, 1H), } 7.22 (dd, 1H), 7.12 (s, 1H), 7.00 - Ho

1 7 6.93 (m, 3H), 6.67 (dd, 2H), 4.15 - PN 4.06 (m, 2H), 2.44 (s, 3H), 2.44 (s, 2H), 2.11 (s, 3H), 1.84 (d , 6H), 5 d, 6H) 8.64 (d, 1H), 7.90 (dd, 1H), 7.82 (s, 490 7] 1H), 7.49 (d, 1H), 7.40 (dd, 1H), 7.23 ( dd, 2H), 6.98 (q, 2H), 6.67 (dd, l | 2H), 4.41 (d, 1H), 4.21 - 4.15 (m,

{

1 2H), 3.40 - 3.26 (m, 2H), 2.53 (5, 2

] 3H), 2.21 (m, 2H), 2.11 (s, 3H), 2.05

1 (t, 2H), 1.88 (s, 6H), 1.72 - 1.61 (m,

! 2H) 8.73 (s, 1H), 7.92 - 7.82 (m, 2H), 482 Yye 7.53 - 7.37 (m, 2H), 7.17 (d, 2H), He 6.97 (s, 2H), 6.66 (s, 2H) , 4.61 (s, p

1H), 4.45 (s, 1H), 4.10 (s, 2H), 3.56 z

| (d, 2H), 3.17 (s, 2H), 2.44 (s, 3H),

‎YAAY

: — YAY — 7 kn 8.47 (s, 1H), 7.90 - 7.87 (m, 1H), 1 492 7.75 (s, 1H), 7.49 (d, 1H), 7.34 (4, 1H), 7.19 (m, 1H), 6.98 - 6.91 (m, as 3H), 6.68 - 6.63 (m, 2H), 4.09 - 3.91 (m, 1H), 3.18 (s, 2H), 3.16 (s, 2H), b | 2.84 - 2.82 (m, 2H), 2.09 (d, 3H), 1.99 (s, 3H), 1.83 (s, 6H), 1.20 - 1.09 i m, 6H ° 8.66 (s, 1H), 7.85 (dd, 1H) , 7.71 (s, 490 77 1H), 7.47 (d, 1H), 7.34 (dd, 1H), 7.22 - 7.16 (m, 1H), 6.98 - 6.87 (m, He 1 33 3H), 6.64 (dd, 2H ), 3.96 (dtd, 2H), A 2.83 (t, 2H), 2.26 (s, 3H), 2.09 s, 3H), 1.83 (s, 6H), 1.35 (s, 3H), 0.73 ! - 0.70 (m, 2H), 0.61 - 0.57 (m, 2H 8.47 (s, 1H), 7.92 (s, 1H), 7.76 (s, 480 YYA k Ho ] 1H), 7.54 (s, 1H), 7.33 ( s, 1H), 7.19 3.96 (s, 2H), 3.49 (s, 2H), 3.31 - 3.31

YAAY

: — YAY - (m, 2H), 2.83 (s, 2H), 2.26 (s, 3H), 2.10 (s, 3H), 1.83 (s, 6H 7.98 (s, 1H), 7.90 (dd, 1H), 7.76 (d, 436 4?? 1H), 7.49 (d, 1H), 7.41 (s, 1H), 7.34 (dd, 1H), 7.19 (t, 1H), 6.96 (d, 1H), T

H™ ~H 6.90 (t, 2H), 6.65 (q, 2H), 3.96 (ddd, 2H), 2.83 (t, 2H), 2.26 (s, 3H), 2.10 s, 3H), 1.83 (d, 6H) Example (730)N-Cyclopropyl-3-[3-[[1-[2-[2-[[(2S)-2-hydroxypropyl]amino] ethoxy]phenyl] cyclopropyl]amino]-2-oxo-1( 2H)-pyrazinyl]-4-methyl-benzamide i

N v º I OH 0 =~ ch-0 : N N ~~

H Hol i 0 = ° ye 3-(3-(1-(2-(2-Chloroethoxy)phenyl)cyclopropylamino)-2 -oxopyrazin-1(2H)-yl)-N- cyclopropyl-4 Highly methylbenzamide

: ! — YAA —- dioxane mL) together at 4 V) (8)-(+)-1-amino-2-propanol and poe 001 ca VV (ex. HPLC h. After purification of cooled solution B YE m for 100 ml) in a sealed tube at 7) to obtain ammonia /+,Y / acetonitrile mobile phase - Xbridge preparation (heading compound column) B "mg) ..

MS: APCI(+ve) 518 (M+H)+. 5' H NMR § (DMSO-d) 8.36 (d,1H), 7.85 (d,1H), 7.68 (s, 1H), 7.53 - 7.43 (m, 2H), 7.39 - { 7.35 (m, 1H), 7.20 (t,1H), 6.96 (d,1H), 6.90 - 6.81 (m, 2H), 6.70 (d,1H), 4.41 (s, 1H), 4.06 (t, 2H), 3.69 (s, 1H) , 2.96 (t, 2H), 2.89 - 2.75 (m, 1H), 2.55-2.52 (m, 2H), 2.06 (s, 3H), 1.24 - 1.12 (m, 4H), 1.02 (d, 3H), 0.71 - 0.62 (m, 2H), 0.56 - 0.48 (m, 2H). (170): (Table 3) In the same way as in the example (YOO YT) the following examples were prepared 0 (Y 9 ) Example N-Cyclopropyl-3-[3-[[1-[2- [2-[(2-methoxyethyl)amino]ethoxy] phenyl]cyclopropyl] amino] -2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide (YY) Example i N-Cyclopropyl- 3-[3-[[1-[2-[2-[4-(2-hydroxyethyl)-1-piperazinyl]ethoxy] 1 phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl] - 4-methyl-benzamide

YAAY i 1 vas i (TFT) Example | N-Cyclopropyl-3-[3-[[1-[2-[2-[(2-hydroxyethyl)amino] ethoxy] phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4- methyl-benzamide (Yr ) Example N-Cyclopropyl-4-methyl-3-[3-[[1-[2-[2-[(1-methylethyl)amino] ° ethoxy]phenyl]cyclopropyl]amino] -2-oxo-1(2H)-pyrazinyl]-benzamide (YVo) Example | N-Cyclopropyl-3-[3-[[1-[2-[2-(hexahydro-4-methyl-1H-1,4-diazepin-1- yl)ethoxy]phenyl]cyclopropylJamino]-2-oxo-1 (2H)-pyrazinyl]-4-methyl-benzamide (1) ( Ex. Ve

N-Cyclopropyl-3-[3-[[1-[2-[2-[(3R)-3-hydroxy-1-pyrrolidinylJethoxy] phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl] -4-methyl-benzamide (YYV) Example N-Cyclopropyl-3-[3-[[1-[2-[2-(dimethylamino)ethoxy]phenyl]cyclopropyl]amino]-2- ! oxo-1(2H)-pyrazinyl]-4-methyl-benzamide Vo

YAAY

. [ { 1 i 1 78.0 (Y¥A) eg N-Cyclopropyl-4-methyl-3-[2-oxo0-3-[[1-[2-[2-(1- pyrrolidinyl)ethoxy) ]phenyl]cyclopropyl]amino]-1(2H)-pyrazinyl]-benzamide | (Y14) Example | N-Cyclopropyl-3-[3-[[1-[2-[2-[(2S)-2-(hydroxymethyl)-1- 5 pyrrolidinyl]ethoxy]phenyl]cyclopropyl]Jamino]-2-oxo-1( 2H)-pyrazinyl}-4-methyl-1 { benzamide

I

. ( 0 ) Example, N-Cyclopropyl-4-methyl-3-[2-oxo0-3-[[1-[2-[2-[(2,2,2- | trifluoroethyl)amino]ethoxy [phenyl]cyclopropyl]amino]-1(2H)-pyrazinyl]-benzamide 01 (YeV) Example | N-Cyclopropyl-3-[3-[[ 1-[2-[2-(ethylmethylamino)ethoxy]phenyl]cyclopropylJamino]-2- ! ox0-1(2H)-pyrazinyl]-4-methyl-benzamide (VEY) Example | N-Cyclopropyl-3-[3-[[1-[2-[2-[(3-hydroxy-2,2- Yo t dimethylpropyl)amino]ethoxy]phenyl]cyclopropyl]Jamino]-2-oxo-1( 2H)-pyrazinyl]-4- methyl-benzamide

) i ; - Yay! (Ye¥) Example 1 N-Cyclopropyl-4-methyl-3-[2-0x0-3-[[1-[2-[2-(1- 1 ! piperazinyl)ethoxy]phenyl]cyclopropyljamino] -1 (2H)-pyrazinyl]-benzamide (Yee ) Example { | N-Cyclopropyl-3-[3-[[1-[2-[2-(3,3-difluoro-1- 5 pyrrolidinyl)ethoxy]phenyl]cyclopropyl]Jamino]-2-oxo-1(2H)-pyrazinyl ] -4-methyl-benzamide (Y£0) Example | N-Cyclopropyl-3-[3-[[1-[2-[2-[(2-fluoroethyl)amino]ethoxy] phenyl] cyclopropyl]amino]- 2-0x0-1(2H)-pyrazinyl]-4- methyl-benzamide 01 ( Yen ) Example | N-Cyclopropyl-4-methyl-3-[3-[[1-[2-[2-[(1-methylpropyl) amino]ethoxy]phenyl]cyclopropylJamino]-2-oxo-1(2H)-pyrazinyl]- benzamide

( Y¢ V) Ex. 1 N-Cyclopropyl-4-methyl-3-[3-[[1-[2-[2-[(2R)-2-methyl-1- Vo i pyrrolidinyl]ethoxy] phenyl[cyclopropylJamino]-2-oxo-1(2H)-pyrazinyl]-benzamide { the

(Y¢ A) Example 3-[3-[[1-[2-[2-(cyclobutylamino)ethoxy]phenyl]cyclopropylJamino]-2-oxo-1(2H)- pyrazinyl]-N-Cyclopropyl -4-methyl- benzamide : (Yea ) Example N-Cyclopropyl-3-[3-[[1-[2-[2-[[(1R)-2-hydroxy-1-methylethyl]amino] © ethoxy]phenyl]cyclopropyl]amino}-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide : (Yor) Example; N-Cyclopropyl-3-[3-[[1-[2-[2-[(3-hydroxypropyl)amino]ethoxy]phenyl] cyclopropyl] amino] -2-oxo-1(2H)-pyrazinyl]-4- methyl-benzamide : (Yor) eg 0 ; 3-[3-[[1-[2-(2-aminoethoxy)phenyl]cyclopropyl]Jamino]-2-oxo-1(2H)-pyrazinyl]-N- cyclopropyl-4-methyl-benzamide The

1 z — Yay - (9) Table 8 J AJ Ns]

CCT YC oo0

MS

1H NMR. § (DMSO-d6) [M+H]+ Example | m/z 8.37 - 8.32 (1H, m), 7.84 (1H, d), 518 79 7.68 (1H, 5), 7.47 (2H, 1), 7.36 (1H, 5), 7.19 (1H, 0, 6.95 ( 1H, d), 6.90 - 6.81 (3H, m), 6.70 (1H, d), 4.06 1(2H, 1), 3.38 (2H, 1), 3.18 (3H, 5), No 2.99 - 2.91 (1H, m), 2.87 - 2.69 (2H, m), 2.06 (3H, 5), 1.27 - 1.10 + (6H, m), 0.73 - 0.61 (2H, m), 0.56 - 0.46 (2H, m (CD30D) 7.81 ( dd, 1H), 7.61 (d, 273 mF YY'Y 1H), 7.55 (dd, 1H), 7.44 (d, 1H), b | 7.22 -7.17 (m, 1H), 6.92 (d , 1H),

YAAY

1 —Ya¢ — 1 6.89 - 6.83 (m, 2H), 6.56 (d, 1H), 4.19 (1, 2H), 3.61 (t, 2H), 2.92 (t, 2H), 2.84 - 2.76 (m, 1H) ), 2.76 - 2.65 (m, 4H), 2.63 - 2.52 (m, 4H), 2.48 (t, 2H), 2.11 (s, 3H), 1.29 - 1.15 (m, 3H), 1.14 - 1.08 (m, 1H) ), 0.79 - 0.72 (m, 2H), 0.61 - 0.55 (m, 2H). 1 8.35 (1H, d), 7.84 (1H, dd), 7.67 504 yyy z (1H, d), 7.52 - 7.43 (2H, m), 7.38 (1H, s), 7.23 - 7.15 (1H, m ), 6.96 (1H, d), 6.89 - 6.82 (2H, m), 6.70 1 (1H, d), 4.42 (1H, 1), 4.06 (2H, 1), Non 2.96 (2H, 1), 2.88 - 2.75 (1H, m), 2.67 (2H, 1), 2.06 (3H, 5), 1.22 - 0.98 (6H, m), 0.71 - 0.61 (2H, m), 0.57 - 0.47 2H, m i oy 1H), 7.48 (t, 2H), 7.35 (s, 1H), 7.20 (t, 1H), 6.96 (d, 1H), 6.89 - 6.82

YAAY

: a 1 z 1990 — s: (m, 3H), 6.71 (d, 1H), 4.05 (¢, 2H), 2.94 (1, 2H), 2.87 - 2.70 (m, 2H), 2.06 (s, 3H), 1.29 - 1.11 (m, 2H), 0.98 (d, 6H), 0.88 - 0.79 (m, 2H), i 0.71 - 0.61 (m, 2H), 0.56 - 0.46 (m, 2H) § (CD30D) 7.79 (dd, 1H), 7.59 (d, 557 Yye 1H), 7.52 (dd, 1H), 7.42 (d, 1H), 7.20 - 7.14 (m, 1H), 6.92 - 6.80 (m, 2H), 6.54 ( d, 1H), 4.12 (t, 2H), 3.02 (t, 2H), 2.93 - 2.87 (m, 4H), 2.82 - rN up 2.74 (m, 1H), 2.69 - 2.62 (m, 4H) , 2.27 (s, 3H), 2.08 (s, 3H), 1.85 - 1.78 (m, 2H), 1.32 - 1.05 (m, SH), 0.89 - 0.81 (m, 1H), 0.77 - 0.70 (m, : 2H ), 0.59 - 0.52 (m, 2H x 5 (CD30D) 7.80 (dd, 1H), 7.59 (s, 530 AR ° 1H), 7.54 (dd, 1H), 7.43 (d, 1H), {Dor : f : 7.21 - 7.15 (m, 1H), 6.91 (d, 1H), 6.88 - 6.82 (m, 2H), 6.55 (dd, 1H),

YAAY

H

;

:

¥i

!

— Yan-

4.35 - 4.29 (m, 1H), 4.15 (t, 2H),

i f 3.04 - 2.85 (m, 4H), 2.82 - 2.75 (mm,

1H), 2.70 - 2.63 (m, 2H), 2.17 - 2.06 (m, 4H), 1.74 - 1.64 (m, 1H),

:

: 1.26 - 1.15 (m, 2H), 1.15 - 1.08 (m,

i t

1H), 0.95 - 0.81 (m, 1H), 0.78 -

i

1

0.71 (m, 2H), 0.59 - 0.54 (m, 2H)

: 8 (CD30D) 7.80 (d, 1H), 7.62 - 488 77

7.53 (m, 2H), 7.46 - 7.39 (m, 1H),

£7.22 - 7.14 (m, 1H), 6.95 - 6.82 (m,

1 2H), 6.57 - 6.50 (m, 1H), 4.19 - 4.10 (m, 2H), 3.32 - 3.25 (m, 2H), like

: 2.91 - 2.84 (m, 2H), 2.82 - 2.74 (m, 1H), 2.41 - 2.34 (m, 6H), 2.12 - 2.05 (m, 3H), 1.32 - 1.07 (m, 4H),

0.78 - 0.71 (m, 2H), 0.60 - 0.52 (m,

{

2H)

: Y¥A (CD30D) 7.80 (dd, 1H), 7.59 (d, 418 1H), 7.54 (dd, 1H), 7.43 (d, 1H), ZAP 7.21 -7.16 (m, 1H), 6.92 (d, 11),

: i : — Yay — 6.88 - 6.82 (m, 2H), 6.54 (d, 1H), : : 4.17 (t, 2H), 3.01 (1, 2H), 2.83 - 2.76 (m, 1H), 2.75 - 2.68 (m, 3H), 2.09 (s, 3H), 1.83 - 1.77 (m, 4H), 1 1.25 - 1.15 (m, 3H), 1.15 - 1.08 (m, 1H), 0.90 - 0.81 (m, 1H), 0.78 - 0.71 (m, 2H), 0.59 - 0.54 (m, 2H (CD30D) 7.83 (d, 1H), 7.63 (s, 544 "1 to 1H), 7.56 (d, 1H), 7.46 (d, 1H), : 7.21 (t, 1H), 6.94 (d, 1H), 6.91 - 6.84 (m, 2H), 6.58 (d, 1H), 4.20 - 4.14 (m, 2H), 3.62 - 3.48 (m, 2H) ), 3.43 - 3.35 (m, 2H), 2.92 - 2.79 (m, ve 2H), 2.74 - 2.66 (m, 1H), 2.54 - OH 2.43 (m, 1H), 2.12 (s, 3H), 1.99 - 1.87 (m, 1H), 1.82 - 1.73 (m, 210), i 1.70 - 1.60 (m, 1H), 1.32 - 1.08 (m, 3 ' 4H), 0.92 - 0.84 (m, 1H), 0.81 - 0.74 (m , 2H), 0.63 - 0.57 (m, 2H

H F

N \ Ex 5 (CD30D) 7.91 - 7.86 (m, 1H), 542 2 “A A A | YAAY

— Y4A — 7.76 - 7.71 (m, 1H), 7.70 - 7.65 (m, 1H), 7.57 - 7.51 (m, 1H), 7.42 - 7.35 (m, 1H), 7.14 - 7.09 (m, 1H), 7.08 - 7.03 (m, 1H), 6.97 - 6.92 (m, 1H), 6.88 - 6.83 (m, 1H), 4.40 - 4.33 (m, 2H), 3.80 - 3.71 (m, 2H), 3.57 - 3.52 (m, 1H) ), 3.51 - 3.46 (m, 2H), 3.25 - 3.21 (m, 1H), 2.93 - 2.85 (m, 1H), 2.26 (s, 3H), 1.58 - 1.52 (m, 1H), 1.52 - 1.44 (m , 2H), 1.41 - 1.34 (m, 1H), 1.28 - 1.21 (m, 1H), 0.89 - 0.83 (m, 2H), 0.70 - 0.64 (m, 2H) (CD30D) 7.81 (d, 1H), 7.68 - 502 vi) 7.58 (m, 2H), 7.46 (d, 1H), 7.34 - 7.27 (m, 1H), 7.05 (d, 1H), 6.99 (t, 1H), 6.87 (d, 1H), 6.77 - 6.72 (m, PN : 1H), 4.47 - 4.40 (m, 2H), 3.77 - 3.59 (m, 2H), 3.50 - 3.43 (m, 1H), 2.93 (s, 3H), 2.85 - 2.76 ( m, 1H), 2.16 (s, 3H), 1.53 - 1.11 (m, 9H), i YAAY i —Ya4 — phoneseasmm | [1 (CD30D) 7.90 (d, 1H), 7.79 (s, 546 vey 1H), 7.70 (d, 1H), 7.56 (d, 1H), z 7.45 - 7.39 (m, 1H), 7.16 (d , 1H), 7.10 (¢, 1H), 6.95 - 6.91 (m, 2H), 4.50 (s, 2H), 3.70 - 3.58 (m, 2H), ] 3.58 - 3.55 (m, 2H), 3.21 (s, 2H), oor 2.93 - 2.86 (m, 1H), 2.30 (s, 3H), : 1.72 - 1.65 (m, 1H), 1.64 - 1.58 (m, 1H), 1.57 - 1.50 (m, 1H), 1.43 - 1.34 (m, 1H), 1.05 (s, 6H), 0.86 (d, 2H), 0.72 - 0.66 (m, 2H § (CD30D) 7.80 (dd, 1H), 7.60 (d, 529 vey x 1H) ), 7.54 (dd, 1H), 7.43 (d, 1H), ) 7.22 -7.16 (m, 1H), 6.91 (d, 1H), ! 6.89 - 6.82 (m, 2H), 6.56 (d, 1H), NH sub Z 4.18 (t, 2H), 2.90 (t, 2H), 2.85 (t, : 3H), 2.82 - 2.76 (m, 1H ), 2.66 - 2.59 (m, 4H), 2.10 (s, 3H), 1.25 - 1.08 (m, 6H), 0.90 - 0.81 (m, 2H),

YAAY i £ - 0.79 - 0.72 (m, 2H), 0.60 - 0.55 (m, 2H £ (CD30D) 7.83 - 7.78 (m, 1H), 550 vid i 7.65 (s, 1H), 7.58 (d, 1H), 7.46 (d, 1H), 7.29 (t, 1H), 7.02 (d, 1H), 6.97 (t, 1H), 6.86 (d, 1H), 6.75 (d, 1H), 4.40 (t, 2H), 3.91 (q, 2H), 3.84 - i 3.75 (m, 1H), 3.70 (t, 3H), 2.85 - As 2.76 (m, 1H), 2.50 - 2.36 (m, 2H), 2.17 (s, 3H), 2.01 (s, 1H), 1.56 -

I

1.46 (m, 1H), 1.45 - 1.31 (m, 2H), 1.22 - 1.12 (m, 1H), 0.80 - 0.71 (m, 2H), 0.61 - 0.55 (m, 2H) 5 3 (CD30D) 7.80 (d , 1H), 7.64 (5, 506 video 1H), 7.57 (d, 1H), 7.46 (d, 1H), 7.31 - 7.23 (m, 1H), 7.03 - 6.93 (m,

H

N

2H), 6.87 (d, 1H), 6.70 (d, 1H), YF 4.69 - 4.64 (m, 1H), 4.57 - 4.52 (m, 1H), 4.41 - 4.35 (m, 2H), 3.70 - 3.55 (m , 2H), 3.52 - 3.39 (m, 2H),

YAAY

a : : : ; i; i 1 - (m, 1H), 2.16 (s, 3H), 2.77 - 2.85 º : (s, 1H), 1.52 - 1.43 (m, 1H), 2.01 ; (m, 3H), 1.19 - 1.10 (m, 1.24 - 1.40 ! 2H), 0.77 (d, 2H), 0.63 - 0.54 (m, { 2H i (s, 1H), 8.45 (s, 1H), 8.27 (s, 516 ven 9.03 1H), 7.85 (d, 1H), 7.75 (s, 1H), 0 (d, 1H), 7.45 (d, 2H), 7.23 - 7.63 (m, 2H), 6.94 - 6.77 (m, 2H), 7.12 : H : (m, 2H), 3.57 - 3.33 (m, 4.15 - 4.36 i 2H), 2.91 - 2.74 (m, 4H), 2.13 (s, i 3H), 1.83 - 1.71 (m, 1H), 1.51 - !(m, 4H), 1.06 - 0.87 (m, 2H), 1.19 : (m, 3H), 0.68 - 0.50 (m, 0.71 - 0.80 ; : 4H (d, 1H), 9.44 (s, 1H), 7.84 (d, 528 vey 8.37 1H), 7.68 (s, 1H), 7.61 (d, 1H), ® N : B2 - 7.04 (d, 1H), 7.26 (t, 1H), 7.46 (m, 1H), 6.94 (t, 1H), 6.87 (d, 6.98 to 1H), 6.73 (d, 1H), 4.39 - 4.31 (m, YAAY +

7.7 2H), 3.88 - 3.29 (m, 2H), 2.90 - 2.76 (m, 1H), 2.30 - 2.13 (m, 2H), 2.07 (s, 3H), 2.03 - 1.77 (m, SH), 1.72 - 1.46 (m, 2H), 1.31 (d, 3H), 1.14 - 0.99 (m, 2H), 0.73 - 0.60 (m, 2H), 0.55 - 0.48 (m, 2H (CD30D) 7.78 (d, 1H), 7.63 - 514 YEA 7.60 (m, 1H), 7.52 (d, 1H), 7.43 (d, 1 1H), 7.22 (t, 1H), 6.97 - 6.89 (m, ag x 2H), 6.89 - 6.85 (m, 1H), 6.64 - 6.60 (m, 1H), 4.30 - 4.25 (m, 2H), 3.82 - 3.72 (m, 1H), 3.49 - 3.40 (m, 2H), 3.38 - 3.33 (m, 1H), 2.83 - 2.75 (m, 1H), 2.19 - 2.09 (m, SH), 2.08 - 1.98 (m, 2H), 1.80 - 1.69 (m, 2H), 1.47 - 1.34 (m, 111), 1.33 - 1.18 (m, 2H) ), 1.17 - 1.10 (m, 1H), 1.05 - 0.97 (m, 1H), 0.88 - 0.81 (m, 1H), 0.79 - 0.72 (m, 2H), 0.60 - 0.53 (m, 2H)

YAAY

z 8.34 (1H, 5), 7.82 (1H, d), 7.66 518 v4 , (1H, s), 7.48 (1H, d), 7.43 (1H, d), 7.32 (1H, 5), 7.17 ( 1H, 1), 6.93 (1H, z d), 6.86 - 6.81 (2H, m), 6.67 (1H, d), 4.52 - 4.43 (1H, m), 4.11 - 3.95 H (2H, m), 3.41 - 3.13 (41, m), 3.03 - and b OH 2.86 (2H, m), 2.85 - 2.77 (1H, m), 2.73 - 2.63 (1H, m), 2.03 (3H, 5), 1.24 - 0.96 (2H, m), 0.92 (3H, d), 0.68 - 0.61 (2H, m), 0.54 - 0.47 (2H, m 8.35 (d, 1H), 7.84 (dd, 1H), 7.67 (d, | 518 Yo. 1H), 7.50 (dd, 1H), 7.46 (d, 1H), 7.41 (s, 1H), 7.19 (td, 1H), 6.95 (d, 1H), 6.88 - 6.83 (m, 2H), 6.69 (d, 1 3 1H), 4.05 (t, 2H), 3.44 (t, 2H), 2.93 yO z (t, 2H), 2.82 (octet, 1H), 2.66 (t, 2H), 2.06 (s , 3H), 1.56 (quintet, º ' 2H), 1.23 - 1.13 (m, 3H), 1.06 - º 1.01 (m, 1H), 0.69 - 0.64 (m, 2H),

YAAY

— NN 8.33 (d, 1H), 7.82 (dd, 1H), 7.65 (d, 460 vol 1H), 7.47 (dd, 1H), 7.44 - 7.42 (m, 2H), 7.17 (td, 1H) , 6.91 (d, 1H), 6.84 - 6.81 (m, 2H), 6.67 (d, 1H),

NH, 3.94 (t, 2H), 2.91 (t, 2H), 2.80 14 (octet, 1H), 2.03 (s, 3H), 1.21 - 1.14 (m, 3H), 1.03 - 1.00 (m, 1H), 0.66 - 0.62 (m, 2H), 0.52 - 0.48 (m, 2H) (YoY) Example N-Cyclopropyl-3-[3-[[1-[2-[2-(ethylamino)ethoxy]phenyl]- 1-methylethyl Jamino]-2-0Xo0- 1(2H)-pyrazinyl]-5-fluoro-4-methyl-benzamide

Ne 0 ZN id

A A

N N

H H

0

F°

YAAY iee 01 — 2-Chloro-5-fluoro-4-methyl-benzoic acid methyl ester (1)

To a solution of Ve (g) dissolved in (Jo £04) ethyl acetate was added: '

: ml); 111( N,N-diisopropylethylamnie dichloro[1,1"-bis(diphenylphosphino)ferrocene]palladium(Il) dichloromethane

© (0.00 g) (VY) methanol s ml). The reaction mixture was stirred at 00°C for yE under (bar) atmosphere in a 58 Luther autoclave. Another amount of ¢ ) carbon monoxide was added as a result of 1 "_bis(diphenylphosphino)ferrocene]palladium(Il) dichloromethane

Add Y,0V (g) and the reaction mixture was heated at 90 C for ? other hours. The cooled reaction mixture was evaporated to dryness and the residue was purified by Sl chromatography and filtered using 756

dichloromethane Ye in iso-hexane to yield the subtitle compound (7,7© g). a

1H NMR § (DMSO-d6) 7.64 - 7.50 (m, 2H), 3.90 (s, 3H), 2.31 (s, 3H).

i 2-Chloro-5-fluoro-4-methylbenzoic acid (<=)

A solution of 2-chloro-5-fluoro-4-methyl-benzoic acid (eg {YoY /la,/a©g) was treated in

| in an atmosphere of (Je YA) molar ¥ sodium hydroxide using a solution of (Je £ + +) methanol

m for an hour. The reaction mixture was extracted using Yo, and the resulting mixture was stirred at .00 \o

| Yo) molar Y hydrochloric acid (excluded) and the aqueous layer was diluted with diethyl ether

ml). The reaction mixture was extracted using ethyl acetate (000 ml). Layers i were dried

Yaay

The combined organic (MgSO4), filtration and evaporation to obtain the subtitle compound (0027) 1H NMR & (DMSO0-d6) 13.66 (s, 1H), 7.68 - 7.39 (m, 2H), 2.36 (s, 3H). (c) 2-Chloro-5-fluoro-4-methyl-3-nitro-benzoic acid © The 2-chloro-5-fluoro-4-methylbenzoic acid solution was treated (example ©),0V « YoY g) dissolved in concentrated sulfuric acid (Je VEY) using potassium nitrate (77.4 g) part by part for 10 minutes at zero 1 in a nitrogen atmosphere and the resulting mixture was allowed to warm to Room temperature before stirring at 00 C for 1 hour. The reaction mixture was quenched by adding ice water and the precipitate was collected and dried in vacuo to obtain the subtitle compound (PEN 10,0).

IHNMR 5 (DMSO-d6) 7.94 (d, 1H), 2.26 (s, 3H). Ve 2-Chloro-5-fluoro-4-methyl-3-nitro-benzoic acid methyl ester ( 3) dallas a solution of (Je Y + +) chlorotrimethylsilane in (Ja Yo +) methanol was made using 2-chloro-5-fluoro-4-methyl-3-nitrobenzoic acid (ex. YoYC; 10.0 g) part by part in nitrogen atmosphere The resulting solution was stirred at 71 °C for 17 an hour. Another © amount of (de 001( chlorotrimethylsilane) was added and the reaction mixture was heated at ov C for 7 hours. The reaction mixture was evaporated to obtain the crude product which was diluted with water and extracted with ethyl Tv +) acetate Ml). The organic layer (MgSO4) was dried, filtered, and evaporated to yield the subtitle compound (57.4 g). ‎YAAYi

1i

¢

Uh 1H NMR 5 DMSO-d6) 7.99 (d, 1H), 4.00 (s, 3H), 2.35 (s, 3H).

3 3-Amino-5-fluoro-4-methyl-benzoic acid methyl ester (e) oy (example "mad 2-Chloro-5-fluoro-4-methyl-3-nitro-benzoic acid methyl ester") i was stirred at (J—©+ +) ethanol together in (a>A+) ammonium formate (a>9) PAIC 70 «(p>

© #Lam for TY 1 hour. The reaction mixture was filtered through celite and the filtrate was evaporated to a solid. This solid was dissolved in cdichloromethane and washed with water. layer has been extracted ;

Also using (Sa Yeo X 9 dichloromethane) and drying and evaporating the combined organic layers (048504). The analysis showed the presence of a large amount of unreacted starting material. It was repeated

Reaction by 5 / Pd/C (4 g) 5 (A+) ammonium formate g) together in ethanol (+0 g) 9) Pd/C / ° h. Ye mm was added again for Yo and heated at (Ja Ye the mixture was filtered within 0 hours 10g) and continued heating for Ae) ammonium formate The collected filtrate was evaporated; Dissolve the celite ethanol and wash the filter paste with more water and wash it. The separated aqueous layer was then extracted with the remaining dichloromethane and the combined organic layers (504p/0 (Je 001 XT) dichloromethane were dried using

. g) Ye, and evaporated to obtain the subtitle compound (No Yo 1H NMR § (CDCI3) 7.15 (s, 1H), 7.12 (dd, 1H), 3.88 (s, 3H), 2.10 (d, 3H) 3-[(Cyanomethyl)amino]-5-fluoro-4-methyl-benzoic acid, methyl ester (Z)

to a stirred solution of 3-amino-5-fluoro-4-methyl-benzoic acid methyl ester (ex.

7 AH No,quot; g) in (Je Yor) THF at room temperature was added: YAAY a “(Je Y£,£1) acetonitrile sbromo was added, then (Je 1),Y) NN-diisopropylethylamnie acetonitrile sbromo was added hour; Added another amount of 01 Heat the mixture when returning for 1 hour! The heating continued for 7 hours. (Je 0",*( N,N-diisopropylethylamnie 5 (Je £,A) ml) 0 ) g 1 HCI The reaction mixture was cooled to room temperature and then concentrated. ml was added). This gives Some solid precipitate that was not dissolved. A+) and R010010:0 © were added to help identify the layers. The bottom organic layer containing (Jo Fev) water solid was separated and part of the water was separated and that part was washed organic matter using 1 M HCI/i aqueous solution (£00 mL of a 1:1 mixture) prior to drying (0/8804). A second drying (Na2S04) was required after separation of the filter drying agent ( It was washed with 500 ml (dichloromethane 001) and then the filtrate was concentrated (about 0 PEN Te then the product was azeotropic distilled using toluene ) in ml) and the final removal of the solvent was given as the subtitle compound (4,4?g). ‎ 1H NMR 5 (CDCI3) 7.30 (d, 1H), 7.17 (s, 1H), 4.24 (d, 2H), 4.15 - 3.99 (m, 1H), 3.92 (s, 3H), 2.12 (s, 3H) : (0) 3-(3,5-Dibromo-2-oxo-2H-pyrazin-1-yl)-5-fluoro-4-methyl-benzoic acid, methyl ester 0 to a stirred solution of (Jo £9 ,4) oxalyl bromide in (J— T+ +) dichloromethane at 0. Nitrogen induces added: 3-[(cyanomethyl)amino]-5-fluoro-4-methyl-benzoic acid methyl ester ( sYoY 64? g) for 11 minutes. The mixture was allowed to warm to room temperature and stir for 0

YAAY

18 — min (Je +, VO) DMF was added and the mixture was heated for VT 1 hour on reflux. after cooling to zero m; Water (Ja Tov) was added for 11 minutes (caution) and then the organic layer was separated; dried (MgSO4) and evaporated. The residue was purified (8:02 chromatography and eluted with (dichloromethane to yield subtitle product EA) g). 1H NMR 6 (DMSO0-d6) 8.11 (s, 1H), 7.94 (s, 1H), 7.85 (dd, 1.5 Hz, 1H), 3.88 (s, 3H), 8 (d, 3H) 2.11 (h): 3-[5-Bromo-3-[[ 1-methyl-1-[2-(phenylmethoxy)phenyl]ethyl] amino]-2-oxo-1(2H)- pyrazinyl]-5 -fluoro-4-methyl-benzoic acid, methyl ester Vo was then treated with a solution of: a,0-dimethyl-2-(phenylmethoxy)-benzenemethanamine (ex. 4 Ed 5.19 g) dissolved in (Je 0 ) dioxane using: 3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-5-fluoro-4-methyl-benzoic acid, methyl ester (eg (Je©, 09) NN-diisopropylethylamnie 5 (04.5 ax “YOY”) in nitrogen atmosphere The resulting solution was stirred at 100 C for 10 hours. The reaction mixture was diluted with water (+0 ml); 0 and extracted with ethyl acetate (001) ml L(Y X) The organic layer “(MgSO04) was dried, filtered and evaporated. The crude product was purified using chromatography 2 and eluting with ethyl acetate AR at 0606-190 ) for subtitle product 000(g). MS: APCI(+ve) 580 M+H)+. YAAY

©101- (i): Z 3-[5-Bromo-3-[[1-methyl-1-[2-(phenylmethoxy)phenyl] ethyl]amino]-2-oxo-1(2H)- pyrazinyl]- N-cyclopropyl-5-fluoro-4-methyl-benzamide A solution of: E3-[5-bromo-3-[[1-methyl-1- [2-(phenylmethoxy)phenyl]ethyljamino]-2-oxo0- was stirred 1(2H)- 8pyrazinyl]-5-fluoro-4-methyl-benzoic acid, methyl ester

V,1Y)amine cyclopropyl ml) using THF (V+ +) g) dissolved in #01 YOY (example

J

Molar THF in 1 7 ml of a solution (isopropylmagnesium chloride) was added dropwise for 10 minutes in a nitrogen atmosphere. The resulting solution was stirred at Yom for an hour. ml) and extract it “0 (saturated ammonium chloride) dilute the reaction mixture using solution 01, filter and evaporate it. Then crush (MgS04) times). Then dry the organic layer (¥) ethyl acetate of the crude product using diethyl ether and its nomination to obtain the subtitle compound (4,A%) (g). ), 5.15 (s, 2H), 4.08 - 3.98 (m, 1H), 2.01 - 1.93 (m, 3H), 1.87 (s, 6H), 0.74 - 0.67 (m, 2H), ~~ 1° 0.59 - 0.52 (m, 2H).: (j) N-cyclopropyl-3-fluoro-5-[3-[[1-(2-hydroxyphenyl)-1-methylethyl Jamino]-2-oxo- 1(2H) -pyrazinyl]-4-methyl-benzamide: to 0YAAY

! TV — — 3-[5-bromo-3-[[1-methyl-1- [2-(phenylmethoxy)phenyl]ethylJamino]-2-oxo-1(2H)-pyrazinyl]-N- cyclopropyl-5 -fluoro-4-methyl-benzamide (ex. caYOY 9.84 g) added Pd/C 701 (4 g) and ammonium formate (£1.70 g). The reaction mixture was heated at VO C for 2 hours, then filtered through celite and washed with ethanol©. The filtrate was collected, the volatiles were removed in vacuo, and the resulting crude product was taken in dichloromethane and washed with water. The organic layer (MgSO4) was dried and the solvent removed! in vacuo and pulverized the residue with diethyl ether to yield subtitle product 1 A (no g). 1H NMR 5 (DMSO-d6) 9.56 - 9.46 (m, H), 8.58 - 8.48 (m, 111), 7.76 (d, 1H), 7.71 (s, 1H), 7.24 (d, 1H), 7.07 - 6.97 (m, 2H), 6.81 - 6.65 (m, 4H), 2.90 - 2.77 (m, 1H), 2.03 (s, Ve 3H), 1.87 - 1.80 (m, 6H), 0.74 - 0.67 ( m, 2H), 0.63 - 0.53 (m, 2H). 2H)-pyrazinyl]-N- cyclopropyl-5-fluoro-4-methyl-benzamide 59 A solution was treated with: N-cyclopropyl-3-fluoro-5-[3-[[1-(2- hydroxyphenyl)-1 -methylethyl[amino]-2-oxo0-1(2H)- pyrazinyl]-4-methyl-benzamide 3 A

11 - potassium carbonate with (Ja 050( acetonitrile g) dissolved in Vio A gYOY (eg | nitrogen suspension was stirred in an atmosphere of (Je VV,00 ) 1-bromo-2- chloroethane 5 g) YY, €Y )

Yoo) hours. The reaction mixture was evaporated to dryness, filtered with water 01 for 1 AY, the yield was evaporated (MgSO04) and the organic layer dichloromethane (ml) was dried and extracted using 'at p0' 190-6 to obtain on diethyl ether 756 The crude product was pulverized with © subtitle (1.88 g). 1H NMR 5 (DMSO0-d6) d 8.57 - 8.48 (m, 1H), 7.76 (d, 1H) , 7.68 (s, 1H), 7.37 - 7.31 (m, ° 1H), 7.25 - 7.17 (m, 1H), 6.98 - 6.90 (m, 3H), 6.70 (s, 2H), 4.26 - 4.15 (m, 2H ), 4.01 - 3.90 (m, 2H), 3.43 - 3.35 (m, 1H), 2.03 (s, 3H), 1.90 (s, 6H), 0.74 - 0.66 (m, 2H), 0.60 - 0.52 (m, 2H) ). 1 : (l) N-Cyclopropyl-3-[3-{[1-[2-[2-(ethylamino)ethoxy]phenyl]-1 -methylethyl]amino]-2-oxo- 1( 2H)-pyrazinyl]-5-fluoro-4-methyl-benzamide : a suspension of 3-[3-[[1-[2-(2-chloroethoxy)phenyl]-1-methylethyl]amino]-2 was treated -oxo-1(2H)-pyrazinyl]-N- \o cyclopropyl-5-fluoro-4-methyl-benzamide 0

Y ) amine ethyl ZV mL) using Y ) dioxane 1-4 (eg 0,000 g) dissolved in 1 001 microwave for 1 hour in a tightly sealed tube. The resulting mixture was stirred at (Ja 1

Waters X-Terra Prep (Column HPLC after evaporation and purification with 0 W) Year ) i

YAAY

a! TAY - - i using a gradient of 759-495 of 70.7 45a ammonia in acetonitrile as a lye) and then obtaining the title compound (p> .,Yoo. MS: APCI) +ve) 508 (M+H)+.1H NMR 5 (DMSO0-d6) 8.57 (s, 1H), 7.75 (d, 2H), 7.69 (s, 1H), 7.40 - 7.29 (m, 1H) , (m, 1H), 6.98 - 6.86 (m, 3H), 6.73 - 6.62 (m, 2H), 4.10 - 3.88 (m, 2H), 3.42 - © 7.13 - 7.24 (m, 1H), 2.91 - 2.79 (m, 2H), 2.04 (s, 3H), 1.89 (s, 6H), 0.92 - 0.80 (m, 5H), 0.76 - 3.24 (m, 2H), 0.61 - 0.48 (m, 2H) 0.64 The following examples (YOA-YeT) (Table 01) were prepared in a manner similar to the (YOY) example (Yor) N-Cyclopropyl-3-fluoro-5-[3- [[1-[2-[2-[(2-hydroxyethyl)amino] ethoxy]phenyl]-1- Vo methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide Example (Yot¢ ) N-Cyclopropyl-3-fluoro-4-methyl-5-[3-[[ 1-methyl-1-[2-[2- [(1-methylethyl)amino] 1 ethoxy[phenyl] ethyllamino]-2-oxo-1(2H)-pyrazinyl]-benamide Example (Yoo) N-Cyclopropyl-3-fluoro-5-[3-[[ 1- [2-[2-[(2-methoxyethyl)amino] ethoxy]phenyl]-1- methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

15 - (Yer ) Example N-Cyclopropyl-3-fluoro-5-[3-[[1-[2-[2-[ [(2R)-2-hydroxypropylJamino]ethoxy]phenyl]- 1-methylethyl [amino]-2-oxo-1(2H)-pyrazinyl] -4-methyl-benzamide (Yov ) Ex. N-Cyclopropyl-3-fluoro-5-[3-[[1-[2-[2 - [(2-hydroxy-2-methylpropyl)amino] ° ethoxy]phenyl]-1-methylethylJamino]-2-oxo-1 (2H)-pyrazinyl]-4-methyl-benzamide (YoA) Example N- Cyclopropyl-3-fluoro-5-[3-[[1-[2-[2-[[(2S)-2-hydroxypropyl] amino ]ethoxy|phenyl]-1- methylethyl]Jamino]-2-oxo-1 (2H)-pyrazinyl]-4-methyl-benzamide

YAAY

—Y\o — (V+) table | 7 0 2 0 L A N

N N

H H

0

MS

1H NMR. § (DMSO-d6) [M-+H]+ Example | m/z 8.57 - 8.44 (m, 1H), 7.81 - 7.68 (m, 524 voy 1H), 7.68 (s, 1H), 7.37 - 7.27 (m, 1H), 7.23 - 7.13 (m, 1H), 7.00 - 6.83 (m, 3H), 6.71 - 6.59 (m, 2H), OH

H

4.44 - 4.31 (m, 1H), 4.01 - 3.88 (m, ~N an 2H), 3.46 - 3.33 (m, 2H), 2.93 - 2.80 (m, 3H), 2.65 - 2.52 (m, 2H), 2.04 ( s, 3H), 1.88 (s, 6H), 0.76 - t 0.64 (m, 2H), 0.60 - 0.48 (m, 2H) 8.57 - 8.48 (m, 1H), 7.76 (d, 1H), Yo ; 522 J

H

7.70 - 7.61 (m, 2H), 7.38 - 7.31 (m, 1 1H), 7.23 - 7.15 (m, 1H), 7.02 -

YAAY

6.86 (m, 3H), 6.74 - 6.64 (m, 2H), 4.03 - 3.87 (m, 2H), 2.95 - 2.79 (m, 3H), 2.77 - 2.61 (m, 1H), 2.05 - 1.93 (m, 3H) ), 1.90 - 1.78 (m, 6H), 0.96 - 0.85 (m, 6H), 0.77 - 0.65 (m, 2H), 0.61 - 0.50 (m, 2H) { 8.54 - 8.45 (m, 1H), 7.79 - 7.69 (m, Yoo 538 1H), 7.68 - 7.58 (m, 1H), 7.37 - 7.27 (m, 1H), 7.22 - 7.13 (m, 1H), 6.99 - 6.83 (m, 3H), 6.72 - 6.60 (m, 0 2H), 4.03 - 3.88 (m, 2H), 3.38 -

Ho \ 3.28 (m, 2H), 3.20 - 3.10 (m, 3H), in 2.91 - 2.81 (m, 3H), 2.70 - 2.60 (m, 2H), 2.05 (s, 3H), 1.88 (s, 6H) , 0.76 - 0.66 (m, 2H), 0.59 - 0.49 (m, 2H 8.55 - 8.49 (m, 1H), 7.75 (d, 1H), 538 vol 7.67 (s, 1H), 7.32 (d, 1H), 7.22 - 77 x 7.16 (m, 1H), 6.99 - 6.86 (m, 3H), A 6.71 - 6.64 (m, 2H), 4.37 - 4.30 (m, 1H), 4.02 - 3.89 (m, 2H), 3.63 -

YAAY

117 - 3.56 (m, 1H), 2.90 - 2.83 (m, 3H), 2.43 (d, 2H), 1.96 (s, 3H), 1.87 - 1.81 (m, 6H), 0.97 (d, 3H), 0.72 - 0.66 (m, 2H), 0.59 - 0.53 (m, 2H 8.55 - 8.48 (m, 1H), 7.74 (d, 1H), ss Yoy 7.61 (s, 1H), 7.33 (d, 1H), 7.24 - 7.15 ( m, 1H), 7.01 - 6.84 (m, 3H), m (m, 2H), 4.05 (s, 1H), 6.62 - 6.72 H N (m, 2H), 2.95 - 2.82 ( m, N 3.90 - 4.03 dun 3H), 2.39 (s, 2H), 1.96 (s, 3H), 1.81 (s, 6H), 1.01 (s, 6H), 0.73 - 0.67 (m, 2H), 0.58 - 0.53 (m, 2H) 8.56 - 8.46 (m, 1H), 7.76 (d, 1H), i.Yo 7.62 (s, 1H), 7.32 (d, 1H), 7.22 - 7.15 (m, 1H), 6.97 - 6.86 (m, 3H), 6.70 - 6.65 (m, 2H), 4.37 - 4.33 (m, WOH 1H), 4.02 - 3.90 (m, 2H), 3.63 - L 3.55 (m, 1H), 2.91 - 2.82 (m, 3H), de 2.43 (d, 2H), 2.02 (s, 3H), 1.85 - 1.80 (m, 6H), 0.97 (d, 3H), 0.72 - 0.66 (m, 2H), 0.58 - 0.53 (m, 2H

YAAY

— TVA — ( 7-4 ) Ex. N-Cyclopropyl-3-fluoro-4-methyl-5-[3-[[1-[2- [2-(methylamino)ethoxy]phenyi] cyclopropyl]amino] -2-oxo-1(2H)-pyrazinyl]-benzamide “ 1 0 ZN 0

N “Re

SCY

0 sah 1:)( oe 3-[5-bromo-2-0x0-3-[[1-[2-(phenylmethoxy)phenyl] cyclopropyl]amino]-1(2H)- pyrazinyl]-5 -fluoro-4-methyl- benzoic acid, methyl ester. A solution of: 1-(2-(benzyloxy)phenyl)cyclopropanamine (ex. t © g) in 001 (dioxane mL) was treated with: Ye 3 -(3,5-dibromo-2-oxo0-2H-pyrazin-1-yl)-5-fluoro-4-methyl-benzoic acid, methyl ester nitrogen was obtained under (Je©,Y7) N -ethyldiisopropylamine (p > 1.5 g; YOY (eg HCI h). The cooled reaction mixture was diluted with A for 100 m with the resulting solution stirred at mL). The organic layers were dried. 7001 X FY) ether and extracted by (Ja Yer) ? molar after purification (chromatography 0. Filtering and evaporation to obtain a crude product “(MgS04) collected Yo L

A compound (iso-hexane in ethyl acetate AX) was obtained and eluted with 2 subheading (1.7 g). 1H NMR 5 (DMSO-d6) 7.82 - 7.76 (m, 2H), 7.59 - 7.49 (m, 3H), 7.41 - 7.26 (m, 3H), 7.24 - 7.15 (m, 1H), 7.06 - 6.98 (m, 2H), 6.89 (t, 1H), 5.22 (s, 1H), 3.85 (s, 2H), 3.31 (s, 3H), 2.03 (d, 3H), 1.25 - 1.07 (m, 4H). 8 ]: (b)z 3-Fluoro-5-[3-[[1-(2-hydroxyphenyl)cyclopropyl]amino]-2-oxo-1 (2H)-pyrazinyl]-4- methyl - benzoic acid, methyl ester : to 3-[5-bromo-2-oxo0-3-[[1- [2-(phenylmethoxy)phenyl]cyclopropylJamino]-1(2H)- 01 pyrazinyl]-5 fluoro-4-methyl-benzoic acid, methyl ester

V¢,+ £) ammonium formate (Je €+ +) ethanol was added at (p>57 dyed (ex. g). The reaction was heated at 70 C for 1 hour; filtered through , 197 (PAC 7700g) dichloromethane and then (Je 001) warm ethanol celite and washing the celite with another amount of \ ++ +) dichloromethane and the combined filtrate was evaporated; diluted by adding (Jo 0001 (0 ml) and washed with water, dried (048504) and evaporated to obtain the subtitle compound (g).

IH NMR 5 (DMSO-d6) 11.23 (s, 1H), 7.85 - 7.73 (m, 2H), 7.48 - 7.42 (m, 1H), 7.16 - 7.04 (m, 1H), 6.91 - 6.86 (m, 1H) , 6.83 - 6.67 (m, 3H), 5.75 (s, 1H), 3.85 (s, 3H), 2.03 (s, 3H), 1.32 - 1.16 (m, 2H), 1.12 - 1.01 (m, 2H). (c) N-Cyclopropyl-3-fluoro-5-[3-[[1 -(2-hydroxyphenyl)cyclopropyl]amino]-2-oxo-1(2H)-©pyrazinyl]-4-methyl -benzamide (THF for (THF mL of ¥ Ml solution in 1 (isopropylmagnesium chloride mL) and 10.11 (amine cyclopropyl min) was added to 0 mL solution) 001 (tetrahydrofuran g) in 1.17" aod (eg Isopropylmagnesium chloride for 1 h. nitrogen was carefully added and the reaction was stirred at room temperature in an atmosphere of 1 µl Ve ml) and the aqueous layer was extracted with 100 (?molar) HCL (Lm001) water, drying of the combined organic extract (804p/0) (Jo Yoo X ¥) dichloromethane, and removal of the solvent to obtain the subtitle compound (©g). 1H NMR 5 (DMSO0-d6) 11.14 (s) , 1H), 8.52 (s, 1H), 8.46 (d, 1H), 7.74 (dd, 1H), 7.64 (s, 1H), 7.46 (dd, 1H), 7.13 - 7.08 (m, 1H), 6.91 ( d, 1H), 6.82 - 6.72 (m, 3H), 2.88 - 2.78 1 (m, 1H), 1.99 (d, 3H), 1.30 - 1.20 (m, 2H), 0.88 - 0.79 (m, 2H), 0.70 - 0.63 (m, 2H), 5 - 0.50 (m, 2H).

YAAY i ; 1 - 771 - : (d)] 3-[3-[[1-[2-(2-chloroethoxy)phenyl]cyclopropyl] amino]-2-oxo-1(2H)-pyrazinyl]-N- cyclopropyl-5-fluoro-4-methyl-benzamide : stirred

N-Cyclopropyl-3-fluoro-5-[3-[[1 -(2-hydroxyphenyl)cyclopropyl]amino]-2-oxo-1(2H)- °pyrazinyl]-4-methyl-benzamide ¥V,0) Cesium carbonate s (Je 8 A) 1-bromo-2-chloroethane s (px © zYoA ) (eg. nitrogen was evaporated for 11 hours in an atmosphere of 5 A+ at (Ja 001) acetonitrile g) together in dichloromethane: extract (Jo 0+ +) reaction mixture cooled to dryness”; and dilute it with water (ml): Yeo X ¥) Yo. filtration and evaporation. The residue (MSO4) was pulverized. The combined organic layers were dried to yield the subtitle compound (4.6 g). diethyl ether : iso-hexane 1 : 1 using 1H NMR 5 (DMSO-d6) 8.45 (d, 1H), 7.72 (d, 1H), 7.60 (s, 1H), 7.51 (d, 1H), 7.27 (s, 1H), 7.24 - 7.16 (m, 1H), 7.00 - 6.84 (m, 2H) ), 6.75 (d, 1H), 4.30 (t, 2H), 4.00 (t, 2H), 2.93 - 2.77 (m, 1H), 1.95 (s, 3H), 1.31 - 1.02 (mm, 4H), 0.75 - 0.62 (m, 2H), 0.58 - 0.47 1 (m, 2H). (e): oxo-1(2H)-pyrazinyl]-benzamide : A

YAAY

7717 - 3-[3-[[1-[2-(2-chloroethoxy)phenyl]cyclopropyljamino] -2-0x0-1(2H)-pyrazinyl]-N- cyclopropyl-5-fluoro-4 -methyl-benzamide (ex. amine methyl Leng (an .,# caved in +,19Y) water mL) at 100 M in dioxane A mL) Jala sealed tube for 74 hours. After purification of the cooled solution with preparative © HPLC (column 86 - mobile phase (ammonia ZY [acetonitrile]) it was obtained

Title compound (0 mg). 1H NMR 5 (DMSO-d6) 8.45 (1H, d), 7.73 (1H, d), 7.60 (1H, s), 7.52 - 7.47 (2H, m), (1H, m), 6.95 (1H , d), 6.89 - 6.82 (2H, m), 6.73 (1H, d), 4.05 (2H, 1), 2.89 7.15 - 7.23 (2H, 1), 2.85 - 2.77 (1H, m), 2.35 ( 3H, 5), 1.96 (3H, d), 1.25 - 0.97 (4H, m), 0.73 - 0.62 (2H, m), 0.57 - 0.48 (2H, m). Vo ex. (Y1+) N-Cyclopropyl-3-fluoro-5-[3-[[1-[2-[2- [(2-hydroxyethyl)amino] ethoxy]phenyl]cyclopropyl] amino] -2-oxo-1(2H)-pyrazinyl] -4-methyl-benzamide 1 J ead 0 COTE H H 0 : heated: YAAY

A: | 71 - E 3-[3-[[1-[2-(2-chloroethoxy)phenyl]cyclopropyl] amino]-2-oxo-1(2H)-pyrazinyl]-N- cyclopropyl-5-fluoro-4 -methyl-benzamide in (J— Y+) dioxane mv 001 at (Je 1) amine ethanol s (a> © 51049 Ji) 11 hr. sealed tube for preparative period (column 8, filtering using HPLC quantities, and after purifying the cooled solution using (©_aqueous) an ammonia product was obtained in 70.7 (v/v) acetonitrile graded from 1 1) diethyl ether | iso-hexane Title (95) , g) after removing the solvent and pulverizing with (Ja 0

MS: APCI(+ve) 522 (M+H)+. 1H NMR 5 (DMSO0-d6) 8.46 (1H, d), 7.73 (1H, d), 7.61 (1H, 5), 7.51 (1H, d), 7.43 (1H, Ve s), 7.19 (1H, 1) , 6.95 (1H, d), 6.92 - 6.80 (2H, m), 6.74 (1H, d), 4.44 (1H, s), 4.06 (2H, t), 3.51 - 3.43 (2H, m), 3.42 - 3.30 (1H, m), 2.97 (2H, 1), 2.90 - 2.77 (1H, m), 2.69 (2H, t), 1.97 3H, s), 1.27 - 1.01 (4H, m), 0.75 - 0.63 (2H, m), 0.57 - 0.50 (2H, m). and 160): Y04) in a manner similar to examples 11 (Table (Y10-Y1Y) The following examples were prepared 0 (Y WN ) Example N-Cyclopropyl-3-fluoro-5-[3 -[[1-[2-[2-[(2-methoxyethyl)amino] ethoxy]phenyl] cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl] -4-methyl-benzamide AA

Example) in particular

N-Cyclopropy!-3-[3-[[1-[2-[2 -(ethylamino)ethoxy]phenyl]cyclopropyl] amino]-2-0xo- 1(2H)-pyrazinyl]-5-fluoro-4- methyl-benzamide ( YA ¥) Example N-Cyclopropyl-3-fluoro-5-[3-[[1-[2-[2-[[(2S)-2-© hydroxypropyl}amino]ethoxy]phenyl ] cyclopropyl Jamino]-2-oxo-1(2H)-pyrazinyl]-4- methyl-benzamide ( 746 ) Example N-Cyclopropyl-3-fluoro-4-methyl-5-[3-[[1- [2-[2-[(1 -methylethyl)amino] ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1 (2H)-pyrazinyl]-benzamide Yo (Yo) Example N-Cyclopropyl-3- fluoro-5-[3-[[1-[2-[2-[ [(2R)-2-hydroxypropyl]amino] ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]- 4-methyl-benzamide

YAAY

º 170 — (11) Table 7 i | iN 0 “ 0 7 0 a 0 a !

MS

1H NMR. § (DMSO0-d6) [M+H]+R Example z 0 8.47 (1H, d), 7.75 (1H, d), 7.63 536 75 (1H, 5), 7.51 (1H, d), 7.42 (1H, 5), 7.20 (1H, 1), 6.96 (1H, d), 6.92 - 6.83 (2H, m), 6.75 (1H, d), 4.07 1 (2H, 1), 3.40 (3H, 1) ), 3.00 - 2.94 Mg (2H, m), 2.90 - 2.81 (1H, m), 2.76 (2H, 1), 1.98 (3H, 5), 1.20 (3H, 5), 1.13 - 0.78 (4H, m) , 0.74 - 0.64 2H, m), 0.60 - 0.49 (2H, m 8.45 (1H, d), 7.73 (1H, d), 7.61 506 yay (1H, s), 7.52 - 7.42 (2H, m), 7.19 ( 1H, 1), 6.95 (1H, d), 6.91 - 6.81 (2H, m), 6.74 (1H, d), 4.05 (2H, 1), 0 2.94 (2H, 1), 2.89 - 2.78 (1H, m) ), kind 2.63 (2H, q), 1.97 3H, 5), 1.25 - 1.08 (4H, m), 1.00 (3H, 1), 0.72 - 0.63 (2H, m), 0.57 - 0.51 2H, m (1H, s), 7.49 (1H, dd), 7.39 (1H, d), % “oH z a

z 7.22 7.17 (1H, m), 6.96 (1H, d), 6.89 - 6.83 (2H, m), 6.73 (1H, d), 4.41 - 438 (1H, m), 4.10 - 4.02 (2H, m) ), 3.72 - 3.63 (1H, m), 2.98 - 2.91 (2H, m), 2.86 - 2.76 (1H, m), 1.96 (3H, 5), 1.25 - 1.13 (4H, m), 1.02 (3H, dd ), 0.88 - 0.80 (2H, m), 0.71 - 0.64 (2H, m), 0.56 - 9 (2H, m 8.44 (1H, d), 7.72 (1H, dd), 7.60 520 vit (1H, 5), 7.49 (1H, dd), 7.37 (1H, 5), 7.23 - 7.15 (1H, m), 6.95 (1H, d), 6.89 - 6.82 (2H, m), 6.74 (1H, d), H 4.04 (2H , 1), 2.94 (2H, 1), 2.88 - lap 217 2.73 (2H, m), 1.96 (3H, d), 1.20 - 1.16 (2H, m), 0.98 (6H, d), 0.87 - 0.80 (2H, m), 0.72 - 0.63 (2H, m), 0.57 - 0.49 2H, m 8.42 (1H, 5), 7.74 - 7.63 (1H, m), 536 Ye 7.61 - 7.54 (1H, m), 7.51 - 7.34 (2H, m), 7.20 - 7.07 (1H, m), 6.96 - 6.76 (2H, m), 6.74 - 6.66 (1H, m), 1 4.45 - 4.32 (1H, m), 4.08 - 3.95 Ag (2H , m), 3.72 - 3.56 (1H, m), 3.41 - 3.21 (1H, m), 3.02 - 2.71 (6H, m), 1.93 (3H, s), 1.27 - 0.88 (6H, m), 0.73 - 0.36 (4H, m

YAAY

(Y11) Example N-Cyclopropyl-3-[3-[[1-[2- [2-(ethylamino)ethoxy]phenyl]-1 -methylethyl]amino]-2-oxo- 1(2H)- pyrazinyl]-4-methyl-benzamide a 2 0

A Nn) J

CCC 0 7” 3,3-Diethyl-2(3H)-benzofuranone (1) 8 Y) Benzofuran-2(3H)-one g) in (Ja ¥,0) DMF was added dropwise to 761 ),YOY) sodium hydride g) in (Jo 01(DMF) at Safram and after 71 minutes; (Ja 51 A) ethyl ajiodo was added dropwise and the reaction mixture was warmed to room temperature and stirred The solids were separated by filtration and washed with acetate ata. and concentrated in vacuo. The crude product (‘) was purified by chromatography 5:02 and filtered using 178 (iso-hexane 2 diethyl ether) to yield: subtitle product (8 VV g). IH NMR 5 (DMSO-d6 ) 7.41 - 7.34 (m, 2H), 7.27 - 7.22 (m, 2H), 1.90 (dseptet, 4H), (t, 6H). Vo 0.58 i : YAAY

(b) Diethyl-2-hydroxy-benzeneacetamide — and a bright ammonia in 10 (methanol) was added to 3,3-diethyl- 2(3H)-benzofuranone Z (ex. YT 4 g) and the reaction mixture was stirred at room temperature for 11 hours. Then add (Je Yo) 480. ammonia and stir the mixture for a few hours. The reaction mixture © was diluted with water and extracted as ethyl acetate. The organic layer (MgSO4) was dried, filtered, and evaporated to yield a crude product (1 YY g). ') HNMR § (CDCI3) 7.47 - 7.44 (m, 1H), 7.40 - 7.35 (m, 1H), 7.00 - 6.93 (m, 2H), 5.10 (s, 2H), 2.19 (dt, 2H) , 1.93 (dt, 2H), 0.73 (t, 6H). (c) a «0. — Diethyl-2-(phenylmethoxy)-benzeneacetamide Ve A solution of “a - diethyl-2-hydroxy-benzeneacetamide” (eg “2Y11 (p> 0) in (Je 4,47) was treated ) DMF using *,A+VY) potassium carbonate g) 3 benzyl (Je +,19¢) bromide under nitrogen . The resulting mixture was stirred at room temperature for 1 hour. Then dilute the reaction mixture with water and extract it as ethyl acetate. The organic layer (MgSO4) was dried, filtered, and evaporated. The crude product (5:02 chromatography and 0 filtration with 1,6-3,6 ethyl acetate at 150-6806) was purified to yield MS subtitle product: APCI(+ve) 298 (M+H)+..). a> 0 YY) o «0. — diethyl-2-(phenylmethoxy)-benzenemethanamine (=) a solution of a co diethyl-2-(phenylmethoxy)-benzenemethanamine (ex. (p > VY z 1) was treated in (Je 1 ) acetonitrile and water (1 ml) using: ‎YAAY

1 ¥) (bis(trifluoroacetoxy)iodo)benzene g) under nitrogen and the reaction mixture was stirred at room temperature for 11 hours. Another amount of: (aa, +) (bis(trifluoroacetoxy)iodo)benzene was added and the reaction mixture was stirred for ? hours. The reaction mixture was diluted with water and ethyl acetate was extracted. The organic layer (MgS04)© was dried, filtered and evaporated. The crude product was purified on SCX resin, filtered with methanol (excluded) and then with 1 N 14113. The basal fractions were collected and the volatiles were extracted in vacuo to obtain the subtitle compound (AY 0 g). 1H NMR 5 (CDCI3) 7.43 - 7.34 (m, 7H), 6.98 - 6.94 (m, 4H), 5.12 (s, 2H), 2.13 (dt, 4H), (t, 6H) 0.74 Yo (2—) : 3-[3-[[1-[2-(2-Chloroethoxy)phenyl]-1-ethylpropylJamino] -2-o0x0-1(2H)-pyrazinyl]-N-cyclopropyl- 4-methyl-benzamide ca -Diethyl-2-(phenylmethoxy)-benzenemethanamine » (Example (AY) converted to: 'a N-cyclopropyl-3-[3-[[1-ethyl-1 -(2-hydroxyphenyl)propyl[amino] -2-0x0-1(2H)- pyrazinyl]-4-methyl-benzamide Vo + using the method described in Example (;71). : 1-bromo-2-chloroethane as described in Example (211) for a product! Subtitle. MS: APCI(+ve) 509 (MH). ' YAAY

_ 1s (5)

N-Cyclopropyl-3-[3-{[1-[2-[2-(ethylamino)ethoxy]phenyl]-1 -methylethyl]amino]-2-oxo- 1(2H)-pyrazinyl]-4-methyl- benzamide : the title compound was prepared from 3-[3-[[1-[2-(2-Chloroethoxy)phenyl]-1-ethylpropyl] amino]-2-oxo-1(2H)-pyrazinyl]-N- ° cyclopropyl-4-methyl-benzamide w.7 Vv) (Ex. 7e) using the example method 1H NMR 5 01450-06( 8.48 - 8.42 (m, 1H), 7.87 (d, 1H), 7.78 ( s, 1H), 7.48 (d, 1H), 7.29 (d, 1H), 7.23 - 7.16 (m, 1H), 7.01 - 6.88 (m, 3H), 6.67 - 6.61 (m, 2H), 4.01 - 3.89 ( m, 2H), 2.89 - 2.76 (m, 3H), 2.47 - 2.27 (m, 4H), 2.26 (s, 3H), 2.11 (s, 3H), 0.71 - 0.61 Yo (m, 8H), 0.57 - 0.52 (m, 2H).(YV) Example N-Cyclopropyl-3-[3-[[1-ethyl-1-[2- [2-(ethylamino)ethoxy]phenyl]propyl]amino]-2- oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

H

J; 0 2 0

N

16

H IH oo \o

YAAY

The title compound was prepared from 3-[3-[[1-[2-(2-chloroethoxy)phenyl]-1 -ethylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-N- cyclopropyl -4-methyl-benzamide ethyl JA Ye. a Method described in example (not 1 or but using ol (example 11 2¥—) using in water. © amine

MS: APCI(+ve) 518 (M+H)+. 1H NMR 5 (DMSO0-d6) 8.44 (d, 1H), 7.86 (d, 1H), 7.77 (s, 1H), 7.49 (d, 1H), 7.28 (d, 1H), 7.23 - 7.16 (m, 1H) ), 7.00 - 6.89 (m, 3H), 6.70 - 6.58 (m, 2H), 4.00 - 3.89 (m, 2H), 2.90 - 2.78 (m, 3H), 2.54 - 2.25 (m, 6H), 2.11 (s , 3H), 0.89 (t, 3H), 0.70 - 0.62 (m, 8H), 0.59 - 0.51 (m, 2H). Ye. ( YA) Example N-Cyclopropyl-4-methyl-3-[3-[[1-[2-[2-(methylamino) ethoxy]phenyl]cyclobutyl] amino]-2-oxo-1(2H) -pyrazinyl]-benzamide :

A

N

N H ~~: love N

H If H

NF0: YAAY

1 -(2-Methoxyphenyl)cyclobutanecarboxamide (1)

To -(2-methoxyphenyl)cyclobutanecarbonitrile 1 (g) sulfuric acid was added

m after one hour; 01 was heated and heated to (Je 01(ele)/794-455 (Ja 00) the mixture was 60 °C and heating continued for ¥ hours. The reaction mixture was cooled to room temperature

© and fried for 11 hours. Heating continued and after one hour V+ (acetic acid ml) was added.

The temperature was increased to Ae 5 and heating continued for 1.70 hours. The z reaction mixture was cooled

to room temperature and then pulverized in about 0.5 mL of ice and extracted with ethyl chloride

The solvent was removed in vacuo to obtain (Na204) and then the acetate organic layer was dried.

Subtitle product (£19g). z 1H NMR § (CDCI3) 8.44 (s, 2H), 7.27 (td, 1H), 7.23 (dd, 1H), 6.99 (td, 1H), 6.90 (d, 01 1H), 3.83 (s, 3H), 2.87 - 2.77 (m, 2H), 2.51 - 2.41 (m, 2H), 2.24 - 2.11 (m, 1H), 1.88 - 1.77 (m, 1H). 1-(2-(Benzyloxy)phenyl)cyclobutanecarboxamide (b) to 1-(2-methoxyphenyl)cyclobutanecarboxamide (eg JYAA 4 g) at 0 m in in Na) da tr, A) boron tribromide (Je Y +) dichloromethane Vo was added and the reaction mixture was warmed to room temperature for ¥ hours. And p (dichloromethane

in ice and extracted it using dichloromethane 9 times) and the organic layers were dried: the solvent was removed in vacuo to obtain (MgSO4)

yyaay

+301 - 1-(2-hydroxyphenyl)eyclobutanecarboxamide (7.57 g) 0 dissolved in (01 DMF (Ja and adding Y,) £) potassium carbonate g) (Je ,84) benzyl bromides and the reaction mixture was stirred for 11 hours. Water was added 5 ethyl acetate 23 separation of the organic layer. The aqueous layer was extracted again with ethyl acetate. The combined organic layers were washed with water (¥ times); Brine, dried (Na2SO4) and eluted solvent in vacuo. The residue was purified (chromatography 2 and elutation with 0—75 ethyl acetate in iso- hexane) to yield the subtitle product (1.94 g). 1H NMR § (CDCI3) 7.43 - 7.21 (m, 7H), 7.02 - 6.95 (m, 2H), 5.73 (s, 1H), 5.10 (s, 2H), (s, 1H), 2.88 - 2.78 (m, 2H), 2.55 - 2.44 (m, 2H), 2.16 (sextet, 1H), 1.88 - 1.74 (m, 5.04 1H). 01(c) 1-(2-(Benzyloxy)phenyl)cyclobutanamine A solution of 1-(2-(benzyloxy)phenyl)cyclobutanecarboxamide (ex. (YA) 4 g) dissolved in ( Je V1) acetonitrile and water (Je V1) in a nitrogen atmosphere using [bis(trifluoroacetoxy)iodojbenzene (€,00 g). The reaction solution was stirred at room temperature, Ye, for 11 hours. The reaction mixture was diluted with water and extracted with diethyl ether. the aqueous layer has been separated; And make it alkaline at a hydrogen number of 1 “ pH by adding NaOH to aqueous substrate and extracting it with ethyl acetate. The combined organic extract of diethyl ether (MgSO4) ethyl acetate/ was dried, filtered, and the solvent removed in vacuo. The residue was dissolved in dichloromethane and filled into a SCX cartridge. The Yo impurities were washed thoroughly with ethyl acetate and then methanol and then excluded. After cascade filtering with YAAY

1 4 — 7p and evaporation in vacuo obtained the subtitle product methanolic ammonia g). 6.91 (m, 2H), 5.10 (s, 2H), 2.62 - 2.42 (m, 2H), 2.28 - 2.06 (m, 3H), 1.85 - 1.63 (m, 1H). :)

Methyl 3-(3-(1 -(2-(benzyloxy)phenyl)cyclobutylamino)-5 -bromo-2-oxopyrazin-1(2H)- yl)-4-methylbenzoate to : 3-(3,5-dibromo -2-oxo0-2H-pyrazin- 1-yl)-4-methyl-benzoic acid, methyl ester (Ex. Y, AY) in dioxane (1 ml) Added: -(2-( benzyloxy)phenyl)cyclobutanamine | 1 0 (eg 0.16 YA g) and (Je©7/7) N,N-diisopropylethylamnie and the reaction mixture was heated at 100°C for 101 hours. After cooling at room temperature Then the reaction mixture was diluted with ethyl acetate and water; the organic layer was separated, dried (MgSO4), filtered, and the crude product was purified (chromatograph 2 and filtered ethyl acetate 760-01 in iso-hexane to obtain Vo product Subtitle (1.87 g). (td, 1H), 7.02 (d, 1H), 6.97 - 6.91 (m, 1H), 6.95 (s, 1H), 5.13 (s, 2H), 3.84 (s, 3H), 2.73 - 2.57 (m, 4H) ), 2.13 (s, 3H), 2.09 - 1.94 (m, 1H), 1.80 - 1.65 (m, 1H).

YAAYX

1717© — (e) 3-(3-(1-(2-(Benzyloxy)phenyl)cyclobutylamino)-5 -bromo-2-oxopyrazin-1(2H)-yl)-N-cyclopropyl- 4-methylbenzamide A solution was treated with: methyl 3-)3-)1 -(2-(benzyloxy)phenyl)cyclobutylamino)-5 -bromo-2-oxopyrazin-1(2H)- 5 yl)- 4-methylbenzoate (eg (p > 0.15 YA) in (Je 40( THF) in nitrogen atmosphere using cyclopropyl +,AA) amine mL) then 1 “Ja 7, 41 M isopropylmagnesium chloride in (THF) dropwise for 0 min. The reaction mixture was stirred at room temperature for 1 hour, then diluted 0 with saturated Sle ammonium chloride (+ Yo ml) and extracted Using ethyl acetate (? times) the combined organic layers (MgSO4) were dried, filtered and evaporated to yield a subtitle product (0,vv/g). MS: APCI(+ve) 599 (M+H)-+. (f): N-Cyclopropyl-3-(3-(1 -(2-hydroxyphenyl)cyclobutylamino)-2-oxopyrazin-1 (2H) )-yl)-4- Yo methylbenzamide to: L

rr - 3-(3-(1-(2-(benzyloxy)phenyl)cyclobutylamino)-5 -bromo-2-oxopyrazin-1(2H)-yl)-N-cyclopropyl-4-methylbenzamide (Example (p > 0.577 AYIA in ethanol (7) mL) ammonium formate (1.777 g) and 75 20/6 (15 45 g) was added and the reaction mixture was heated at 5°C for 1 hour . The mixture was filtered through celite and the solid was washed through dichloromethane y ethanol. The filtrate was collected and the volatile substances removed in an incubator. Then purify the residue (chromatograph 5102 and filter with zero-diethyl ether IY in (dichloromethane to yield the subtitle product) ¢ 0 JAY g). MS: APCI(+ve) 431 (M+H)+.0 (g): -(2-(2-Chloroethoxy)phenyl)cyclobutylamino)-2-oxopyrazin- 1(2H)-yl) -N- 1(-3(-3 cyclopropyl-4-methylbenzamide) to : N-cyclopropyl-3-(3-(1 -(2-hydroxyphenyl)cyclobutylamino)-2-oxopyrazin-1 (2H) -yl)-4- º methylbenzamide Vo (ex. TA and in (Ja \ v) acetonitrile (Je 1,1 A) 1-bromo-2-chloroethane Cesium carbonate was added ) a g) and the reaction mixture was heated at 60 C for YA hr. Clay ethyl acetate was added and the organic layer was separated; washed with water and brine and dried YAAY z

Si02 was filtered and the solvent removed in an incubator medium. After purification (chromatography “(MgS04)) iso-hexane / ethyl acetate IVa - 5 product was obtained. and eluting using ©. x Y) dichloromethane The drying agent was re-washed with 0 (pan Yet) mL) and the solvent was removed to yield the subtitle product again (77; mg).

MS: APCI(+ve) 493 (M+H)+. 5 : (h) N-Cyclopropyl-4-methyl-3-[3-[[1-[2- [2-(methylamino)ethoxy]phenyl] cyclobutyl]Jamino]-2-oxo-1(2H )-pyrazinyl] -benzamide : The title compound was prepared from 3-(3-(1 -(2-(2-chloroethoxy)phenyl)cyclobutylamino)-2-oxopyrazin- 1(2H)-yl)-N- 0 cyclopropyl-4-methylbenzamide (VY) using a method similar to that described in example amine methyl 5 (example 85 g)

MS: APCI(+ve) 488 (M+H)+. 1H NMR 5 (DMSO-d6) 8.37 (d, 1H), 7.85 (d, 1H), 7.69 (s, 1H), 7.48 (t, 2H), 7.24 (s, ° 1H), 7.18 (1, 1H) , 6.96 - 6.88 (m, 2H), 6.73 (d, 1H), 6.62 (d, 1H), 3.99 (t, 2H), 2.87 (t, \o 2H), 2.89 - 2.78 (m, 1H), 2.74 - 2.55 (m, 4H), 2.33 (s, 3H), 2.07 (s, 3H), 2.11 - 1.97 (m, 1H), 1.86 - 1.64 (m, 1H), 0.72 - 0.62 (m, 2H), 0.57 - 0.48 (m, 2H).

YAAY

(° 215) Example, N-Cyclopropyl-3-[3-[[1-[2-[2-(ethylamino)ethoxy]phenyl]cyclobutyl Jamino] -2-0Xo0- 1(2H)-pyrazinyl]- 4-methyl-benzamide

N o 5 N OS oN INT

A No N

CY

H i 2 0 Pe : “The title compound was prepared from © 3-(3-(1-(2-(2-chloroethoxy)phenyl)cyclobutylamino)-2-oxopyrazin-1(2H)-yl)-N- cyclopropyl-4-methylbenzamide (VY) using a method similar to that described in the example amine ethyls (SYA) (example MS: APCI(+ve) 502 (M+H)+.1H NMR § (DMSO-d6) ) 8.36 (d, 1H), 7.85 (dd, 1H), 7.69 (d, 1H), 7.51 - 7.45 (m, 2H), 01 7.20-7.16 (m, 2H), 6.96 - 6.88 (m, 2H) ), 6.74 (d, 1H), 6.63 (d, 1H), 3.98 (t, 2H), 2.89 (1, 2H), 2.85 - 2.80 (m, 1H), 2.69 (t, 3H), 2.60 - 2.54 ( m, 2H), 2.50 (d, 2H), 2.06 (s, 4H), 1.80 - 1.71 (m, 1H), 0.96 (t, 3H), 0.69 - 0.64 (m, 2H), 0.54 - 0.51 (m, 2H) ( YV.) Example N-Cyclopropyl-3-[3-[[1-[2-[2-[(2-hydroxyethyl)amino] ethoxy]phenyl \o

Jeyclobutyllamino]-2-o0x0-1(2H)-pyrazinyl]-4-methyl-benzamide

N

0 m N 0 h INT OH /\ N

N = X

N love N 0 A : Then prepare the title compound from 3-(3-(1-(2-(2-chloroethoxy)phenyl)cyclobutylamino)-2-oxopyrazin-1 (2H)-yl)-N- cyclopropyl-4-methylbenzamide. or 1 Y) using a method similar to that described in the example amine ethyl (oY TA) (example °

MS: APCI(+ve) 518 (M+H)+. 1H NMR 5 (DMSO0-d6) 8.37 (d, 1H), 7.84 (d, 1H), 7.69 (s, 1H), 7.49 (q, 2H), 7.31 (s, 1H), 7.19 (t, 1H), 6.93 (q, 2H), 6.73 (d, 1H), 6.62 (d, 1H), 4.07 (s, 2H), 3.49 (s, 2H), 3.09 (s, 2H), 2.70 (s, 7H), 2.08 (s, 5H), 0.67 (d, 2H), 0.53 (d, 2H) (example Y) except 0

N-Cyclopropyl-4-methyl-3-[3-[[1-[2-[2-[(1-methylethyl)amino] ethoxy]phenyl]cyclobutyl]amino]-2-oxo-1(2H)-pyrazinyl ]- benzamide

N a N

AJ AA

Ho | 1}

A

: The title compound was prepared from

YAAY

0p -(2-(2-chloroethoxy)phenyl)cyclobutylamino)-2-oxopyrazin-1 (2H)-y)-N- 3-3-1 cyclopropyl-4-methylbenzamide (ex. amine ethyl 5 (OYA) using a method similar to that described in Example (51) MS: APCI(+ve) 516 (M+H)+. 1H NMR 5 (DMSO0-d6) 8.37 (s, 1H), 7.84 ( d, 1H), 7.69 (s, 1H), 7.49 (q, 2H), 7.27 (s, e 1H), 7.19 (t, 1H), 6.98 - 6.89 (m, 2H), 6.83 (s, 1H ), 6.63 (s, 1H), 4.05 (s, 2H), 3.05 - 2.96 (m, 3H), 2.83 - 2.83 (m, 1H), 2.71 (s, 4H), 2.08 (s, 3H), 1.84 - 1.69 (m, 2H), 1.02 (s, 6H), 0.67 (d, 2H), 0.53 (d, 2H) Example ) YVY ( N-Cyclopropyl-3-[3-[[ (1R,2R)-3-hydroxy-1 -(2-methylphenyl)-2-methylpropyl[amino]-2- 01 oxo-1(2H)-pyrazinyl]-4-methyl-benzamide °N 2 0 : , © N T N ! OH = 0 (1) : N-[(1R,2R)-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy] -2-methyl-1-(2 - methylphenyl)propyl]-2-methyl-2-propanesulfinamide \o The title compound was prepared from: YAAY

(2S)-3-[[(1,1-dimethylethyl)diphenylsilylJoxy] -N-methoxy-N,2-dimethyl-propanamide (V1) using methods described in example o-tolylmagnesium chloride (y= (example) 1H NMR 5 (CDCI3) 7.63 - 7.58 (2H, m), 7.53 - 7.48 (2H, m), 7.42 - 7.27 (6H, m), 7.19 - 7.10 (4H, m), 4.86 (1H, dd), 3.59 (1H, d), 3.53 (1H, dd), 3.42 (1H, dd), 2.38 (3H, 5), 2.14-2.04 (1H, m), 1.14 (9H, s), 1.03 (9H, s) , 0.91 (3H, d).©

(b) 3-[3-[[(1R,2R)-3-hydroxy-2-methyl-1-(2-methylphenyl)propyl]Jamino]-2-oxo-1(2H)- pyrazinyl]-4-methyl-benzoic acid methyl ester

: The title compound was prepared from (ZY) (Ex. 777?a) using the method described in Example 0 1H NMR 5 (01150-06) 7.96 (2H, d), 7.85 (s, 1H), 7.80 (1H). , 5), 7.61 - 7.48 (3H, m), 7.30 (2H, d), 7.23 (2H, 1), 7.01 (2H, d), 6.91 (2H, t), 6.79 (2H, d), 6.68 and 6.67 (2H, 2 x d), 5.37 (1H, though 4.66 - 4.59 (1H, m), 3.88 - 3.76 (4H, m), 3.29 - 3.12 (2H, m), 2.24 - 2.10 (1H, m) , 2.16 and 2.09 (3H, 2 x 5), 0.86 (3H, d).

0(c): N-Cyclopropyl-3-[3-[[(1R,2R)-3-hydroxy-1-(2-methylphenyl)-2-methylpropyljamino}-2- ox0-1( 2H)-pyrazinyl]-4-methyl-benzamide

‎YAAY

The title compound was prepared from 3-[3-[[(1R,2R)-3-hydroxy-2-methyl-1-(2-methylphenyl)propyl]Jamino]-2-oxo-1(2ZH)- pyrazinyl]-4-methyl-benzoic acid, methyl ester . (2) 1 ) (Example No B using the method described in the example

MS: APCI(+ve) 447 (M+H+). © 1H NMR 5 (DMSO-d6) 8.45 and 8.36 (1H, 2 x d), 7.89 - 7.82 (1H, m), 7.78 - 7.61 (2H, m), 7.55 - 7.44 (2H, m), 7.20 - 7.05 ( 3H, m), 6.82 - 6.76 (1H, m), 6.67 - 6.61 (1H, m), 5.26 (1H, t), 4.71 - 4.60 (1H, 2 x 1), 3.29 - 3.05 (2H, m), 2.93 - 2.76 (1H, m), 2.56-2.46 (3H, overlapped with DMSO), 2.28 - 2.13 (1H, m), 2.13 and 2.04 3H, 2 x 5), 0.98 - 0.91 (3H, m), 0.74 - 0.48 (4H, m). Ye (Y YY) Example N-Cyclopropyl-3-[3-[[(1R,2R)-3-hydroxy-1-(3-methylphenyl)-2-methylpropyl Jamino]-2-oxo-1( 2H)-pyrazinyl]-4-methyl-benzamide

AJL

Toy "OH 0 - : (0 \o

YAAY

N-[(1R,2R)-3-[[(1,1-Dimethylethyl)diphenylsilyl]Joxy]-2-methyl-1-(3- methylphenyl)propyl]-2-methyl-2-propanesulfinamide : was prepared Title compound of (29)-3-[[(1,1-dimethylethyl)diphenylsilylJoxy]-N-methoxy-N,2-dimethyl-propanamide (VF) using the methods described in example m-tolylmagnesium chloride { 11 (example © 111 NMR 6 (00013) 7.67 - 7.61 (2H, m), 7.59 - 7.53 (2H, m), 7.46 - 7.30 (6H, m), 7.20 (1H, 1), 7.11 - 7.02 (3H, m), 4.53 (1H, dd), 3.83 (1H, d), 3.54 (1H, dd), 3.39 (1H, dd), 2.33 (3H, s), 2.26 - 2.14 (1H, m), 1.17 (9H , s), 1.06 (9H, s), 0.90 (3H, d). : (b) N-Cyclopropyl-3-[3-[[(1R,2R)-3-hydroxy-1-(3) -methylphenyl)-2-methylpropyljamino]-2- 01 oxo-1(2H)-pyrazinyl]-4-methyl-benzamide : The title compound was prepared from

N-[(1R,2R)-3-[[(1,]-dimethylethyl)diphenylsilyl]oxy]-2-methyl-1-(3- methylphenyl)propyl]-2-methyl-2-propanesulfinamide .)D1 and (ZV) using the methods described in Example TYVY (Example 10

MS: APCI(+ve) 447 (M+H+). the

1H NMR 6 (01150-06) 8.44 and 8.38 (1H, 2 x d), 7.91 - 7.79 (2H, m), 7.75 and 7.69 (1H, 2 x d), 7.49 and 7.47 (1H, 2 x d), 7.24 - 7.13 (3H, m), 7.07 - 7.00 (1H, m), 6.78 and 6.77 (1H, 2 x d), 6.65 and 6.64 (1H, 2 x d), 5.03 - 4.95 (1H, m), 4.78 and 4.72 (1H, 2 x t), 3.23 - 3.11 (2H, m), 2.90 - 2.78 (1H, m), 2.30 (3H, s), 2.26 - 2.14 (1H, m), 2.12 and 2.06 (3H, 2 x 5), 0.86 (3H, d), 0.72 - 0.63 (2H, m), 0.59 - 0.50 (2H, m).

N-Cyclopropyl-3-[3-[[(1R,2R)-3-hydroxy-1-(2-methoxyphenyl)-2-methylpropyl]amino]- 2-0x0-1(2H)-pyrazinyl]-4- methyl-benzamide

IN

0 = ~ °N 0

AL gS 0 - : (0 01

N-[(1R,2R)-3-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-1-(2-methoxyphenyl)-2- methylpropyl]}-2-methyl-2-propanesulfinamide The title compound was prepared From: (25)-3-[[(1,1-dimethylethyl)diphenylsilylJoxy]-N-methoxy-N,2-dimethyl-propanamide . ab v1) using the methods described in example 0

YAAYX

17 He - 1H NMR 6 (CDCI3) 7.62 - 7.58 (2H, m), 7.53 - 7.49 (2H, m), 7.41 - 7.25 (6H, m), 7.20 - 7.16 (2H, m), 6.88 (1H , dt), 6.82 (1H, d), 4.58 (1H, dd), 4.34 (1H, d), 3.76 (3H, s), 3.45 (1H, dd), 3.33 (1H, dd), 2.25 - 2.13 ( 1H, m), 1.17 (9H, s), 1.03 (9H, 5), 0.96 (3H, d). (b): 3-[3-[[(1R,2R)-3-Hydroxy-2-methyl-1-(2-methoxyphenyl)propyl]Jamino]-2-oxo-1(2H)- 6 pyrazinyl]- 4-methyl-benzoic acid, methyl ester: The title compound was prepared from

N-[(1R,2R)-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-2-methyl-1-(2-methoxyphenyl)propyl]-2-methyl-2-propanesulfinamide (277) ‏ Using the methods described in the example IYVE (ex. 0 1H NMR 6 (DMSO0-d6) 7.96 (1H, d), 7.85 and 7.80 (1H, s), 7.61 - 7.48 (2H, m), 7.30 (1H, d), 7.23 (1H, t), 7.01 (1H, d), 6.91 (1H, m), 6.79 (1H, d), 6.68 and 6.67 (1H, 2 x d), 5.37 (1H, q), 4.63( 1H, , if 3.90 — 3.80 (6H, m), 3.29 - 3.12 (2H, m), 2.24 - 2.10 (1H, m), 2.16 and 2.09 (3H, 2 x s), 0.86 (3H, d). O°(c): N-Cyclopropyl-3-[3-[[(1R,2R)-3-hydroxy-1-(2-methoxyphenyl)-2-methylpropylJamino]- 2-o0x0-1 (2H)-pyrazinyl]-4-methyl-benzamide YAAY

The title compound was prepared from 3-[3-[[(1R,2R)-3-hydroxy-2-methyl-1-(2-methoxyphenyl)propyl]amino]-2-oxo-1(2H)-pyrazinyl]- 4-methyl-benzoic acid, methyl ester. (2) 5) using the method described in the example

MS: APCI(+ve) 463 (M+H+). © 1H NMR 6 (DMSO-d6) 8.44 and 8.38 (1H, 2 x d), 7.86 (1H, m), 7.76 and 7.69 (1H, 2 x d), 7.56 — 7.45 (2H, m), 7.31 and 7.27 (1H , 2 x dd), 7.23 (1H, m), 7.03 - 6.99 (1H, m), 6.94 - 6.87 (1H, m), 6.80 and 6.80 (1H, 2 x d), 6.67 and 6.66 (1H, 2 x d) , 5.41 - 5.32 (1H, m), 4.67 - 4.59 (1H, m), 3.830 and 3.825 (3H, 2 x s), 3.27 - 3.22 (1H, m), 3.21 - 3.12 (1H, m), 2.90 - 2.78 (1H, m), 2.25 - 2.14 (1H, m), 2.13 and 2.05 (3H, 2 x 5), 0.87 01 and 0.85 (3H, 2 x d), 0.72 - 0.63 (2H, m), 0.59 - 0.50 ( 2H, m). (YVo) Example N-Cyclopropyl-3-[3-[[(1R,2S)-1-(2-methylphenyl)-2-methyl-3-(1-pyrrolidinyl)propyl] amino]-2 -oxo-1(2H)-pyrazinyl]-4-methyl-benzamide 0 ~ °N 2 © 7 : . M 0 1 : The title compound was prepared from

1 —

N-cyclopropyl-3-[3-[[(1R,2R)-3-hydroxy-1-(2-methylphenyl)-2-methylpropylJamino]-2- oxo-1(2H)-pyrazinyl]-4-methyl- benzamide (VFA) 5 (NYA) using the methods described in the example (YVY Jb)

MS: APCI(+ve) 500 (M+H+). 1H NMR 5 (DMSO-d6) 8.57 and 8.39 (1H, 2 x d), 8.45 and 8.37 (1H, 2 x d), 7.88 - 7.83 © (1H, m), 7.74 and 7.67 (1H, 2 x d), 7.48 ( 1H, t), 7.41 and 7.37 (1H, 2x d), 7.22 - 7.08 (3H, m), 6.77 and 6.76 (1H, 2 x d), 6.62 and 6.61 (1H, 2 x d), 5.34 - 5.26 (1H, m), 2.89 - 2.77 (1H, m), 2.48 (3H, 5), 2.49 - 2.33 (6H, m), 2.21 - 2.12 (1H, m), 2.11 and 2.02 (3H, 2 x 5), 1.75 - 1.64 (4H, m), 0.85 and 0.84 (3H, 2 x d), 0.72 - 0.63 (2H, m), 0.59 - 0.49 (2H, m). Ve (77 ) Example N-Cyclopropyl-3-[3-[[(1R,2S)-1-(3-methylphenyl)-2-methyl-3-(1-pyrrolidinyl)propyl] amino]- 2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide = 0 7 lm © 1 1 0 = : The title compound is prepared from 59

YAAY

7 4/0 -

N-cyclopropyl-3-[3-[[(1R,2R)-3-hydroxy-1-(3-methylphenyl)-2-methylpropylJamino]-2-oxo-1(2H)-pyrazinyl]-4-methyl- benzamide (VTA) (WTA) (Example 777) using the methods described in the example

MS: APCI(+ve) 500 (M+H+). 1H NMR 6 (DMSO0-d6) 9.11 and 8.93 (1H, 2 x d), 8.45 and 8.41 (1H, 2x d), 7.89 - 7.83 5 (1H, m), 7.74 and 7.69 (1H, 2 x d), 7.48 and 7.47 (1H, 2 x d), 7.22 (1H, t), 7.14 - 7.02 (3H, m), 6.74 and 6.73 (1H, 2 x d), 6.62 (1H, d), 5.07 - 4.99 (1H, m), 2.89 - 2.79 (1H, m), 2.61 - 2.28 (6H, m), 2.31 (3H, s), 2.11 and 2.05 (3H, 5), 2.06 - 1.97 (1H, m), 1.82 - 1.65 (4H, m) ), 0.79 and 0.78 (3H, 2 x d), 0.73 - 0.64 (2H, m), 0.59 - 0.50 (2H, m). (Y vv) Example 0

N-Cyclopropyl-3-[3-[[(1R,2S)-1-(2-methoxyphenyl)-2-methyl-3-(1- pyrrolidinyl)propyl]amino]-2-oxo-1(2H)- pyrazinyl]-4-methyl-benzamide 7 E free grate 0 2 °N 0 2 2) Rahb 0 - \ : The title compound was prepared from

N-cyclopropyl-3-[3-[[(1R,2R)-3-hydroxy-1-(2-methoxyphenyl)-2-methylpropylJamino]- Ye 2-ox0-1(2H)-pyrazinyl]-4-methyl -benzamide the

(YA) 5 (FA) using the methods described in the YVE example (Example MS: APCI(+ve) 516 (M+H+). 1H NMR § (DMSO-d6) 8.49 and 8.31 (1H) , 2 x d), 8.45 and 8.40 (1H, 2 x d), 7.86 (1H, dt), 7.75 and 7.69 (1H, 2 x d), 7.48 and 7.47 (1H, 2 x d), 7.23 (2H, t), 7.01 (1H, d), 6.93 (1H, t), 6.77 and 6.76 (1H, 2 x d), 6.632 and 6.628 (1H, 2 x d), 5.59 - 5.50 (1H, m), 3.82 © (3H, s), 2.90 - 2.78 (1H, m), 2.59 - 2.31 (6H, m), 2.11 and 2.04 (3H, 2 x 5), 2.14 - 2.03 (1H, m), 1.79 - 1.61 (4H, m), 0.78 (3H) , d), 0.74 - 0.63 (2H, m), 0.60 - 0.49 (2H, m).(Yv A) Example N-Cyclopropyl-3-[3-[[1-[5-fluoro-2-] [2-(methylamino)ethoxy]phenyl] cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl] -4-methyl-benzamide

H

0 ZN 9

H H

0

F

1 -[5-Fluoro-2-(phenylmethoxy)phenyl]-cyclopropanamine 0 ) diethyl ether ml of solution? MV of ¥0,Y) ethylmagnesium bromide and (00mM YY) tetraisopropyl orthotitanate was added slowly to a mixture stirred with a mechanical tool and cooled to (Je 5001) diethyl ether in (p>VY). ) 2-(benzyloxy)-5-fluorobenzonitrile \o for 10 minutes and then heated to a temperature of -5 VA C. The resulting solution was stirred at VA

YAAY

— Yo. — the room for an hour. V¥,Y'A) Boron trifluoride etherate mL) was added and the mixture was stirred for Ve min. The reaction mixture was quenched with 1 M HCI (£00 (de) and the aqueous layer was separated. The diethyl ether layer was extracted again in 1 M HCI 001 XY mL). The aqueous layers collected in ice ales were cooled to base using a 1 M aqueous NaOH© solution. Then the resulting precipitate was filtered through a cellite and the filling was washed well with water (Yoo ml) 5,001 X £) dichloromethane ml) and then MeOH [dichloromethane: 9: Na ml). The combined filtrate was separated and the organic layer was extracted again in (XY 001 dichloromethane ml). The combined organic layers (MgSO04) were dried and evaporated and the residue was purified with SCX resin (filtered with methanol and then ammonia 701 Yt). The basic fractions were evaporated to yield the subtitle compound (methanol). in 0 g). ), 6.88 - 6.82 (2H, m), 5.13 (2H, 5), 2.13 (2H, 5), 1.00 - 0.95 (2H, m), 0.86 - 0.82 (2H, m). 1(j): 3-[5-Bromo-3-[[1-[5-fluoro-2-(phenylmethoxy)phenyl]cyclopropyl]Jamino]-2-oxo-1(2H)- pyrazinyl [-4-methyl- benzoic acid methyl ester] A solution of 1-[5-fluoro-2-(phenylmethoxy)phenyl]-cyclopropanamine (manal) was treated using (Ja 001 (dioxane g) in 11 1/4

YAAY

— Yor-

3-(3,5-dibromo-2-oxo0-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methyl ester (example 4 g) (Ja VV) N-ethyldiisopropylamine s in atmosphere of nitrogen The resulting solution was stirred at 100°C for A hours. The cooled reaction mixture was diluted with HCl ¥ M (Yo 0 mL); and extracted it using (XY) diethyl ether 700 ml). The © Organic (048504) layers were dried, filtered and evaporated to obtain a crude product. After crushing with iso-

Hexane The subtitle compound was obtained (7,895 g). 1H NMR 5 (DMSO0-d6) 7.98 - 7.91 (1H, m), 7.87 (1H, s), 7.62 (1H, s), 7.56 - 7.24 (6H, m), 7.05 - 6.98 (3H, m) ), 3.85 (3H, 5), 3.58 - 3.55 (2H, m), 2.13 (3H, 5), 1.32 - 1.05 (4H, m).

© 0 3-[3-[[1-(5-fluoro-2-hydroxyphenyl)cyclopropylJamino]-2-oxo-1(2H)-pyrazinyl]-4- methyl- benzoic acid methyl ester to: 3 -[5-bromo-3-[[1-[5-fluoro-2-(phenylmethoxy)phenyl]jcyclopropyl]amino]-2-oxo- : 1(2H)-pyrazinyl]-4-methyl- benzoic acid, methyl ester \o g) ©) ammonium formate (Jo Y+ +) ethanol added at (pa 7.8 “a¥VA) (example h) filtered through celite sad 2 Vo g The reaction mixture was heated at 1 (Pa/C 70 and ml).

E1" — washed with water; (do 001( dichloromethane combined filtrate), evaporated, then diluted in g.VY), dried (8504/0) and evaporated to yield compound 1H NMR 5 (DMSO0- d6) 11.12 (1H, s), 8.43 (1H, 5), 7.96 (1H, dd), 7.85 (1H, d), 7.56 (1H, d), 7.23 (1H, dd), 6.98 - 6.91 (1H, m), 6.83 (2H, dd), 6.77 - 6.72 (1H, m), 3.84 (3H, s), 2.12 BH, 5), 1.28 - 1.24 (2H, m), 1.18 - 1.07 (2H, m). °: (3)

N-cyclopropyl-3-[3-[[1-(5-fluoro-2-hydroxyphenyl)cyclopropylJamino]-2-oxo-1(2H)- pyrazinyl]-4-methyl- benzamide for (THF molar in 1 mL of a solution of isopropylmagnesium (©,A7) = chloride mL) and Y,+711)amine cyclopropyl min were added to a solution of Ye 0 0 3-[3-[[1-(5) -fluoro-2-hydroxyphenyl)cyclopropyl[amino]-2-oxo-1(2H)-pyrazinyl]-4- methyl-benzoic acid nitrogen at room temperature in (Ja Yoo) THF g) in 011 zYVA (example molar) 1 HCl was extracted then carefully 0 water was added then the reaction mixture was stirred for 1 hour the solvent (MgSO4) was removed and the aqueous layer (Je 001 XY) dichloromethane was dried using © .g) 1 for the subtitle compound 1H NMR 65 (DMSO-d6) 8.58 - 8.48 (1H, m), 8.41 - 8.35 (1H, m), 7.86 (1H, d), 7.72 (1H, s), 7.48 (1H, d), 7.28 - 7.21 (1H, m), 7.05 - 6.86 (2H, m), 6.83 - 6.72 (2H, m), 3.65 - 3.57

YAAY

— YoVv — (2H, m), 2.89 - 2.78 (1H, m), 2.10 (3H, s), 1.80 - 1.72 (2H, m), 0.73 - 0.63 (2H, m), 0.58 - 0.49 (2H, m) ). (e): 3-[3-[[1-[2-(2-chloroethoxy)-5-fluorophenyl]cyclopropylJamino}-2-oxo-1(2H)- pyrazinyl]-N-cyclopropyl-4 -methyl-benzamide © : stirred

N-Cyclopropyl-3-[3-[[1-(5-fluoro-2-hydroxyphenyl)cyclopropylJamino]-2-oxo-1(2H)- pyrazinyl]-4-methyl- benzamide ( Example 278d 1.22 g), 1 -bromo-2-chloroethane 4,10) Cesium carbonate s (J Y,¢) 1-bromo-2-chloroethane 5 (aa 0.77 aYVA) (eg 11 hr nitrogen was evaporated under atmosphere of 1 Av at (Je 001 (acetonitrile g) together in 0 ml) and extracted with Yorele cooled reaction mixture to dryness; diluted with and filtered (MgSO4) ml). The combined organic layers (XY) 001 dichloromethane were dried to obtain diethyl ether : iso-hexane 1:1 and evaporated. Residue was crushed using g. VY) Subtitle 1H NMR 6 (DMSO-d6) 8.37 (1H, d), 7.84 (1H, dd), 7.69 (1H, d), 7.46 (1H, d). ), 7.33 - Yo 7.27 (2H, m), 7.08 - 6.95 (2H, m), 6.89 (1H, d), 6.73 (1H, d), 4.29 (2H, t), 3.99 (2H, 1), 2.89 - 2.76 (1H, m), 2.06 (3H, s), 0.71 - 0.60 (2H, m), 0.57 - 0.48 (ZH, m).

YAAY

7 © — : (f) N-Cyclopropy!-3-[3-[[1-[5-fluoro-2-[2- (methylamino)ethoxy]phenyl]cyclopropyl]Jamino]-2-oxo -1(2H)-pyrazinyl] -4-methyl- benzamide : stirred © 3-[3-[[1-[2-(2-chloroethoxy)-5-fluorophenyl]cyclopropylJamino]-2-oxo-1 (2H)-pyrazinyl]-N-cyclopropyl-4-methyl-benzamide in 1 001 aie Las ml) 1 (in amine methyl water 740 g) and +,Y0 —aYVA (example h. After purification of the cooled solution with YE ml) in a sealed tube for a period of A) dioxane to obtain ammonia / +,Y / acetonitrile mobile sh - 6 preparation (column 1101© 0 0 mg .ARI)) on the title component

MS: APCI(+ve) 492 (M+H)+. 1H NMR § (DMSO-d6) 8.37 (1H, d), 7.85 (1H, d), 7.69 (1H, s), 7.58 (1H, 5), 7.46 (1H, d), 7.30 (1H, dd), 7.06 - 6.91 (2H, m), 6.88 (1H, d), 6.71 (1H, d), 4.03 (2H, t), 2.90 - 2.79 (3H, m), 2.34 (3H, 5), 2.06 (3H, s), 1.25 - 1.06 (4H, m), 0.70 - 0.62 (2H, m), 0.57 - Yo 0.50 (2H, m)

PYVA In a manner similar to example 780-7174 the two examples are prepared

— Yoo — (Yva ) Example N-Cyclopropyl-3-[3-[[1-[5-fluoro-2-[2-[(2-hydroxyethyl)amino]ethoxy] phenyl]cyclopropyl]amino] -2-oxo-1(2H)-pyrazinyl] -4-methyl-benzamide

H

N

#7 oN J The A Labak Saim 00 Tahir F MS: APCI(+ve) 522 M+H)+. © 1H NMR 5 (DMSO-d6) 8.37 (1H, d), 7.85 (1H, dd), 7.69 (1H, d), 7.49 (1H, s), 7.46 (1H, d), 7.29 (1H, dd) , 7.05 - 6.93 (2H, m), 6.89 (1H, d), 6.72 (1H, d), 4.45 - 4.40 (1H, m), 4.03 (2H, 1), 3.46 (2H, q), 2.94 (2H , 0. 2.88 - 2.78 (1H, m), 2.67 (2H, 0.2.06 (3H, s), 1.26 - 1.07 (4H, m), 0.71 - 0.62 (2H, m), 0.56 - 0.49 (2H, m) (YA: ) Example Ye

N-Cyclopropyl-3-[3-[[1-[2-[2-(¢thylamino)ethoxy]-5-fluorophenyl]cyclopropyl jamino]- 2-0x0-1(2H)-pyrazinyl]-4-methyl- benzamide 3 , rod

SOTO

F

MS: APCI(+ve) 506 (M+H)+.

YAAY

1H NMR 5 (DMSO0-d6) 8.37 (1H, d), 7.85 (1H, dd), 7.69 (1H, d), 7.52 (1H, 5), 7.46 (1H, d), 7.29 (1H, dd), 7.05 - 6.93 (2H, m), 6.88 (1H, d), 6.72 (1H, d), 4.03 (2H, 1), 2.92 (2H, t), 2.88 - 2.79 (1H, m), 2.61 (2H, ,Lu 2.06 (3H, s), 1.26 - 1.06 (4H, m), 0.99 (3H, 1), 0.70 - 0.63 (2H, m), 0.55 - 0.49 (2H, m) (YA (example) ©

N-Cyclopropyl-3-fluoro-5-{3-[(1-{5-fluoro-2-[2-(methylamino)ethoxy]phenyl} cyclopropyl)amino]-2-oxopyrazin-1(2H)-yl} -4-methylbenzamide

H

1 p. A x 2

YY

F F

: 0

Methyl 3-[3-({1-[2-(benzyloxy)-5-fluorophenyl]cyclopropyl} amino)-5-bromo-2- Ye oxopyrazin-1(2H)-yl]-5-fluoro-4-methylbenzoate : The subtitle compound was prepared from 1-(2-(benzyloxy)-5-fluorophenyl)cyclopropanamine ( Lavi Y) using a method similar to that described in example (OY oY (example Al

— YoV — 'H NMR § (DMSO-dg) 7.83 - 7.76 (2H, m), 7.66 - 7.63 (1H, m), 7.55 - 7.49 (2H, m), 7.41 - 7.28 (4H, m), 7.08 - 7.00 (3H, m), 5.20 (2H, s), 3.85 (3H, 5), 2.04 (3H, 5), 1.29 - 1.10 (4H, m). (b) N-Cyclopropyl-3-fluoro-5-[3-{[1-(5-fluoro-2-hydroxyphenyl)cyclopropyl] amino }-2- 2 oxopyrazin-1(2H)-yl] -4-methylbenzamide : the subtitle compound was prepared from methyl 3-[3-({1-[2-(benzyloxy)-5-fluorophenyl]cyclopropyl} amino)-5-bromo-2-oxopyrazin-1(2H) )-yl]-5-fluoro-4-methylbenzoate (ZV) and (wV01) using methods similar to those described in the example YAY (ex. 0 1H NMR 5001150-00 8.58 (1H, s), 8.48 (1H, d), 7.75 (1H, d), 7.65 (1H, s), 7.24 (1H, dd), 6.99 - 6.73 (4H, m), 2.90 - 2.77 (1H, m), 2.00 (3H, 5 ), 1.31 - 1.13 (4H, m), 0.75 - 0.63 (2H, m), 0.59 - 0.50 (2H, m). : (c) 3-[3-({1-[2-(2) -Chloroethoxy)-5-fluorophenyl]cyclopropyl ( amino)-2-oxopyrazin-1(2H)- Yo yl]-N-cyclopropyl-5-fluoro-4-methylbenzamide : The subtitle compound was prepared from L

1 ©

N-cyclopropyl-3-fluoro-5-[3-{[1-(5 -fluoro-2-hydroxyphenyl)cyclopropyl]amino} -2- oxopyrazin-1(2H)-yl]-4-methylbenzamide . d oq ) b using a method similar to that described in example AY (example 1H NMR 5 (DMSO0-d6) 8.46 (1H, d), 7.73 (1H, d), 7.61 (1H, s) , 7.35 - 7.26 (2H, m), 7.10 - 6.94 (2H, m), 6.90 (1H, d), 6.77 (1H, d), 4.32 - 4.24 (2H, m), 4.02 - 3.94 (2H, m) , 9 2.88 - 2.78 (1H, m), 1.96 (3H, 5), 1.41 - 1.09 (4H, m), 0.76 - 0.46 (4H, m): (d) N-Cyclopropyl-3-fluoro- 5-{3-[(1-{5-fluoro-2-[2-(methylamino)ethoxy] phenyl} cyclopropyl)amino]-2-oxopyrazin-1(2H)-yl}-4-methylbenzamide : Then prepare Subtitle compound of 0 3-[3-({1-[2-(2-chloroethoxy)-5-fluorophenyl]cyclopropyl } amino)-2-oxopyrazin-1(2H)- yl]-N-cyclopropyl-5 -fluoro-4-methylbenzamide using a method similar to that described in Example (70949E). (#YA) (Example MS: APCI(+ve) 510.2 (M+H)+.1H NMR 6 (DMSO0-d6) ) 8.47 (1H, d), 7.73 (1H, d), 7.65 - 7.61 (2H, m), 7.30 (1H, dd), Yo 7.06 - 6.92 (2H, m), 6.90 (1H, d), 6.75 ( 1H, , for 4.03 (2H, t), 2.91 - 2.77 (3H, m), 2.35 (3H, s), 1.97 (3H, d), 1.28 - 1.05 (4H, m), 0.73 - 0.64 (2H , m), 0.59 - 0.47 (2H, m). the

— 5e Example ) (YAY N-Cyclopropyl-3-fluoro-5-[3-{[1-(5-fluoro-2-{2- [(2-hydroxyethyl)amino] ethoxy } phenyl) cyclopropylJamino}-2-oxopyrazin-1(2H)-yl] -4-methylbenzamide A what ovo M A H | L H 2 0 F 8 was prepared Title compound from: 3-[3-({1-[2-(2-chloroethoxy)-5-fluorophenyl]cyclopropyl} amino)-2-oxopyrazin-1(2H)- y1]-N-cyclopropyl-5-fluoro -4-methylbenzamide (3) TY) using a method similar to that described in the amine ethanol example 5 (z YAY) (example MS: APCI(+ve) 540 (M+H)+. 1H NMR 5 (DMSO0- d6) 8.46 (1H, d), 7.73 (1H, d), 7.61 (1H, 5), 7.53 (1H, 5), 7.29 (1H, 01 dd), 7.06 - 6.92 (2H, m), 6.90 (1H , d), 6.76 (1H, d), 4.42 (1H, 0.4.03 (2H, t), 3.46 (2H, ), 2.94 (2H, 0.2.89 - 2.78 (1H, m), 2.67 (2H) , t), 1.97 (3H, d), 1.28 - 1.04 (4H, m), 0.72 - 0.61 (2H, m), 0.58 - 0.45 (2H, m) (Y AY) Example N-Cyclopropyl-3 -[3-({1-[3-fluoro-2-(2-{[(2R)-2-hydroxypropylJamino} Yo ethoxy)phenyl]cyclopropyl }amino)-2-oxopyrazin-1(2H)-yl]- 4-methylbenzamide

YAAY

A NO N I OH ZN 0 0 H H A he 1 RH ] H [ 0 2-(Benzyloxy)-3-fluorobenzonitrile (1) benzyl alcohol added ) (0.01 (Je) dropwise for 71 minutes to a stirred suspension of sodium hydride (7.174 g dispersed Zs in mineral oil) 5 2,3-difluorobenzonitrile ° (except g) in (Ja 0 ) THF using an external ice bath for cooling to maintain ia temperature around ©7 m. After the addition is completed; The reaction mixture was stirred at room temperature for YE 1 h; quenching with water (Ja Yoo), extraction in (Je 171 X ¥) ethyl acetate, drying of the combined organic layers (MgSO04) and evaporation. The remaining oil was purified (chromatograph 2 and filtered with ether 7X in hexane to yield the subtitle compound Yo as VY oil (9 g).

IH NMR § (CDCI3) 7.54 - 7.44 (2H, m), 7.40 - 7.26 (SH, m), 7.10 - 7.01 (1H, m), 5.33 (2H, s) 1-[2-(Benzyloxy)-3 -fluorophenyl]cyclopropanamine ( < ) A solution of ethylmagnesium bromide ¢ ¥ M in (Je YAY) diethyl ether 10 was added as a slow stream to a mechanically stirred mixture of 9 06 (tetraisopropyl orthotitanate mL) and- 2 (benzyloxy)-3-fluorobenzonitrile (ex. 7 g HM) in diethyl ether (460 mL) and cooled to VAS 0°C. The resulting solution was stirred at -4 Nom for 10 min and then warmed to YAAY

11- Room temperature for an hour and a half. An ice bath was placed around the reaction mixture and the addition of (1 0 ds) boron trifluoride etherate was observed as a slow stream (caution; exothermic reaction) and the mixture was stirred for 0 min. The mixture (salad) (= plea) was cooled with Aqueous 1 M HCl ml added dropwise (0) All layer was separated and the diethyl ether layer also extracted in 1 M HCl © ethyl acetate (Jo 001 XY) added to diethyl ether to help dissolve). The ASL layer was cooled in an ice bath and transferred to alkaline medium with stirring with 1 M aqueous NaOH. The resulting precipitate was filtered through a cellite; The packing was washed with water (Ja 00) then (Ja 001 X £) DCM then Yoo 0:1 (DCM/MeOH mL). The combined filtrate was separated and the aqueous layer was extracted again with You (XY) DCM ml). Done 0 | drying and evaporation of combined organic layers (MgSO4); The residue was purified on SCX resin (© g), filtered with methanol (DCM (excluded) and eluted with + ammonia /Y in methanol to obtain the subtitle compound as oil (4 7.5 g). 1H NMR 5 (CDCI3) 7.54 - 7.50 (1H, m), 7.43 - 7.31 (2H, m), 7.06 - 6.89 (SH, m), 5.22 (2H, s), 0.96 - 0.93 (2H, m) , 0.84 - 0.80 (2H, m).

He) 0

Methyl 3-[3-({1-[2-(benzyloxy)-3-fluorophenyl]cyclopropyl }amino)-5-bromo-2- oxopyrazin-1(2H)-yl]-4-methylbenzoate : from ( YoY (prepared using a method similar to eg Tel methyl 3-(3,5-dibromo-2-R) 1 -(2-(benzyloxy)-3-fluorophenyl)cyclopropanamine oxopyrazin-1(2H)-yl )-4-methylbenzoate (G007). ), 7.44 - 7.32 (5H, m), 7.23 - 7.16 (1H, m), 7.11 - 7.03 (1H, m), 5.19 (2H, 5), 3.83 (3H, 5), © 2.11 (3H, s) , 1.26 - 1.14 (4H, m) : (d) Methyl 3-[3-{[1-(3-fluoro-2-hydroxyphenyl)cyclopropyl]amino} -2-oxopyrazin-1(2H)-yl [-4-methylbenzoate : Prepared using a method similar to Example ( 7 j) from Ye (z YAY Ji) (2H)-yl]-4-methylbenzoate 1H NMR 6 (DMSO0-d6)) 8.63 (1H, s) , 7.96 (1H, dd), 7.86 (1H, d), 7.56 (1H, d), 7.27 (1H, d), 7.09 - 7.02 (1H, m), 6.90 (1H, d), 6.80 (1H, d) ), 6.79 - 6.74 (1H, m), 3.84 (3H, s), 2.13 (3H, s), 1.32 - 1.26 (2H, m), 1.12 - 1.09 (2H, m): (e) 0

N-Cyclopropyl-3-[3-{[1-(3-fluoro-2-hydroxyphenyl)cyclopropylJamino} -2-oxo0pyrazin- 1(2H)-yl]-4-methylbenzamide

The subtitle compound was prepared from methyl 3-[3-{[1-(3 -fluoro-2-hydroxyphenyl)cyclopropyl]amino}-2-oxopyrazin-1 (2H)-yl]-4-methylbenzoate. (&Y oY ) d using a method similar to that described in example AY (example 1H NMR 5 (DMSO-d6) 8.75 (1H, s), 8.39 (1H, d), 7.85 (1H, dd) , 7.73 (1H, d), 7.47 (IH, ° d), 7.28 (1H, d), 7.10 - 7.03 (1H, m), 6.92 (1H, d), 6.82 (1H, d), 6.80 - 6.74 ( 1H, m), 2.88 - 2.79 (1H, m), 2.10 (3H, s), 1.32 - 1.09 (4H, m), 0.72 - 0.65 (2H, m), 0.58 - 0.50 (2H, m) + (9 ) 3-[3-({1-[2-(2-Chloroethoxy)-3-fluorophenyl]cyclopropyl} amino)-2-oxopyrazin-1(2H)- 01 yl]-N-cyclopropyl-4-methylbenzamide : The subtitle compound was prepared from

N-cyclopropyl-3-[3-{[1-(3-fluoro-2-hydroxyphenyl)cyclopropyl] amino }-2-oxopyrazin- 1(2H)-yl]-4-methylbenzamide . d oq ) e) using a method similar to that described in the example YAY (Example \o 1H NMR § (DMSO0-d6) 8.41 - 8.36 (1H, m), 7.88 - 7.82 (1H, m) ), 7.71 - 7.67 (1H, m), 7.51 - 7.38 (2H, m), 7.24 - 6.99 (2H, m), 6.87 - 6.82 (1H, m), 6.74 - 6.70 (1H, m), 4.40 -

YAAY

016 — 4.32 (2H, m), 4.07 - 4.00 (2H, m), 2.89 - 2.78 (1H, m), 2.07 (3H, 5), 1.29 - 1.16 (41, m), 0.71 - 0.63 (2H, m) ), 0.57 - 0.51 (2H, m) (g): N-cyclopropyl-3-[3-{[1-(3 -fluoro-2-hydroxyphenyl)cyclopropyljamino}-2-oxopyrazin- 1(2H) -yl]-4-methylbenzamide©: stirred

A) dioxane mv 001 at lea g) +”)£Y) 2-aminoethanol g) and ,0 (ex. 8” g) preparation (HPLC column ml) In a sealed tube for 7 hours, after purification with the title compound (MeCN / ammonia 7 +,Y lysate Xterra 0 g) LI q 4 ) 1 0

MS: APCI(+ve) 536 (M+H)+. 1H NMR 5 (DMSO0-d6) 8.38 (1H, s), 8.30 (1H, d), 7.85 (1H, d), 7.69 (1H, s), 7.49 - 7.35 (2H, m), 7.14 (1H, t ), 7.07 - 6.94 (1H, m), 6.89 - 6.83 (1H, m), 6.73 - 6.67 (1H, m), 4.49 - 4.42 (1H, m), 4.19 - 4.03 (2H, m), 3.80 - 3.66 (1H, m), 3.33 (2H, s), 2.95 (2H, 5), 2.88 - 2.78 (1H, m), 2.58 - 2.54 (1H, m), 2.06 (3H, s), 1.32 - 1.08 (2H , m), 1.07 - 0.99 (2H, m), Vo 0.89 - 0.78 (2H, m), 0.70 - 0.64 (2H, m), 0.58 - 0.48 (2H, m). Using a method similar to that described in (VY (Table (YAV-YAL)) the following examples were prepared “AY:” Example YAAY

(784) Example 3-[3-({1-[2-(2-Aminoethoxy)-3-fluorophenyl]cyclopropyl} amino)-2-oxopyrazin-1(2H)- y1]-N-cyclopropyl- 4-methylbenzamide

(YAS) Example N-Cyclopropyl-3-[3-{[1-(3-fluoro-2-{2-[(2- 8 hydroxyethyl)amino]ethoxy} phenyl)cyclopropyl]amino}-2- oxopyraz in-1(2H)-yl1]-4- methylbenzamide

(YAR) Example N-Cyclopropyl-3-{3-[(1-{2-[2-(ethylamino)ethoxy]-3 -fluorophenyl} cyclopropyl)amino]- 2-oxopyrazin-1(2H)- yl}-4-methylbenzamide Yo

(YAY) Example N-Cyclopropyl-3-{3-[(1-{3-fluoro-2-[2-(methylamino)ethoxy]phenyl } cyclopropyl)amino]-2-oxopyrazin-1(2H) -yl}-4-methylbenzamide

the

(VY) table rr ym N

H H

0

MS

1H NMR. § (DMSO-d6) [M+H]+ Example m/z H 8.54 - 8.30 (2H, m), 7.84 (1H, d), 7.69 478 Ny | TA (1H, 5), 7.45 (1H, d), 7.39 (1H, d), 7.12 (1H, 1), 6.99 (1H, q), 6.85 (1H, d), 6.69 (1H, d), 4.07 - 3.99 (2H, m), 2.96 (2H, £), 2.88 - 2.77 (1H, m), 2.06 (3H, s), 1.27 - 1.06 (4H, m), 0.73 - 0.46 (4H, m) 0 8.38 (2H, 5), 7.88 - 7.81 (1H, m), 7.71 - 522 Ramhalab | TAC 7.67 (1H, m), 7.50 - 7.37 (2H, m), 7.20 - 7.08 (1H, m), 7.05 - 6.96 (1H, m), 6.86 (1H, 1), 6.70 (1H, 1), 4.49 - 4.41 (1H, m), 4.16 - 4.06 (2H, m), 3.55 - 3.45 (2H, m), 3.00 - 2.90 (2H, m), 2.88

YAAY

- 2.79 (1H, m), 2.76 - 2.65 (2H, m), 2.06 (3H, d), 1.29 - 1.04 (4H, m), 0.75 - 0.59 (2H, m), 0.58 - 0.50 (2H, m 0 8.45 - 8.34 (2H, m), 7.85 (1H, d), 7.69 506 fr | 75 (1H, s), 7.46 (1H, d), 7.39 (1H, d), 3 (1H, 1), 7.06 - 6.95 (1H, m), 6.84 (1H, d), 6.69 (1H, d), 4.17 - 4.02 (2H, m), 2.97 - 2.88 (2H, m), 2.86 - 2.81 (1H, m), 2.73 - 2.58 (2H, m), 2.06 (3H, 5), 1.28 - 1.10 (4H, m), 1.09 - 0.99 (3H, m), 0.74 - 0.61 (2H, m), 0.56 - 0.48 (2H, m) ) 1 8.45 (1H, s), 8.37 (1H, d), 7.84 (1H, d), 492 Vive | TAY 7.68 (1H, 5), 7.46 (1H, d), 7.39 (1H, d), 7.12 ( 1H, 1), 7.04 - 6.93 (1H, m), 6.85 (1H, d), 6.68 (1H, d), 4.18 - 4.02 (2H, m), 2.95 - 2.78 (2H, m), 2.38 (3H, 5), 2.06 (3H, 5), 1.26 - 1.07 (4H, m), 0.70 - 0.63 (2H, m), 0.57 - 0.50 (2H, m)

YAAY

18 - Example (YAN) N-Cyclopropyl-4-ethyl-3-{3-[(1-methyl-1-{2-[2-(methylamino)ethoxy]phenyl}ethyl) amino ]-2-oxopyrazin-1(2H)-yl} benzamide H ZN 4 0 N oR COCO A 0 Methyl! 3-[(cyanomethyl)amino]-4-ethylbenzoate 0© to a stirred solution of methyl 3-amino-4-ethylbenzoate (+).1 (in ©1,V)THF mL) at 0 In the room, (Je 11,84) Hunig base was added, followed by the addition of bromo and (Je 4 ) acetonitrile. The mixture was heated on reflux for 06 hours. The reaction mixture was cooled to room temperature and concentrated to obtain to compound subtitle 01 as oil ([PEN Vv, . vacuo] added aqueous DCM ¢ 1 HCl was added; organic layer was separated; dried (MgS04) and 1H NMR 5 (DMSO0-d6) ) 7.35 (d, 1H), 7.24 - 7.18 (m, 2H), 5.97 (t, 1H), 4.34 (d, 2H), (d, 2H), 3.32 (d, 3H), 1.15 (t, 3H) 3.84 Methyl 3-(3,5-dibromo-2-oxopyrazin-1(2H)-yl)-4-ethylbenzoate : (<2) yo The title compound Al =— was prepared from methyl 3-[(cyanomethyl)amino]-4-ethylbenzoate (example (TYAA) using the same method as in the (OVO) YAAY example

— yaa - 1H NMR 5 (DMSO-d6) 8.14 (d, 1H), 8.06 (s, 2H), 8.04 - 8.02 (m, 1H), 3.87 (s, 3H), 1.11 (t, 3H) Other resonances obscured under solvent peak (2.4 ppm): (c) Methyl 3-[3-({1-[2-(benzyloxy)phenyl]-1 -methylethyl }amino)-5-bromo-2-oxopyrazin- 1( 2H)-yl]-4-ethylbenzoate©: The subtitle compound was prepared from (Ex. 4AP) and 3-(3,5-dibromo-2-oxopyrazin-1 (2H)-yl)-4 ethylbenzoate using (2) 4A Jie) o ¢ oa dimethyl-2-(phenylmethoxy)- benzenemethanamine (zY oY) in the same way as in the example

MS: APCI(+ve) 576 M+H)+. 0 : (d) d) 3-[3-({1-[2-(Benzyloxy)phenyl]-1-methylethyl}amino)-5 -bromo-2-oxopyrazin-1(2H)- yl] -N-cyclopropyl-4-ethylbenzamide : Then prepare the subtitle compound of methyl 3-[3-({1-[2-(benzyloxy)phenyl]-1-methylethyl }amino)-5-bromo-2-oxopyrazin - Vo 1(2H)-yl]-4-ethylbenzoate

YAAYX

—YV. — . (&Y oY ) c using the same method as in the example YAA (Example MS: APCI(+ve) 601 (M+H)+.1H NMR 5 (DMSO-d6) 8.42 (d, 1H), 7.91 (dd, 1H), 7.73 (d, 1H), 7.45 - 7.21 (m, 9H), 7.10 (t, 2H), 6.96 (t, 1H), 5.12 (s, 2H), 2.90 - 2.82 (m, 1H), 2.39 (q, 2H), 1.84 (d, 6H), 1.06 (t, 3H), 0.74 - 0.67 (m, 2H), 0.58 - 0.53 (m, 2H) © (e): N -Cyclopropyl-4-ethyl-3-[3-{[1-(2-hydroxyphenyl)-1 -methylethyl]amino}-2- oxopyrazin-1(2H)-yl]benzamide : The subtitle compound was prepared from 3-[3-({1-[2-(benzyloxy)phenyl]-1-methylethyl }amino)-5 -bromo-2-oxopyrazin-1(2H)-yl]- 01

N-cyclopropyl-4-ethylbenzamide using the same method as in Example (07J).

MS: APCI(+ve) 433 (M+H)+. (f) 3-[3-({1-[2-(2-Chloroethoxy)phenyl]-1-methylethyl} amino)-2-oxopyrazin-1(2H)-yl]-N- Ve cyclopropyl -4-ethylbenzamide: The subtitle compound was prepared from

YAAY

1 —

N-cyclopropyl-4-ethyl-3-[3-{[1 -(2-hydroxyphenyl)-1-methylethyl]amino} -2-oxopyrazin- 1(2H)-yl]benzamide (YoY) e) using the same Method as in example YAA (example MS: APCI(+ve) 495 (M+H)+.1H NMR 5 (DMSO0-d6) 8.43 (d, 1H), 7.91 (dd, 1H), 7.71 ( d, 1H), 7.52 (d, 1H), 7.34 (dd, ° 1H), 7.21 (t, 1H), 6.97 - 6.91 (m, 3H), 6.65 (q, 2H), 4.26 - 4.13 (m, 2H ), 3.93 (t, 2H), 2.89 - 2.81 (m, 1H), 2.45 - 2.38 (m, 2H), 1.87 (s, 3H), 1.84 (s, 3H), 1.06 (t, 3H), 0.70 - 0.67 (m, 2H), 0.57 - 0.54 (m, 2H) : (g) N-Cyclopropyl-4-ethyl-3-{3-[(1-methyl-1-{2-[2-( methylamino)ethoxy] Yo phenyl} ethyl)amino]-2-oxopyrazin-1(2H)-yl} benzamide : The subtitle compound was prepared from 3-[3-({1-[2-(2-chlorocthoxy) phenyl]-1-methylethyl } amino)-2-oxopyrazin-1(2H)-yl]-N- cyclopropyl-4-ethylbenzamide ?l).007) using the same method as in example AA (example Yo

MS: APCI(+ve) 490.4 (M+H)+. 1H NMR 5 (DMSO0-d6) 8.43 (d, 1H), 7.91 (dd, 1H), 7.69 (d, 1H), 7.51 (d, 1H), 7.34 (d, 1H), 7.20 (t, 1H), 6.98 - 6.88 (m, 3H), 6.67 - 6.62 (m, 2H), 4.02 - 3.88 (m, 2H), 2.90 - 2.80 (m, 3H), 2.45 - 2.35 (m, 2H), 2.26 (s, 3H) ), 1.82 (s, 6H), 1.06 (t, 3H), 0.70 - 0.66 (m, 2H), 0.55 - 0.53 (m, 2H). Ye. hill

7- The following examples (YAS) to (YAY) (VF table) were prepared using a method similar to that described in the (TAA) example from: 3-[3-({1-[2) -(2-chloroethoxy)phenyl]-1-methylethyl} amino)-2-oxopyrazin-1(2H)-yl]-N- cyclopropyl-4-ethylbenzamide (Example 2881 and suitable amine amine 5) R1 AA Jus) © suitable Ex ( 3( N-Cyclopropyl-4-ethyl-3-[3-({1-[2-(2-{[(2 S)-2-hydroxypropyl]amino}ethoxy) phenyl]-1- methylethyl}amino)-2-oxopyrazin-1(2H)-ylJbenzamide Ex. (Ya+) N-Cyclopropyl-4-ethyl-3-{3-[(1-{2) - [2-(ethylamino)ethoxy]phenyl}-1- Ye methylethyl)amino]-2-oxopyrazin-1(2H)-yl} benzamide (Yay) Joe N-Cyclopropyl-4-ethyl- 3-[3-{[1-(2-{2- [(2-hydroxyethyl)amino]ethoxy} phenyl)-1- methylethylJamino}-2-oxopyrazin-1(2H)-yl]benzamide ( Yay) Ji.

Yo 1-[2-(2-Aminoethoxy)phenyl]-1-methylethyl} amino)-2-oxopyrazin-1(2H)-yl]-N- {(-3[-3 cyclopropyl-4- ethylbenzamide YAAY

—YVY - () ¥) Table 7 R

ZN0

AT4!

N N

H5H

MS

1H NMR. § (DMSO-d6) [M+H]+ Example m/z YA4 8.44 (s, 1H), 7.91 (d, 1H), 7.71 (s, 534 1H), 7.51 (d, 1H) , 7.33 (d, 1H), 7.22 - 7.17 (m, 1H), 6.98 - 6.90 (m, 3H), HOH roll 6.65 (d, 2H), 4.38 (s, 1H), 3.98 - 3.94 (m , 2H), 3.61 (s, 1H), 2.95 - 2.81 (m, 4H), 2.45 (d, 2H), 1.84 (s, 6H), 1.06 (d, 3H), 1.00 (d, 3H), 0.69 ( d, 2H), 0.56 (s, 2H) 8.43 (d, 1H), 7.91 (d, 1H), 7.70 (d, 504 va. 1H), 7.51 (d, 1H), 7.34 (d, 1H), 7.19 (t, 1H), 6.98 - 6.88 (m, 3H), 6.65 (q, H lap 2H), 4.02 - 3.89 (m, 2H), 2.91 - 2.82 m, 3H), 2.54 - 2.51 (m, 2H), 2.45 -

YAAY

2.35 (m, 2H), 1.84 (s, 3H), 1.83 (5, 3H), 1.06 Pa) 3H), 0.90 (t, 3H), 0.70 - 0.66 (m, 2H), 0.56 - 0.54 (m - 6.87 (m, 3H), 6.64 (q, H 2H), 4.38 (t, 1H), 4.01 - 3.90 (m, 2H), Non 3.39 (q, 2H), 2.94 - 2.81 (m, 3H), 2.59 ( t, 2H), 2.45 - 2.34 (m, 2H), 4 (s, 3H), 1.82 (s, 3H), 1.06 (t, 3H), 0.70 - 0.67 (m, 2H), 0.56 - 0.54 (m, 2H 8.44 (d, 1H), 7.90 (dd, 1H), 7.69 (d, 476 5 1H), 7.51 (d, 1H), 7.34 (d, 9 (t, 1H), 6.97 - 6.88 (m, 3H) , 6.67 - A NH, 6.62 (m, 2H), 3.91 - 3.84 (m, 2H), 2.89 - 2.83 (m, 3H), 2.42 - 2.38 (m, 2H), 1.84 (s, 3H), 1.83 (s, 3H), 1.06 (t, 3H), 0.70 - 0.66 (m, 2H), 0.57 - 0.54 (m, 2H)

YAAY

A — No _ The following examples (YAY) to (TAA) (VE table) were prepared using a method similar to that described in Example (771) using: 3-(3-(1-) 2-(2-chloroethoxy)phenyl) cyclopropylamino)-2-oxopyrazin-1(2H)-yl)-N- cyclopropyl-4-methylbenzamide © (ex. amine s (—V TY appropriate. Ex. 3 Ya ( N-Cyclopropyl-3-[3-({1-[2-(2-{[(IR)-1- (hydroxymethyl)-2-methylpropyl]amino} ethoxy)phenyl]cyclopropyl } amino)-2-oxopyrazin-1 (2H)-yl]-4-methylbenzamide Ex. (Ya¢) N-Cyclopropyl-3-[3-({1-[2-(2-{[2-- hydroxy-1 -(hydroxymethyl)ethyl]amino } ethoxy) 01 ‎phenyl]cyclopropyl}amino)-2-oxopyrazin-1 (2H)-yl]-4-methylbenzamide Example (Yao) N-Cyclopropyl- 3-[3-{[1-(2-{2-[(1,1 -dioxidotetrahydrothiophen-3-yl)amino]ethoxy} ‎phenyl) cyclopropyl]Jamino}-2-oxopyrazin-1(2H)-yl ] -4-methylbenzamide (Ya) Ja.

Ve N-Cyclopropyl-3-{3-[(1-{2-[2-(5,6-dihydroimidazo[1,2-a] pyrazin-7(8H)- yDethoxy]phenyl}cyclopropyl) amino]-2-oxopyrazin-1 (2H)-yl}-4-methylbenzamide Example (aq) N-Cyclopropyl-4-methyl-3-{3-[(1-{2-[2-(1-) methyl-1,4,6, 7-tetrahydro-5H-imidazo[4,5-¢]pyridin-5-yl)ethoxy]phenyl}cyclopropyl)amino] -2-oxopyrazin-1(2H)-yl} benzamide Ye. YAAY i (¥ AA) eg N-Cyclopropyl-4-methyl-3-{2-oxo-3-[(1-{2-[2-(propylamino)ethoxy]phenyl} cyclopropyl)amino]pyrazin-1(2H)-yl}benzamide

J

0 22 0

A for “N N

H H

0 o

MS

1H NMR. 6 (DMSO-d6) [M+H]+R Example m/z 8.02 (d, 1H), 7.81 (s, 1H), 7.77 (d, 546 0 OH Yay 1H), 7.64 (d, 1H ), 7.40 (t, 1H), 7.14 ab (d, 1H), 7.11 - 7.04 (m, 2H), 6.75 (s, 1H), 4.38 - 4.31 (m, 2H), 3.92 - 3.84 (m , 1H), 3.72 - 3.64 (m, 2H), 3.51 (s, 2H), 3.35 - 3.26 (m, 2H), 3.04 - 2.97 (m, 1H), 2.73 - 2.66 (m, 1H), 2.31 (s , 3H), 2.11 - 2.01 (m, 1H), 1.52 - 1.26 (m, 4H), 1.21 - 1.07 (m, 6H), 0.97 (d, 2H), 0.82 - 0.75 (m, 2H). 8.37 - 8.32 (m, 1H), 7.87 - 7.81 (m, 534 H and 1H), 7.69 - 7.65 (m, 1H), 7.54 7.42 lap oH (m, 2H), 7.39 - 7.34 (m , 1H), 7.23 - 1 7.14 (m, 1H), 6.98 - 6.92 (m, 1H), OH 6.89 - 6.81 (m, 2H), 6.72 - 6.66 (m, 1H), 4.43 - 4.34 (m, 2H) , 4.10 - 4.02 (m, 2H), 3.05 - 2.96 (m, 2H), 2.86 - 2.79 (m, 1H), 2.65 - 2.58 (m, 1H), 2.22 - 2.10 (m, 5H), 1.25 - 1.13 ( m, 4H), 1.12 - 0.99 (m, 2H), 0.70 - 0.62 m, 2H), 0.56 - 0.49 (m, 2H).

YAAY

7.81 (d, 1H), 7.61 (d, 1H), 7.49 (d, 578 0 Yao 1H), 7.44 (d, 1H), 7.18 (t, 1H), 6.92 laps (d, 1H), 6.88 - 6.82 (m, 2H), 6.60 - hE 6.55 (m, 1H), 4.16 - 4.07 (m, 2H), £0 3.64 - 3.54 (m, 1H), 3.46 (q, 2H), 0 3.16 - 2.97 ( m, 3H), 2.95 - 2.84 (m, 2H), 2.83 - 2.75 (m, 1H), 2.39 - 2.24 (m, 1H), 2.11 (d, 2H), 2.05 - 1.86 (m, 1H), 1.39 - 1.20 (m, 3H), 1.15 (t, 3H), 1.10 - 0.96 (m, 1H), 0.79 - 0.71 (m, 2H), 0.63 - 0.55 (m, 2H). 8.35 (d, 1H), 7.84 (dd, 1H), 7.68 (d; 566 0 1H), 7.48 (dd, 1H), 7.46 (d, 1H), 7.28 Co 5 (s, 1H), 7.21 (td, 1H), 7.00 (d, 1H), > N 6.99 (d, 1H), 6.89 - 6.85 (m, 2H), 6.81 (d, 1H), 6.70 (d, 1H), 4.22 (t, 2H), 3.95 (t, 2H), 3.79 (d, 1H), 3.75 (d, 1H), 3.01 (d, 4H), 2.87 - 2.78 (m, 1H), 2.05 (s, 3H), 1.25 - 1.03 (m, 4H ), 0.69 - 0.64 (m, 2H), 0.54 - 0.50 (m, 2H 8.35 (d, 1H), 7.84 (dd, 1H), 7.68 (d, 580 / Yay 1H), 7.47 (m, 2H), 7.36 (s, 1H), 7.25 N (s, 1H), 7.20 (dt, 1H), 7.00 (d, 1H), CI 2 6.86 (dt, 1H), 6.86 (d, 1H), 6.70 (d, 3 N 1H), 4.19 (t, 2H), 3.52 (s, 2H), 3.44 (s, 3H), 2.98 (t, 2H), 2.88 (t, 2H), 2.85 - 2.79 (m, 1H), 2.56 (t , 2H), 2.05 (s, 3H), 1.27 - 1.03 (m, 4H), 0.69 - 0.63 (m, 2H), 0.55 - 0.49 (m, 2H).07.81 (d, 1H), 7.61 (5, 1H) ), 7.53 (d, 502 1 Yan 1H), 7.43 (d, 1H), 7.19 (t, 1H), 6.92 NA (d, 1H), 6.89 - 6.83 (m, 2H), 6.57 (d, 1H), 4.14 (t, 2H), 3.09 - 3.01 (m, 2H), 2.84 - 2.75 (m, 1H), 2.61 (6 2H), 2.10 (s, 3H), 1.66 - 1.32 (m, 3H), 1.31 - 1.05 (m, SH), 0.86 (t, 4H), 0.78 - 0.71 m, 2H), 0.60 - 0.54 (m, 2H).

YAAY

— YVA — (Y44) Example N-Cyclopropyl-3-[3-({1-[2-({(2R)-2-hydroxy-3- [(2-hydroxyethyl)amino]propyl} oxy) phenyl[cyclopropyl }amino)-2-oxopyrazin-1 (2H)-yl]-4-methylbenzamide

HO, ~~_-OH v yum © H

AS God ha l NA 9 1 righteousness 0 H : ( ) °

N-Cyclopropyl-4-methyl-3-{3-[(1-{2-[(2R)-oxiran-2-ylmethoxy]phenyl} cyclopropyl) amino]-2-oxopyrazin-1(2H)-yl}benzamide : mg to ¥1,0) cesium fluoride 5 mg) Y 17) potassium carbonate added

N-cyclopropyl-3-(3-(1 -(2-hydroxyphenyl)cyclopropylamino)-2-oxopyrazin- 1(2H)-yl)-4- methylbenzamide Ve: Add aad and stir the mixture for an hour. (Je 4) DMF mg) in 500 pd 17 (ex. mg) and the reaction mixture was stirred for ? 7011 ((R)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate) days. The reaction mixture was used without isolation / purify.

MS: 01) 473 (M+H)+. (b): ve

N-Cyclopropyl-3-[3-({1-[2-({(2R)-2-hydroxy-3 -[(2-hydroxyethyl)amino]propyl} oxy)phenyl] cyclopropyl }amino)-2-oxopyrazin -1(2H)-yl] -4-methylbenzamide : to (Je 1) amine ethanol was added

YAAY

— TV -

N-cyclopropyl-4-methyl-3-{3-[(1-{ 2-[(2R)-oxiran-2-ylmethoxy]phenyl} cyclopropyl) amino]-2-oxopyrazin-1(2H)-yl} benzamide all night. done on ml). The reaction mixture was heated at ©(DMF g) in VA) 754 (ex. bulk (504p01); gan all then dried layers DCM partitioning the reaction mixture between water and filtering with preparative Xbridge quantities (HPLC column, filtered and evaporated. After purification with © a product (45 ammonia volume) Jans) 7 0.7 in acetonitrile graded diethyl ether g.) was obtained after removing the solvent and pulverizing with 0.07( Title 1H NMR 5 (CD30D) 7.82 - 7.76 (m, 1H), 7.61 - 7.52 (m, 2H), 7.45 - 7.39 (m, 1H), 7.21 -7.14 (m, 1H), 6.93 - 6.81 (m, 3H), 6.57 - 6.53 (m, 1H), 4.20 - 4.11 (m, 1H), 4.03 - 3.98 (m, 2H), 3.64 - 3.56 (m, 2H), 2.96 - 2.88 (m , 1H), 2.85 - 2.68 (m, 4H), 2.11 - 2.07 (m, Yo 3H), 1.28 - 1.07 (m, 4H), 0.79 - 0.71 (m, 2H), 0.60 - 0.53 (m, 2H).

MS: APCI(+ve) 534 (M+H)+. 0 example) m

N-Cyclopropyl-3-[3-{[1-(2-{[(2R)-3 -(ethylamino)-2-hydroxypropyl] oxy} phenyl)cyclopropylJamino}-2-oxopyrazin-1(2H)-yl] -4-methylbenzamide Yo 0 = M" 0

A i

N N =

H o H Ra: The title compound was prepared using a method similar to that described in Example (4b) of Tal

Im(R)-N-cyclopropyl-4-methyl-3-(3-(1 -(2-(oxiran-2-ylmethoxy)phenyl)cyclopropylamino)- 2-oxopyrazin-1(2H)-yl) benzamide (ex.amine ethyl 5 (1Y44) MS: APCI(+ve) 518 (M+H)+.1H NMR § (CD30D) 7.80 (dd, 1H), 7.59 (s, 1H) , 7.55 (dd, 1H), 7.42 (d, 1H), 7.21 - ° (m, 1H), 6.93 - 6.82 (m, 3H), 6.55 (d, 1H), 4.22 - 4.12 (m, 1H) , 4.00 (d, 2H), 2.94 - 7.14 (m, 1H), 2.84 - 2.72 (m, 2H), 2.70 - 2.60 (m, 2H), 2.09 (s, 3H), 1.28 - 1.18 (m, 4H), 2.87 (m, 4H), 0.78 - 0.71 (m, 2H), 0.60 - 0.53 (m, 2H). 1.04 - 1.14 Example (1 ¥) N-Cyclopropyl-3-[3-{ [1-(2-{[(2R)-2-hydroxy-3 -(methylamino)propyljoxy} 01 ‎phenyl)cyclopropyl]amino}-2-oxopyrazin-1(2H)-yl] -4-methylbenzamide HO 7 N < q?7< 4 1 I 00 OY o A The title compound was prepared using a method similar to that described in Example 4b from: (R)-N-cyclopropyl-4-methyl -3-(3-(1-(2-(oxiran-2 -ylmethoxy)phenyl)cyclopropylamino)- 2-oxopyrazin-1(2H)-yl)benzamide Vo (Ex. 19 (IY and . amine ethyl YAAY

M 81 -

MS: APCI(+ve) 504 (M+H)+. 1H NMR § (CD30D) 7.81 - 7.79 (m, 1H), 7.60 (d, 1H), 7.57 - 7.54 (m, 1H), 7.43 (d, 1H), 7.21 - 7.16 (m, 1H), 6.93 - 6.83 (m, 3H), 6.57 (d, 1H), 4.20 - 4.12 (m, 1H), 4.02 - 3.99 (m, 2H), 2.91 - 2.83 (m, 1H), 2.84 - 2.72 (m, 2H), 2.40 (d, 3H), 2.1 0(s,3H), 1.28 - 1.13 (m, 4H), 1.14 - 1.09 (m, 1H), 0.79 - 0.71 (m, 2H), 0.61 - 0.54 (m, 2H). © (YY ) Example N-Cyclopropyl-3-[3-({1-[2-({(28)-2-hydroxy-3- [(2-hydroxyethyl)amino] propyl } oxy)phenyl] cyclopropyl} amino)-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide

HO 7 N ~._-OH 0 27 yum 0

AN12

N = N

H_o H: (“01

N-Cyclopropyl-4-methyl-3-{3-[(1-{2-[(2S)-oxiran-2-ylmethoxy] phenyl} cyclopropyl) amino]-2-oxopyrazin-1(2H)-yl} benzamide (1743) the subtitle compound was prepared using a method similar to that described in the example of -cyclopropyl-3-(3-(1 -(2-hydroxyphenyl)cyclopropylamino)-2-oxopyrazin-1 (2H)-yl )-4-Yo methylbenzamide

YAAY

— YAY - .(S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate, (2) TV) (Example MS: APCI(+ve) 473 (M+H)+.: (b) N-Cyclopropyl-3-[3-({1-[2-({(28)-2-hydroxy-3- [(2-hydroxyethyl)amino]propyl} oxy)phenyl]cyclopropyl }amino)-2- oxopyrazin-1 (2H)-yl]-4-methylbenzamide 5 : The title compound was prepared using a method similar to that described in Example (4b) of

N-cyclopropyl-4-methyl-3-{3-[(1-{2-[(2S)-oxiran-2-ylmethoxy]phenyl} cyclopropyl)amino]-2-oxopyrazin-1(2H)-yl} benzamide

Ivey (example MS: APCI(+ve) 534 (M+H)+. Ve 1H NMR 5 (CD30D) 7.80 (dd, 1H), 7.60 (d, 1H), 7.56 (dd, 1H), 7.43 (d, 1H), 7.21 - 7.15 (m, 1H), 6.92 (d, 2H), 6.89 - 6.83 (m, 1H), 6.56 (d, 1H), 4.23 - 4.12 (m, 1H), 4.01 (d , 2H), 3.63 - 3.58 (m, 2H), 2.97 - 2.90 (m, 1H), 2.85 - 2.67 (m, 4H), 2.10 (s, 3H), 1.27 - 1.07 (m, 4H), 0.79 - 0.71 (m, 2H), 0.60 - 0.54 (m, 2H).(v 0 ¥) Jie 0

N-cyclopropyl-3-[3-{[1-(2-{[(2S)-3 -(ethylamino)-2-hydroxypropyl]oxy} phenyl)cyclopropyl]amino}-2-oxopyrazin-1(2H)- yl]-4-methylbenzamide

YAAY

— YAY - 0 “ZN 0

AN0

N N

H o H: The title compound was prepared using a method similar to that described in Example (49 ¥<) from

N-cyclopropyl-3-[3-({1-[2-({(28)-2-hydroxy-3- [(2-hydroxyethyl)amino]propyl} oxy)phenyl]cyclopropyl}amino)-2-oxopyrazin -1 (2H)-yl]-4-methylbenzamide (vey) (example ©

N-Cyclopropyl-4-methyl-3-{3-[(1-{2-[(2S)-oxiran-2-ylmethoxy]phenyl} cyclopropyl) amino] -2-oxopyrazin-1(2H)-yl}benzamide

MS: APClI(+ve) 518 M+H)+. 1H NMR 5 (CD30D) 7.80 (dd, 1H), 7.59 (d, 1H), 7.55 (dd, 1H), 7.42 (d, 1H), 7.20 - 7.15 (m, 1H), 6.91 (d, 1H), 6.88 - 6.82 (m, 2H), 6.55 (d, 1H), 4.19 - 4.12 (m, 1H), 4.03 - Ve 3.97 (m, 2H), 3.46 (q, 2H), 2.93 - 2.87 (m, 1H) , 2.82 - 2.71 (m, 2H), 2.70 - 2.59 (m, 2H), 2.09 (s, 3H), 1.28 - 1.19 (m, 3H), 1.15 (t, 3H), 1.08 (td, 3H), 0.78 - 0.72 (m, 2H), 0.59 - 0.54 (m, 2H). (v « € ) Example N-Cyclopropyl-3-[3-{[1-(2-{[(2S)-2-hydroxy-3 -(methylamino)propyl]oxy} phenyl) Yo cyclopropyl]amino }-2-oxopyrazin-1(2H)-yl] -4-methylbenzamide

YAAY

16 -

H

AS)

ON 5

H o H ZZ : Then prepare the title compound using a method similar to that described in Example 49 “b of

N-cyclopropyl-3-[3-({1-[2-({(2S)-2-hydroxy-3-[(2-hydroxyethyl)amino]propyl} oxy)phenyl]cyclopropyl }amino)-2-oxopyrazin -1(2H)-yl]-4-methylbenzamide (vey) (ex. 0

MS: APCI(+ve) 504 (M+H)+. 1H NMR § (CD30D) 7.80 (dd, 1H), 7.60 (d, 1H), 7.56 (dd, 1H), 7.42 (d, 1H), 7.21 - 7.15 (m, 1H), 6.94 - 6.82 (m, 3H) ), 6.56 (d, 1H), 4.21 - 4.12 (m, 1H), 4.04 - 3.96 (m, 2H), 2.92 - 2.83 (m, 1H), 2.83 - 2.71 (m, 2H), 2.40 (d, 3H) ), 2.10 (s, 3H), 1.29 - 1.19 (m, 3H), 1.18 - 1.09 (m, 2H), 0.79 - 0.71 (m, 2H), 0.60 - 0.54 (m, 2H). Vo 0 « 0 ) Example 3-[3-{[1-(2-{[(2R)-2-Amino-3-hydroxypropylJoxy} phenyl)-1-methylethyl J]amino}-2-oxopyrazin- 1(2H)-yl]-N-cyclopropyl-4-methylbenzamide

HO

H,N70 27-0

OA 0 1

LT

YAAY

— and () : N-Cyclopropyl-4-methyl-3-[3-{[1-methyl-1-(2-{[(4S)-2-0x0-1,3 -oxazolidin-4- ylJmethoxy} phenyl)ethyl]amino } -2-oxopyrazin-1(2H)-yl] benzamide A solution of: N-cyclopropyl-3-(3 -(2-(2-hydroxyphenyl)propan-2-ylamino) was treated )-2-oxopyrazin-1(2H)-yl)-4- 5 methylbenzamide (ex. 4 0+ (pa in (Je V+) acetonitrile using potassium carbonate )£40,+g ) and TYE ) (S)-(2-ox0oxazolidin-4-yl)methy! 4-methylbenzenesulfonate 2 g) in a nitrogen atmosphere V+ the resulting mixture was stirred at 80 C for 1 hour V. The reaction mixture was diluted with water and extracted with DCM. Then the organic layer (MgSO4) was dried, filtered and evaporated to obtain the sub-title compound as a solid (1 g). MS: APCI(+ve) 518 0411+ (b): 3-[3-{[1-(2-{[(2R)-2-Amino-3-hydroxypropyl]Joxy} phenyl)-1- methylethyl Jamino } -2- \o oxopyrazin-1(2H)-yl]-N-cyclopropyl-4-methylbenzamide Solution was treated with: YAAY

5m78

N-cyclopropyl-4-methyl-3-[3-{[1-methyl-1-(2-{[(4S)-2-0x0-1,3-oxazolidin-4-yl]methoxy}phenyl)ethyl] Jamino} -2-oxopyrazin-1 (2H)-yl]benzamide potassium hydroxide using (Ja 0 ) MeOH (Ja 01) in water (p > 1) (iv vo) (eg h. diluted 07 mm for ov The resulting mixture was stirred at nitrogen g) under an atmosphere of 1 9 The (Je YOu) ethyl acetate phase was dried and extracted (Jo Yoo) reaction mixture with water ©

Phenomenex (preparative HPLC, filtration, and evaporation. After purification with organic “(MgSO4) in 70.7 (vol] acetonitrile using a graded amount of Lindh and filtered by Gemini ammonia _aqueous) gravel was collected. L on the title compound as a solid 0.000(g) MS: APCI(+ve) 520 (M+H)". 'H NMR § (DMSO-dg) 8.45 (s, 1H), 7.86 ( d, 1H), 7.75 - 7.67 (m, 1H), 7.49 (d, 1H), 7.3 1 Ye (d, 1H), 7.24 - 7.15 (m, 1H), 7.01 (d, 1H), 6.92 - 6.84 (m, 2H), 6.68 - 6.60 (m, 2H), 4.00 (m, 2H), 3.64 - 3.48 (m, 2H), 2.90 - 2.74 (m, 2H), 2.24 (s, 6H), 2.05 (s, 3H), 1.77 3.92 - (s, 6H), 0.74 - 0.64 (m, 2H), 0.60 - 0.50 (m, 2H). (Yen) Example N-Cyclopropyl-3 -[3-{[1-(2-{[(2R)-2-(dimethylamino)-3 -hydroxypropyl]oxy}phenyl)-1- \o methylethyl]amino}-2-oxopyrazin-1(2H)- yl]-4-methylbenzamide ( HO

N (

Al 0 m 0 blinking H 0 H a

YAY — — treated with a solution of: 3-[3-{[1-(2-{[(2R)-2-amino-3-hydroxypropyl]oxy} phenyl)-1 -methylethyl]amino}-2 -oxopyrazin-1(2H)-yl]-N-cyclopropyl-4-methylbenzamide (YO Yeo Ji), + g) in (Je V+) dichloroethane using formaldehyde 771 aqueous © (671 mL) In a nitrogen atmosphere, the resulting mixture was stirred at 1 01 for 10 minutes before adding 0 (p> 7 77) sodium triacetoxyborohydride, and the resulting mixture was stirred at Yo C for 101 hours. Dilute the reaction mixture with water (16 ml) and extract it using (YO (DCM) ml). The organic phase (48504/0) was dried, filtered, and evaporated. After purification by preparative HPLC (Phenomenex Gemini column) eluting with a graded amount of acetonitrile in 7 y (vol/ammonia) (p=aqueous ) and then obtaining the title compound as a solid) 18« PEN MS: APCI(+ve) 520 (M+H)+. 1H), 7.75 - 7.67 (m, 1H), 7.49 (d, 1H), 7.31 (d, 1H), 7.24 - 7.15 (m, 1H), 7.01 (d, 1H), 6.92 - 6.84 (m, 2H) , 6.68 - 6.60 (m, 2H), 4.00 - 3.92 (m, 2H), 3.64 - 3.48 (m, 2H), 2.90 - 2.74 (m, 2H), 2.24 (s, 6H), 2.05 (s, 3H) , 1.77 (s, 6H), 0.74 - 0.64 (m, 2H), 0.60 - 0.50 (m, 2H).

N-Cyclopropyl-3-fluoro-5-[3-{[1-(2-{[(2R)-2-hydroxy-3 -(methylamino)propyi] oxy}phenyl)-1-methylethyl]Jamino}-2 -oxopyrazin-1(2H)-yl] -4-methylbenzamide YAAY

- 7/8/8 °F ~ b N d 0 A ex H 0 F (1) : N-Cyclopropyl-3-fluoro-4-methyl-5-[ 3-({1-methyl-1- [2-(2R)-(oxiran-2-ylmethoxy) phenyl] ethyl } amino)-2-oxopyrazin-1(2H)-yl]benzamide 2 and prepared from : N-cyclopropyl-3-fluoro-5-[3-[[1-(2-hydroxyphenyl)-1 -methylethyl]amino]-2-oxo-1(2H)- pyrazinyl]-4-methyl- benzamide (eg (YoY) and (R)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate using a method similar to that described in MS (1739) Example: APCI(+ve) 493 (M+H)+. Ye (b): N-Cyclopropyl-3-fluoro-5-[3-{[1-(2-{[(2R)-2-hydroxy-3 -(methylamino)propyl]oxy} phenyl) -1-methylethylJamino}-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide The title compound was prepared using a method similar to that described in Example (©Y29) from: YAAY

-N-cyclopropyl-3-fluoro-4-methyl-5-[3-({1-methyl-1- [2-(2R)-(oxiran-2- ylmethoxy)phenyl]ethyl}amino) -2-oxopyrazin-1 (2H)-yl]benzamide (ex. (vey MS: APCI(+ve) 524 (M+H)+.'H NMR 5 (DMSO-d) 8.53 (s) , 1H), 7.71 (d, 2H), 7.26 (d, 2H), 6.98 - 6.89 (m, 3H), 6.68 ° (s, 2H), 4.84 (s, 1H), 3.93 - 3.88 (m, 3H), 2.91 - 2.78 (m, 1H), 2.59 - 2.57 (m, 2H), 2.23 (s, 3H), 2.00 (s, 3H), 1.85 (s, 6H), 0.64 (m, 4H) Ex. 0 A) ( N-Cyclopropyl-3-[3-{[1-(2-{[(2R)-3 -(ethylamino)-2-hydroxypropyl]oxy} phenyl)-1- methylethyl]amino}-2-oxopyrazin-1(2H)-yl}-5 -fluoro-4-methylbenzamide 01 H 3 ™ 2 ND 0 N N CL 0 H F Done Prepare the title compound using a method similar to that described in example (q) from: N-cyclopropyl-3-fluoro-4-methyl-5-[3-({1-methyl-1-[2-(2R)- (oxiran-2-ylmethoxy) phenyl] ethyl } amino) -2-oxopyrazin-1(2H)-yl]benzamide 0 (example (rev YAAY)

— Yq. —

MS: APCI(+ve) 538 (M+H)+. 'H NMR 5 (DMSO-dg) 8.52 (s, 1H), 7.75 (d, 1H), 7.66 (s, 1H), 7.25 (d, 2H), 6.97 - 6.89 (m, 3H), 6.68 (s, 2H), 4.83 (s, 1H), 3.88 (s, 3H), 2.92 - 2.79 (m, 1H), 2.68 - 2.57 (m, 4H), 2.00 (s, 3H), 1.85 (s, 6H), 0.95 (s, 3H), 0.63 (m, 4H) (v9 ) Example ©

N-Cyclopropyl-3-[3-{[1-(2-{[(25)-3 -(ethylamino)-2-hydroxypropyl]oxy} phenyl)-1- methylethyl]amino}-2-oxopyrazin-1) 2H)-y1]-5-fluoro-4-methylbenzamide

H 9 > Web

ANNA

H0H

F

: (1)

N-Cyclopropyl-3-fluoro-4-methyl-5-[3-({1-methyl-1-[2-(2 S)-(oxiran-2-ylmethoxy) 0 phenyl] ethyl}amino)-2- oxopyrazin-1(2H)-yl[benzamide The subtitle compound was prepared using a method similar to that described in Example (49?a): from N-cyclopropyl-3-fluoro-5-[3-[[ 1 -(2-hydroxyphenyl)-1-methylethylJamino]-2-oxo- 1(2H)- pyrazinyl]-4-methyl-benzamide Vo

.(8)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate and (cs YoY ) (example MS: APCI(+ve) 493 (M+H)+.: (b) N-Cyclopropyl -3-[3-{[1-(2-{[(2S)-3-(ethylamino)-2-hydroxypropyl]oxy} phenyl)-1- methylethyl]amino } -2-oxopyrazin-1(2H)- [yl]-5-fluoro-4-methylbenzamide 5 : from (Vee ) the title compound was prepared using a method similar to that described in the example

N-cyclopropyl-3-fluoro-4-methyl-5-[3-({1-methyl-1-[2-(2S)-(oxiran-2-ylmethoxy)phenyl] ethyl} amino)-2-oxopyrazin- 1(2H)-yl]benzamide ?). 7.75 (d, 1H), 7.66 (s, 1H), 7.32 (d, 1H), 7.19 (t, 1H), 6.97 - 6.86 (m, 3H), 6.68 (q, 2H), 4.83 (s, 1H) , 3.93 - 3.81 (m, 3H), 2.88 - 2.82 (m, 1H), 2.68 - 2.55 (m, 4H), 1.99 (s, 3H), 1.84 (s, 6H), 0.97 - 0.92 (m, 3H) , 0.70 (m, 2H), 0.55 (m, 2H).(FV) Example Yo

N-Cyclopropyl-3-fluoro-5-[3-{[1-(2-{[(25)-2-hydroxy-3- (methylamino)propyl]oxy } phenyl)-1-methylethyl]amino} -2 -oxopyrazin-1(2H)-yl]-4- methylbenzamide

YAAY

197 - For: No aves ae

F

: from (v vo) The title compound was prepared using a method similar to that described in the example

N-cyclopropyl-3-fluoro-4-methyl-5-[3-({1-methyl-1-[2-(2S)-(oxiran-2- ylmethoxy)phenyl]ethyl }amino)-2-oxopyrazin- 1(2H)-yl[benzamide ved (ex. 0

MS: APCI(+ve) 524 (M+H)+. 'H NMR & (DMSO-dg) 8.52 (s, 1H), 7.75 (d, 1H), 7.65 (s, 1H), 7.32 (d, 1H), 7.18 (t, 1H), 6.98 - 6.86 (m, 3H), 6.70 - 6.66 (m, 2H), 4.84 (s, 1H), 3.93 - 3.88 (m, 3H), 2.88 - 2.82 (m, 1H), 2.61 - 2.54 (m, 2H), 2.23 (d, 3H), 2.00 (s, 3H), 1.84 (s, 6H), 0.70 (m, 2H), 0.56 (m, 2H). Ve (*V)) Example 3-[3-({1-[2-(2-Aminoethoxy)phenyl]-1-methylethyl } amino)-2-oxopyrazin-1 (2H)-yl]-N - cyclopropyl-5-fluoro-4-methylbenzamide 1 NH,

ZN

and m 0 1

N N

CL o H

F

YAAY

— yay — The title compound was prepared using a method similar to that described in example vod e) from: 3-[3-[[1-[2-(2-chloroethoxy)phenyl]- 1-methylethylJamino]-2- oxo-1 (2H)-pyrazinyl]-N- cyclopropyl-5-fluoro-4-methyl-benzamide (dvoy) (example MS: APCI(+ve) 480.2 (M+H)+. © ' H NMR 5 (DMSO-dg) 8.61 - 8.44 (m, 1H), 7.77 (d, 1H), 7.68 (s, 1H), 7.40 - 7.30 (m, 1H), 7.24 - 7.15 (m, 1H), 6.99 - 6.87 (m, 3H), 6.73 - 6.61 (m, 2H), 3.96 - 3.80 (m, 2H), 2.93 - 2.77 (m, 3H), 2.05 (5, 3H), 1.88 (s, 6H), 0.76 - 0.64 (m, 2H), 0.62 - 0.50 (m, 2H).(*VY) Example N-(2-{2-[1-({4-[5-(Cyclopropylcarbamoyl)-3-fluoro) -2-methylphenyl]-3-ox0-3,4- Yo dihydropyrazin-2-yl}amino)-1-methylethyl]phenoxy} ethyl)glycine 0

N N

H0H

F

: A solution has been processed from

YAAYX

vat — — 3-(3-(2-(2-(2-aminoethoxy)phenyl)propan-2-ylamino)-2-oxopyrazin-1 (2H)-yl)-N- cyclopropyl-5 -fluoro-4-methylbenzamide (eg (pa +, VV «TY] dissolved in THF (01 ml) with triethylamine (£1 + ml) (So ,,.14 ) methyl bromoacetate In Joe's ©0107086. The resulting mixture was stirred at VO mm © for 1 hour. The reaction mixture was diluted with 27 ¥ aqueous (¥) methanol 5 (J—Y) mL). The solution was stirred at room temperature for 1 hour, acidified with acetic acid (Je 0+) ethyl acetate, and extracted with aqueous in Z+,Y ammonia using graded volumes of 45-75 of Phenomenex Gemini as a filter solution. sequentially) the title compound (0.07 g) was obtained. acetonitrile Ve

MS: APCI(+ve) 538 (M+H)+. 'H NMR § (DMSO-d) 8.61 - 8.50 (m, 1H), 7.74 - 7.64 (m, 2H), 7.36 (d, 1H), 7.24 - 7.14 (m, 1H), 7.01 - 6.85 (m, 3H) ), 6.69 - 6.62 (m, 1H), 6.58 - 6.52 (m, 1H), 4.11 - 3.99 (m, 2H), 3.15 (s, 2H), 3.03 (t, 2H), 2.91 - 2.82 (m, 1H) ), 1.94 (s, 3H), 1.81 (s, 6H), 0.71 - 0.57 (m, 4H) yo (11) Example N-(2-{2-[1-({4-[5- (Cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-3-oxo-3,4- ‎dihydropyrazin-2-yl}amino)-1-methylethyl[phenoxy} ethyl)-beta-alanine AGA

0 2 a" 0

A S$

N N

H0H

F

The title compound was prepared from 3-(3-(2-(2-(2-aminoethoxy)phenyl)propan-2-ylamino)-2-oxopyrazin-1(2H)-yl)-N-cyclopropyl-5- fluoro-4-methylbenzamide “acting”_using a method similar to that described for bromopropanoate 5 (YY) (Example ©. (*VY) Example MS: APCI(+ve) 552.4 (M+H)+ 'H NMR § (DMSO-dg) 8.73 - 8.59 (m, 1H), 7.78 - 7.65 (m, 2H), 7.35 (d, 1H), 7.25 - 7.12 (m, 1H), 7.06 - 6.86 (m, 3H), 6.70 - 6.58 (m, 2H), 4.05 - 3.93 (m, 2H), 3.03 - 2.90 (m, 2H), 2.86 - 2.73 (m, 3H), 2.18 (t, 2H), 2.05 (s, 3H), 1.87 (s, 6H), 0.74 - 0.61 (m, 2H), 0 0.61 - 0.48 (m, 2H) (v 1 ) Example 3-[3-({1-[2-(2) -Aminoethoxy)phenyl]cyclopropyl }amino)-2-oxopyrazin-1(2H)-yl]-N-cyclopropyl-S-fluoro-4-methylbenzamide

YAAY

— rat - 1 NH, 0 27- m 0

A1

N N

H0H

F

The title compound was prepared from 3-[3-[[1-[2-(2-chloroethoxy)phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-5- fluoro-4-methyl-benzamide using a method similar to that described in Example (4e).

MS: APCI(+ve) 478.2 (M+H)+. 'H NMR § (DMSO-dg) 8.45 (1H, d), 7.73 (1H, d), 7.60 (1H, s), 7.53 - 7.45 (2H, m), 7.19 (1H, t), 6.98 - 6.80 ( 4H, m), 6.76 - 6.72 (1H, m), 3.97 (2H, 0.2.94 (2H, 1), 2.89 - 2.75 (1H, m), 1.96 (3H, s), 1.27 - 0.98 (4H, m) ), 0.72 - 0.64 (2H, m), 0.57 - 0.51 (2H, m) a(11) Example Vo

N-Cyclopropyl-3-fluoro-5-[3-{[1-(2-{2-[(2-hydroxyethyl)(methyl)amino] ethoxy} phenyl)cyclopropyl]amino}-2-oxopyrazin-1(2H) )-yl]-4-methylbenzamide

J

1

AL 0 oN 0

N N Ay

H CX o H

F

YAAY

The title compound was prepared from: 3-[3-[[1-[2-(2-chloroethoxy)phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-N- cyclopropyl-5 -fluoro-4-methyl-benzamide . (— Yod ) d using a method similar to that described in example oq (Example MS: APClI(+ve) 536.2 (M+H)+. © 'H NMR § (DMSO-d) 8.45 (1H , d), 7.72 (1H, d), 7.60 (1H, s), 7.48 (1H, d), 7.28 (1H, s), 7.19 (1H, t), 6.96 (1H, d), 6.89 - 6.82 ( 2H, m), 6.74 (1H, d), 4.35 - 4.26 (1H, m), 4.08 (2H, 0.3.55 - 3.45 (2H, m), 2.83 (2H, t), 2.54 (2H, 0.2.31 (3H, 5), 1.96 (3H, 5), 1.21 - 1.02 (4H, m), 0.74 - 0.62 (2H, m), 0.57 - 0.48 (2H, m) (9 (eg Ve 3-Fluoro- N-methoxy-4-methyl-5-{3-[(1-methyl-1-{2-[2-(methylamino)ethoxy] phenyl }ethyl)amino]-2-oxopyrazin-1(2H)-yl} benzamide

H

I

0 “ZN 0 0 4 and diamond N

H o H

F

:)(

Methyl 3-fluoro-5-[3-{[1-(2-hydroxyphenyl)-1-methylethylJamino}-2-oxopyrazin- Vo 1(2H)-yl1]-4-methylbenzoate

YAAY

— TAA - : The subtitle compound was prepared from 3-[5-Bromo-3-[[ 1-methyl-1-[2-(phenylmethoxy)phenyl]ethylJamino]-2-oxo-1(2H)- pyrazinyl ]-5-fluoro-4-methyl-benzoic acid, methyl ester (YoY) using a method similar to that described in example 2 YOY (ex' H NMR 5 (DMSO-dg) 9.55 (s, 1H), 7.82 (d, 1H), 7.77 (s, 1H), 7.25 (d, 1H), 7.09 - 6.94 b (m, 2H), 6.80 - 6.66 (m, 4H), 3.94 (s, 3H), 2.10 (s, 3H), 1.89 (s, 6H) : (b) Methyl 3-[3-({1-[2-(2-chloroethoxy)phenyl]-1-methylethyl ( amino) -2-oxopyrazin-1(2H)- yl]-5-fluoro-4-methylbenzoate : The subtitle compound was prepared from 0 methyl 3-fluoro-5-[3-{[1-(2-hydroxyphenyl)- 1-methylethyl[Jamino}-2-oxopyrazin-1(2H)- yl]-4-methylbenzoate (Example 1 (IVY) using a method similar to that described in Example (YOY) MS: APCI(+ve ) 474 (M+H)+.0(c): 3-[3-({1-[2-(2-Chloroethoxy)phenyl]-1-methylethyl ( amino)-2-oxopyrazin-1 (2H)-yl]-5-fluoro-4-methylbenzoic acid : to (Je©) in water (a> +, VV) lithium hydroxide monohydrate was added

YAAY

ras — — methyl 3-[3-({1-[2-(2-chloroethoxy)phenyl]- 1-methylethyl } amino)-2-oxopyrazin-1(2H)-yl]-5- fluoro-4-methylbenzoate (Example b) [PEN VOY in (Ja 0 ) THF and the reaction mixture was stirred for § hours at room temperature. Water was added and the solution was acidified by adding ¥ 0 M HCI and the product was extracted in ethyl acetate (twice). The combined organic layers (MS04) were dried, filtered, and evaporated to yield the Atwan subcomplex as a solid 1 (g). MS: APCI(+ve) 460 (M+H)+. (d): 3-[3-({1-[2-(2-Chloroethoxy)phenyl]-1-methylethyl ( amino)-2 -oxopyrazin-1(2H)-yl]-5- Ye fluoro-N-methoxy-4-methylbenzamide to: 3-[3-({1-[2-(2-chloroethoxy)phenyl]- 1-methylethyl ( amino)-2-oxopyrazin-1(2H)-yl]-5- fluoro-4-methylbenzoic acid Yo (ex. 1 z¥ 51 g) in DMF 9 mL) ADDED : O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) YAAY

Oral (cap) 5 g A) N,N-diisopropylethylamnie mL). The reaction mixture was stirred for VO min; Then add (£V) O-methylhydroxylamine hydrochloride, + g). The reaction mixture was stirred at room temperature overnight; Then dilute it with water and extract it ethyl acetate. The organic layer (MgSO4) was dried, filtered, and evaporated to yield the subtitle compound © (17, g). MS: APCI(+ve) 489 (M+H)+.(e): 3-Fluoro-N-methoxy-4-methyl-5-{3-[(1-methyl-1-{2-) [2-(methylamino)ethoxy] phenyl }ethyl)amino]-2-oxopyrazin-1(2H)-yl } benzamide 0 The title compound was prepared from: 3-[3-({1-[ 2-(2-chloroethoxy)phenyl]-1-methylethyl ( amino)-2-oxopyrazin-1(2H)-yl]-5- fluoro-N-methoxy-4-methylbenzamide (Jb) 371) but using dioxane as solvent and Jeli time 0 min. MS: APCI(+ve) 484.2 (M+H)+.'H NMR 6 (DMSO0-dg) 7.60 (d, 2H), 7.26 (d, 2H), 6.95 - 6.91 (m, 3H), 6.67 (s, 2H), 3.96 0 (s, 2H), 3.70 (s, 3H), 2.84 (s, 2H), 2.27 (s, 3H), 2.00 (s, 3H), 1.83 (s, 6H).

fy = - Example (FV) N-Methoxy-4-methyl-3-{3-[(1-{2-[2-(methylamino)ethoxy]phenyl } cyclopropyl)amino]- 2 -oxopyrazin-1(2H)-yl} benzamide H I ZN 0 0 to 0 N | = yum 7 H o H go oe (): Methyl 3-[3-({1-[2-(2-chloroethoxy)phenyl]cyclopropyl}amino)-2-oxopyrazin-1(2H) - yl]-4-methylbenzoate A solution was treated with: methyl 3-(3-(1-(2-hydroxyphenyl)cyclopropylamino)-2-oxopyrazin-1(2H)-yl)-4- methylbenzoate Ye (VY JU) 80 + g) dissolved in A) acetonitrile ml) with potassium carbonate (Y,0A4 g) (Je +,30Y) 1-bromo-2-chloroethane s In a nitrogen atmosphere, the resulting suspension was stirred at AY C for 10 hours. The reaction mixture was evaporated to dryness, diluted with water (Jo Yoo), and extracted with DCM V0.5 Drying the organic bed (08504), filtering, and evaporating to yield the sub-title compound as foam (+,0Y g). MS: APCI(+ve) 454 (M+H)+.YAAY

7, 4(b): 3-[3-({1-[2-(2-Chloroethoxy)phenyl]cyclopropyl} amino)-2-oxopyrazin-1(2H)-yl]-4- methylbenzoic acid Preparation of the subtitle compound from: methyl 3-[3-({1-[2-(2-chloroethoxy)phenyl]cyclopropyl}amino)-2-oxopyrazin-1(2H)- 2 yl]-4-methylbenzoate (Example (IF) Y using a method similar to that described in Example 7) (z¥1 MS: APCI(+ve) 440 (M+H)+. 'H NMR § (DMSO -dg) 7.95 (dd, 1H), 7.86 (s, 1H), 7.66 (d, 1H), 7.55 (d, 1H), 7.29 (t, 1H), 7.05 (d, 1H), 6.99 - 6.94 (m, 2H), 6.86 (d, 1H), 4.35 (t, 2H), 4.07 - 4.00 (m, 2H), Vo (s, 3H), 1.18 (t, 4H). 1.99 (c) : 3-[3-({1-[2-(2-Chloroethoxy)phenyl]cyclopropyl} amino)-2-oxopyrazin-1(2H)-yl]-N- methoxy-4-methylbenzamide 5 The subtitle compound was prepared from: 3-[3-({1-[2-(2-chloroethoxy)phenyl]cyclopropyl } amino)-2-oxopyrazin-1(2H)-yl]-4- methylbenzoic acid YAAY

ERT

. (av 1 ) (example not b) using a method similar to that described in example

MS: APCI(+ve) 469 (M+H)+. (d) N-Methoxy-4-methyl-3-{3-[(1-{2-[2-(methylamino)ethoxy]phenyl} cyclopropyl)amino]- 2-oxopyrazin-1(2H) -yl} benzamide © : the title compound was prepared from 3-[3-({1-[2-(2-chloroethoxy)phenyl]cyclopropyl }amino)-2-oxopyrazin-1(2H)-yl]-4 - methylbenzoic acid. (—a¥ 1 ) (example no a la using a method similar to that described in the example

MS: APCI(+ve) 464 (M+H)+01 'H NMR 5 & 01150-0) 7.76 (d, 1H), 7.58 (s, 1H), 7.49 (d, 3H), 7.19 (t, 1H), 6.96 (d, 1H), 6.85 - 6.85 (m, 2H), 6.69 (d, 1H), 4.06 (t, 2H), 3.67 (s, 3H), 2.91 (t, 2H), 2.36 (s , 3H), 2.06 (s, 3H), 0.85 (d, 2H), 1.07 (s, 2H). 0 1 A) Example N-cyclopropyl-5-{3-[(1-{2-[2-(ethylamino)ethoxy|phenyl} cyclopropyl)amino]-2- \o oxopyrazin-1(2H)- yl}-2-fluoro-4-methylbenzamide

YAAY

N

AN2

N N

H o H

F

5-Bromo-4-fluoro-2-methylaniline (1) g) in water (V,)€Y) ammonium chloride (pa 4,7) A mixture of iron powder was heated for 1 min. To that hot mixture was Ve 100 m for 1-bromo-2-fluoro-4-methyl-5-nitrobenzene Addition © m overnight.The mixture was cooled to a temperature of 0.01 reaction on reflux (00 ml).XY) ethyl acetate was filtered through a cellite bed and extracted using odd all (MgSO4) ml) and dried V+ (+) mL) and brine 001 XV) the organic solution with water Ju and concentrated under reduced pressure to obtain the subtitle compound (99, g) as a solid. ), 3.49 (s, 2H), 2.11 (s, 3H) 01 2-(5-Bromo-4-fluoro-2-methylphenylamino)acetonitrile (=) d¥VA (ex. 5-bromo-4-fluoro- 2-methylaniline to (Jo 1,)¢) Hunig acetonitrile base and bromo were added followed by the addition of 4d yall at a temperature of (Ja 0+) THF g) in 94 ml ). The reaction mixture was heated to reflux overnight. The reaction mixture was cooled to V, £00) and the organic layer suspension was DCM ¢ 1 HCI at room temperature and concentrated. Yo g (HY) was added and concentrated to obtain the subtitle compound as a solid (MgSO4) and dried YAAY

— © YF11 - (d, 1H), 6.80 (d, 1H), 4.13 (d, 2H), 3.78 (s, 1H), 2.13 (s, 3H). 6.92 (yl000) § 'H NMR [(5-Bromo-4-fluoro-2-methylphenyl)amino]acetonitrile© to a solution of 2-(5-bromo-4-fluoro-2-methylphenylamino)acetonitrile (Ex. 1b?g) dissolved In (Ja VY) ethyl acetate base 1 €, YV (Hunig V) mL) methanol (¢ © mL) and 0 mM (00012)2 was added. The resulting mixture was stirred at 00 C overnight under an atmosphere of: carbon monoxide (© Bar). The cooled reaction mixture was evaporated to dryness and the residue was passed through a sealite filler; and filtered with hexane : ethyl acetate 1 : 1 . The filtrate was evaporated in a culture medium to obtain the individual title compound as a solid (1 mg). 'H NMR 5 (CDCl3) 7.19 (d, 1H), 6.95 (d, 1H), 4.19 (d, 2H), 3.93 (s, 3H), 2.21 (s, 3H) Methyl 5-(3, 5-dibromo-2-oxopyrazin-1(2H)-yl)-2-fluoro-4-methylbenzoate : (3) 0 to a stirred solution of (Je©,4Y) oxalyl bromide in [{ (Jo A ) upon safram in Cad nitrogen atmosphere add dropwise solution of: [(5-bromo-4-fluoro-2-methylphenyl)amino Jacetonitrile (ex. Mag EV) g) in (Je AA) DCM The reaction mixture was allowed to warm to room temperature for 1 min before adding DMF (¥YA + 0, mL). The reaction mixture was then heated on reflux overnight. The reaction mixture was cooled to cp Lia and water (Jo 001) was added for 11 min (caution); then the organic layer (+7 from other DOM extracts) was separated, dried (MgSO4) and then Pour it into the YAAY filling

— te — The solvents were removed in vacuo to obtain the title compound DCM silica and filtered with sub (£.47 g). NMR § (DMSO-d) 8.09 (s, 1H), 8.00 ( d, 1H), 7.48 (d, 1H), 3.86 (s, 3H), 2.18 (s, 3H) (e): Methyl 5-[3-({1-[2-(benzyloxy)phenyl] cyclopropyl}amino)-5-bromo-2-oxopyrazin- ° 1(2H)-yl]-2-fluoro-4-methylbenzoate g) in V,+Y1) 1-(2-(benzyloxy)phenyl)cyclopropanamine A solution of: was treated with (Je V+) dioxane d1 (eg methyl 5-(3,5-dibromo-2-oxopyrazin-1(2H)-yl)-2-fluoro-4-methylbenzoate 001 The resulting solution was stirred at nitrogen in an atmosphere of (Jo +,4¥1) Huing g) and 0.0 M base and extracted with 1 HCL h. The cooled reaction mixture was diluted by adding 11 M sad and evaporated to obtain (MgSO4). The combined organic layers were dried. diethyl ether as foam. (pa 7,71) Subtitle compound

MS: APCI(+ve) 580, 582 (M+H)+ 'H NMR § (DMSO-d) 7.87 - 7.49 (m, 4H), 7.48 - 7.41 (m, 1H), 7.40 - 7.26 (m, 3H) ), Vo 7.25 - 7.16 (m, 1H), 7.06 - 7.00 (m, 2H), 6.93 - 6.85 (m, 1H), 5.22 (s, 2H), 3.83 (s, 3H), 2.11 (s, 3H) , 1.30 - 1.05 (m, 4H). Expensive

VY — _ (f) : Methyl 2-fluoro-5-[3-{[1-(2-hydroxyphenyl)cyclopropyl]amino}-2-oxopyrazin-1(2H)-yl]-4 methylbenzoate to : 5-[3-({1-[2-(benzyloxy)phenyl]cyclopropyl} amino)-5-bromo-2-oxopyrazin-1(2H)-yl]-2-© fluoro -4-methylbenzoate (Ex. 718 H; 7.71 g) in (Jo Y'+) ethanol ammonium formate (1 m g) (10 47 PAC) was added. The reaction mixture was heated at Vo m Yaad hours. Another volume of Hunig's base (©mL) was added and the reaction mixture was heated at 40 °C for ; hours. 0 and another amount of ammonium formate catalyst and Hunig's base were added and the reaction mixture was heated at 0 m for ; hours. The reaction mixture was then warmly filtered through ade fiber glass dala); and washed thoroughly with ©0000 ml cethanol and then with 0 ml DCM and then with 9.60 ml of DCM / methanol 701. The DCM and MecOH/DCM filtrate products were collected, evaporated and divided remaining between DCM and water. The organic layer VO was separated, dried (MgSO4), filtered, and evaporated to yield the sub-title compound as solid 17 01 (g). MS: APCI(+ve) 410 (M+H)+.YAAY

- $A — 'H NMR § (CDCls) 11.29 (s, 1H), 7.77 (d, 1H), 7.39 (dd, 1H), 7.23 - 7.18 (m, 1H), 7.12 (d, 1H), 7.03 ( s, 1H), 6.93 - 6.90 (m, 2H), 6.86 (td, 1H), 6.42 (d, 1H), 3.90 (s, 3H), 2.17 (s, 3H), 1.37 - 1.23 (m, 4H) : (g).

N-Cyclopropyl-2-fluoro-5-[3-{[ 1-(2-hydroxyphenyl)cyclopropyl]amino }-2-oxopyrazin-© 1(2H)-yl]-4-methylbenzamide for (THF molar In 1 mL of a solution of 0.14) Isopropylmagnesium chloride 0 min was added to a solution of 0.87 (amine cyclopropyl mL) and methyl 2-fluoro-5-[3-{[1 -(2-hydroxyphenyl)cyclopropyl]amino}-2-oxopyrazin-1(2H)- yl]-4-methylbenzoate 01 (Example 11 AVY Rag) in (Je Ye ) THF and fry it at room temperature in an atmosphere of 0 . The reaction mixture was stirred for an hour. 1 mol HCL was carefully added and the volatiles were removed in vacuo. The residue was converted to a basic medium by adding a saturated aqueous sodium bicarbonate solution and extracted in DCM. The organic layers were collected, dried 0 (048804), and evaporated to yield a subtitle compound 0.1845 (g). MS: APClI (+ve) 435 (M+H)+.'H NMR § (CDCls) 11.35 (s, 1H), 7.92 (d, 1H), 7.41 - 7.36 (m, 1H), 7.24 - 7.17 (m, 1H), (d, 1H), 7.03 - 7.01 (m, 1H), 6.94 - 6.92 (m, 1H), 6.92 - 6.89 (m, 1H), 6.89 - 6.82 7.08 YAAY

— 94m (m, 1H), 6.79 - 6.72 (m, 1H), 6.43 - 6.41 (m, 1H), 2.97 - 2.86 (m, 1H), 2.18 - 2.14 (m, 3H), 1.41 - 1.23 (m, 4H), 0.92 - 0.83 (m, 2H), 0.65 - 0.57 (m, 2H). : (h) 5-[3-({1-[2-(2-Chloroethoxy)phenyl]cyclopropyl} amino)-2-oxopyrazin-1(2H)-yl]-N-cyclopropyl-2-fluoro -4-methylbenzamide© : to a solution of

N-cyclopropyl-2-fluoro-5-[3-{[1-(2-hydroxyphenyl)cyclopropyl]Jamino}-2-oxopyrazin- 1(2H)-yl]-4-methylbenzamide potassium carbonate (Jo) added +) acetonitrile in (0.184 ax (ex. 18 g ml). The reaction mixture 4.9 4 (1-bromo-2-chloroethane g) was heated and followed by the addition of ¥,VA) 0 The reaction mixture was collected at room temperature; nitrogen 1 hour under TY at 40 °C for a period of time. acetonitrile and its filtration through celite; And wash the reaction paste with another quantity of . (p> 1 A) Filtration and desolventization in vacuo to obtain the subtitle compound

MS: APCI(+ve) 497/498 (M+H)+. 'H NMR § (CDCls) 7.80 (d, 1H), 7.57 (dd, 1H), 6.98 (d, 1H), 6.87 (t, 1H), 6.84 - 6.82 Yo (m, 1H), 6.74 (d, 1H) ), 6.69 - 6.63 (m, 1H), 6.23 (d, 1H), 4.25 - 4.20 (m, 2H), 3.84 - 3.80 (m, 2H), 2.86 - 2.80 (m, 1H), 2.08 (s, 3H) ), 1.23 - 1.16 (m, 3H), 1.10 - 1.06 (m, 1H), 0.83 - 0.76 (m, 2H), 0.56 - 0.50 (m, 2H).

YAAY

: (i) N-Cyclopropyl-5-{3-[(1-{2-[2-(ethylamino)ethoxy]phenyl}cyclopropyl)amino]-2- oxopyrazin-1(2H)-yl} -2-fluoro-4-methylbenzamide f (THF mL of ¥ MV ¥,+ VY) amine ethyl A solution of 5-[3-({1-[2-(2-chloroethoxy)) was heated phenyl]cyclopropyl }amino)-2-oxopyrazin-1(2H)-yl]-N-© cyclopropyl-2-fluoro-4-methylbenzamide in a sealed tube 1 001 h at YE for (Ja ¥) dioxane mg) in Yoo Ah YA (example M. THF in 1 mL of 0.007 solution (amine ethyl more Jas added)

Preparative Xbridge (HPLC column) Heat the reaction mixture for another 7 h. Purification with (45% ammonia (v/v) JAA acetonitrile and filtration with graduated amounts of 0 mg). Title compound as solid 'H NMR 5 (DMSO-d) 8.33 (s, 1H), 7.52 - 7.28 (m, 4H), 7.23 - 7.14 (m, 1H), 6.95 (d, 1H), 6.90 - 6.79 ( m, 2H), 6.65 (s, 1H), 4.05 (s, 2H), 2.99 - 2.87 (m, 2H), 2.79 (s, 1H), 2.67 - 2.58 (m, 2H), 2.08 - 1.98 (m, Yo ( * 4 ) Example N-Cyclopropyl-2-fluoro-4-methyl-5-{3-[(1-{2-[2-(methylamino)ethoxy]phenyl ( cyclopropyl)amino]-2-oxopyrazin- 1(2H)-yl} benzamide L

N

A Ig

N N

H JH

F

: to a solution of 5-[3-({1-[2-(2-chloroethoxy)phenyl]cyclopropyl } amino)-2-oxopyrazin-1 (2H)-yl]-N-cyclopropyl-2-fluoro- 4-methylbenzamide ml (in 1.1) by weight dissolved in water 1/0 « methylamine 3 mg) 001 AH 18 (example © mg). The reaction mixture was stirred at YV,£) potassium iodide (Je 1( dioxane) added at room temperature overnight; then heated at £0 overnight. The reaction mixture was heated at and filtered (Preparative Phenominex Gemini (HPLC column m for £4 h. After purification with 8 b and then acetonitrile at 70.7 (vol/vol) with graded amounts of ammonia at 70.7 (vol/vol) acetonitrile in graduated amounts of Xbridge column aay 0 0 mg (aqueous) (VY) to obtain the title compound as a solid 1H NMR 5 (DMSO-d6) 8.34 (s, 1H), 7.51 - 7.41 (m) , 3H), 7.33 (d, 1H), 7.19 (t, 1H), 6.95 (d, 1H), 6.88 - 6.81 (m, 2H), 6.64 (d, 1H), 4.09 - 4.00 (m, 2H), 2.94 - 2.85 (m, 2H), 2.83 - 2.75 (m, 1H), 2.35 (s, 3H), 2.03 (s, 3H), 1.24 - 1.00 (m, 4H), 0.71 - 0.61 (m, 2H), 0.55 - 0.48 (m, 2H).

MS: APCI(+ve) 492.2 (M+H)+

YAAY

- 17 - (©710) Example N-Cyclopropyl-3-fluoro-4-methyl-5-[3-{[1-methyl-1-(2-{[2-(methylamino)ethyl] sulfanyl } phenyl)ethyl[amino}-2-oxopyrazin-1(2H)-yl]Jbenzamide

H

I

ASN

Aran H oH

F

2-(Benzyloxy)ethanethiol 0 ° : To (p>Y),Y) potassium carbonate (ml) A®) ml)/water V+) methanol was added in (a> A, 0Y) S-2-(benzyloxy)ethyl ethanethioate Done. ethyl acetate min. Water was added and the 010 mixture was extracted. The reaction mixture was stirred for a while, its concentration was (MgSO4) aqueous, and ammonium chloride was dried. The organic layers were collected and washed with B. in vacuo to obtain the subtitle compound (Arai g) 01 'H NMR § (CDCl) 7.33 - 7.24 (m, SH), 4.54 (m, SH), 4.54 (H) 2H), 3.61 (q, 2H), 2.72 (q , 2H), 1.59 (t, 1H) 2-{[2-(Benzyloxy)ethyl]sulfanyl} benzonitrile (b): using (Je 01 (DMF g) in ©,AC) 2- nitrobenzonitrile solution was treated with

YAAY

2-(benzyloxy)ethanethiol (example p. 64 g) and a solution of potassium (Y,VT) hydroxide g) in water (© (Ja) was added drop by drop in a nitrogen atmosphere, the resulting mixture was stirred at 0 C for 2 hours.The reaction mixture was quenched with water, extracted in ethyl acetate, and the combined organic layers were washed with brine, dried (MgSO4), concentrated in vacuo, and the residue purified (S102 chromatography) and filtered with diethyl ether 7 On Jon in iso-hexane ) to obtain the subtitle compound as a solid Vio A (g). 'H NMR § (CDCl) 7.60 (d, 1H), 7.46 (d, 2H), 7.32 - 7.23 (m, 6H), 4.54 - 4.53 (m, 2H), 3.72 (t, 2H), 3.24 (t, 2H) 2-(2-{[2-(Benzyloxy)ethyl]sulfanyl} phenyl)propan-2-amine (z) ov mL) at t+) THF dissolved in (pa 3,00) cerium (III) ) chloride A suspension of 01 was stirred for ? Hours in Joe by «©010088. The resulting suspension was cooled and: 2-{[2-(benzyloxy)ethyl]sulfanyl} benzonitrile (Ex. 0b; ©g) was added. The mixture was cooled to -0 C before methyllithium was added (1.0 M solution complexed with lithium bromide 1 ml). The mixture was maintained at -01°C for Ye min before extinguishing by adding ammonia (88+0ml). The mixture was stirred at room temperature for 1 hour; Then the solids were separated by filtration and discarded. The filtrate was diluted with water and ethyl acetate was extracted. The organic layer “(MgS04) was dried, filtered and evaporated to obtain the crude product. then dilute the crude product by adding 1 M aqueous HCL; and extracted by diethyl ether (and discarded). The aqueous layer was converted to a basic medium by adding ammonia 8860 and extracting it using ethyl acetate.

YAAY

- 415 = g.TY) Sub-oil (Ra NMR § (J00) 7.47 - 7.43 (m, 2H), 7.30 - 7.26 (m, SH), 7.15 (t, 2H), 4.52 (s, 2H), 3.69 (t, 2H), 3.22 (t, 2H), 2.17 (s, 2H), 1.63 (s, 6H) :)(

Methyl 3-[3-{[1-(2-{[2-(benzyloxy)ethyl]sulfanyl } phenyl)-1-methylethyl amino} -5- bromo-2-oxopyrazin-1(2H)-yl]-5 -fluoro-4-methylbenzoate : H from YoY) The subtitle compound was prepared using a method similar to the example (methyl 3-(3,5-dibromo-2-oxopyrazin-1(2H)-yl)- 5-fluoro-4-methylbenzoate (z¥Y- (ex. 2-(2-{[2-(benzyloxy)ethyl]sulfanyl} phenyl)propan-2-amine) and (ovey 00

MS: APCI(-ve) 639 (M-H). amino} -5-bromo-2- oxopyrazin-1(2H)-yl]-N-cyclopropyl-5-fluoro-4-methylbenzamide : the subtitle compound was prepared from 9 methyl 3-[3-{[1- (2-{[2-(benzyloxy)ethyl]sulfanyl} phenyl)-1-methylethylJamino}-5- bromo-2-oxopyrazin-1(2H)-yl]-5-fluoro-4-methylbenzoate

YAAY

-© (Example 10D Using a method similar to that described in Example 0 (LY) the crude product was pulverized in diethyl ether and the solid was separated by filtering to yield the subtitle product (Y,YYg). The filtrate was concentrated in vacuo that was purified (chromatograph 58:02 and filtered with diethyl ether 70010 to ethyl acetate 7001). The fractions containing the product © were collected and concentrated in vacuo to yield the subtitle compound again (1,7 g) as a solid. MS: APCI(+ve) 665 (M+H)". : (f) 3-[3-{[1-(2-{[2-(Benzyloxy)ethyl] sulfanyl } phenyl)- 1 -methylethyl Jamino ( -2-oxopyrazin- 1(2H)-yl]-N-cyclopropyl-5-fluoro-4-methylbenzamide Ye : to (ex. 117e; 0.0g) in (Je ¥©) ethanol (Y,Y00) ammonium formate g) PAC (44 5 g) was added and the resulting solution was heated at Vo C for 1 hour. After cooling to ad yall temperature, then A paste of type 8 lia (p> 171 ) Pd/C / 01 was added in 0 muscat” (© Ja) and the reaction mixture was heated for VO m for an hour. The reaction mixture was filtered through a cellite. The filtrate was concentrated in vacuo and then extracted in DCM The organic solution (MgS04) was dried and concentrated in vacuo to obtain the subtitle compound.(p>5)

MS: APCI(+ve) 587 (M+H)+. the

(g): -1- ( assay[ N-Cyclopropyl-3-fluoro-5-{3-[(1-{2-[(2-hydroxyethyl)sulfanyl methylethyl)amino]-2-oxopyrazin-1 (2H)-yl} -4-methylbenzamide stirred: 3-[3-{[1-(2-{[2-(Benzyloxy)ethyl]sulfanyl} phenyl)-1-methylethyl]amino}-2- oxopyrazin- ~~ © 1(2H)-yl]-N-cyclopropyl-5-fluoro-4-methylbenzamide (Ex. 17o; 017 g) in (Je VY) DCM and cooled to saphram. Add boron (YAY) tribromide, + ml of a 1 Mol solution in (DCM) dropwise at a ica and the reaction mixture was stirred for 0 minutes at zero 5. Another equivalent of a solution was added boron tribromide Ve after an hour and heated to room temperature The reaction mixture was diluted with phi water and extracted with ethyl acetate The organic layers were collected, dried (504 p/0), filtered and evaporated in vacuo to obtain the product CThe crude product was purified (chromatography 2 and eluted with diethyl ether 7001 to ethyl acetate 7001 (to yield the subtitle compound as a solid), +1 g). MS: APCI(+ve) 497 (M+H) )". sulfanyl} phenyl)ethyl]amino}-2-oxopyrazin-1(2H)-yl]benzamide stirred: N-Cyclopropyl-3-fluoro-5-{3-[(1-{2-[(2) -hydroxyethyl)sulfanyl]phenyl}-1- methylethyl)amino]-2-oxopyrazin-1(2H)-yl}-4-methylbenzamide Ye YAAY

(eg 1.15 “SFY g) in (Ja Yo) DOM and cooled to - 0 4 C before adding triethylamine (£7, + mL) 5 Y£) methanesulfonyl chloride 0 , + ml). The reaction mixture was warmed to room temperature and Z€ (amine methyl water) (Z€ + water) ethanol (© ml) was added. The reaction mixture was then stirred for VA for 1 hour at 100 C. The reaction mixture was concentrated in vacuo; Then © was purified on SCX gil), Lali filtered with ethanol (and excluded), and flushed with IY + methanol 8 ammonia . The crude product was purified by preparative HPLC (Phenomenex “Gemini” column filtered with a Jo—4o0 gradient of aqueous Z+,Y ammonia at 2610010116). The fractions containing the desired compound were evaporated to dryness to obtain the title compound as a solid (¥ mg). 1H NMR § (DMSO-d6) 8.54 (s, 1H), 7.75 (d, 1H), 7.63 (s, 1H), 7.45 (d, 1H), 7.31 (d, 01 1H), 7.17 (s , 2H), 6.86 (s, 1H), 6.59 (d, 2H), 2.97 (s, 2H), 2.85 (s, 1H), 2.61 (s, 2H), 2.23 (s, 3H), 2.00 ( s, 3H), 1.84 (d, 6H), 0.63 (d, 4H) MS: APCI(+ve) 510 (M+H)+.(YY) Example 3-{3-[( 1-{2-[(2-Aminoethyl)sulfanyl|phenyl}-1-methylethyl)amino]-2-oxopyrazin- Yo 1(2H)-yl}-N-cyclopropyl-5-fluoro-4-methylbenzamide

NH,

J

LLD 0

F

God

= 178 - )( : 3-{3-[(1-{2-[(2-chloroethyl)sulfanyl]phenyl}-1-methylethyl)amino]-2-oxopyrazin- 1(2H)-yl} -N-cyclopropyl-5-fluoro-4-methylbenzamide A solution was treated with: ‎N-cyclopropyl-3-fluoro-5-{3-[(1-{2-[(2-hydroxyethyl)sulfanyl]phenyl} -1- 5 methylethyl)amino]-2-oxopyrazin-1(2H)-yl}-4-methylbenzamide (ex. 701 g; 0.109 g) dissolved in (Js Y) acetonitrile Using v,+£A) triethylamine mL) triethylamine hydrochloride (5.13 mg) in nitrogen atmosphere the resulting solution was stirred at 0 5 before adding p-toluenesulfonyl chloride (00 + ,+ g) for © minutes. Then Lithium chloride (kd) was added and the mixture was stirred at room temperature for 11 hours. The reaction mixture was diluted with Yoo (elo ml) and extracted with DCM ( Ja Yoo).

0(b): -1-methylethyl)amino]-2-oxopyrazin- ( to stam[ 3-{3-[(1-{2-[(2-Aminoethyl)sulfanyl) 1(2H) -yl}-N-cyclopropyl-5-fluoro-4-methylbenzamide

The title compound was prepared from: ‎YAAY‎

3-{3-[(1-{2-[(2-chloroethyl)sulfanyl] phenyl} - 1-methylethyl)amino]-2-oxopyrazin- 1(2H)-yl}-N-cyclopropyl-5-fluoro- 4-methylbenzamide (BYYO) using a method similar to that described in Example IVY + (Example MS: APCI(+ve) 496 (M+H)+. 'H NMR § (DMSO-d) 8.54 ( d, 1H), 7.75 (d, 1H), 7.62 (s, 1H), 7.45 (dd, 1H), 7.32 - © 7.29 (m, 1H), 7.19 - 7.14 (m, 2H), 6.86 (s, 1H) ), 6.59 (dd, 2H), 2.91 (t, 2H), 2.87 - 2.84 (m, 1H), 2.63 (t, 2H), 2.00 (d, 3H), 1.84 (d, 6H), 1.54 (s, 1H), 0.70 (q, 2H), 0.56 (q, 2H) (v YY ) Example N-Cyclopropyl-3-fluoro-5-[3-({1-[2-({2-[( 2-hydroxyethyl)amino]ethyl} sulfanyl)phenyl]- 1-methylethyl }amino)-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide Yo

J H

7 NH 0 “ZN ÷ N 0

F

The title compound was prepared from 3-{3-[(1-{2-[(2-chloroethyl)sulfanyl|phenyl}-1-methylethyl)amino]-2-oxopyrazin- 1(2H)-yl}- N-cyclopropyl-5-fluoro-4-methylbenzamide

YAAY

(YOY) (Example 17©a) was purified using a method similar to that described in Example and filtered using a 5-50/preparative X-Bridge gradient (HPLC column using the crude product to obtain Title compound as a solid. (aqueous acetonitrile at 7.7 ammonia

MS: APCI(+ve) 496 (M+H)+. 1H NMR § (DMSO-d6) 8.54 (d, 1H), 7.75 (d, 1H), 7.62 (s, 1H), 7.45 (dd, 1H), 7.32 - o 7.29 (m, 1H), 7.19 - 7.14 ( m, 2H), 6.86 (s, 1H), 6.59 (dd, 2H), 2.91 (t, 2H), 2.87 - 2.84 (m, 1H), 2.63 (t, 2H), 2.00 (d, 3H), 1.84 (d, 6H), 1.54 (s, 1H), 0.70 (q, 2H), 0.56 (q, 2H) (* Y 9 Ex. N-Cyclopropyl-3-fluoro-4-methyl-5-{3 -[(1-methyl-1-{2-[3-(methylamino)propyl] phenyl }ethyl)amino]-2-oxopyrazin-1(2H)-yl} benzamide

HN

0 2 N

NO TO ® o H PZ

F

(Z)-3-(2-Cyanophenyl)acrylic acid 00 with (Je Yo) THF dissolved in (p>© ) 1-nitrosonaphthalen-2-ol solution of dallas mixture stirred The reaction was at nitrogen in an atmosphere of (1,1 ax ) p-toluenesulfonyl chloride (g) in water (££) sodium hydroxide for an hour. The mixture was treated with a solution of M71 V0

YAAY

(Je" 1 (drip for ye min. JF of yo m. The reaction mixture was diluted with water yor mL) and extracted with 100 (diethyl ether mL) (excluded The aqueous layer was acidified by adding ¥ M HCI, extracted (T+ + (ethyl acetate ml), dried (MgSO4), filtered, and evaporated. The residue was pulverized with 756 diethyl ether in iso-hexane © _ to obtain Subtitle compound as solid (£,Y0) g). {' (d, 179.0 Hz, 1H). 6.24 3-(2-Cyanophenyl)propanoic acid (<) A slurry of J) (Z)-3-(2-cyanophenyl)acrylic acid was added 8 g) in (Je ©+) ethanol 0 to (YY) palladium Zo, + g) in (Je ©) ethanol and hydrogenated under p*bar for 2 hours. The reaction mixture was filtered and the filtrate was evaporated. AD (g) la) to dryness to obtain the subtitle compound as a substance. - 7.38 (m, 1H), 3.02 (t, 2H), 2.62 (t, 2H) 2-(3-hydroxypropyl)benzonitrile(z) ~~ 06 Aug 77,; g) in 71 Jie) 3-(2-cyanophenyl)propanoic acid, a solution of (Je 4) propanoic acid was treated in an atmosphere of 0100860. The solution was stirred (Je, 77) oxalyl chloride using (Je 4) DCM for an hour Then the reaction mixture was evaporated to dryness and azeotropic distilled with 1 Yo yielded at sodium borohydride ml) THF (¥'+) was added The solid was dissolved in 00©«©.

YAAY

(V,AAY) g). The mixture was stirred at 17°C for 11 hours. Another quantity of (an ,887( sodium borohydride) was added and stirred for ; hours. The reaction required ¥ more days and the addition of another quantity of (YAAY) sodium borohydride g). The reaction mixture was evaporated, diluted with Yoo (ele ml) and extracted with (Sa You) ethyl acetate. 8 The organic phase “(MgSO4) was dried, filtered and evaporated to yield the sub-title compound as oil (¥,AY) g). 'H NMR § (DMSO-dg) 7.78 (d, 1H), 7.68 - 7.62 (m, 1H), 7.50 (d, 1H), 7.44 - 7.38 (m, 1H), 3.02 (t, 2H) , 2.62 (t, 2H) 2-(3-(Benzyloxy)propyl)benzonitrile (3) Ve treated solution of 2-(3-hydroxypropyl)benzonitrile (eg VAY ¥YY g) in (Je £4) DMF in a nitrogen atmosphere using 7/068 (sodium hydride (€),) g) and stirred at room temperature for an hour before adding (Y,AY) benzyl bromide ml ). The resulting solution was stirred at 1 0 C for 1 hour. The reaction mixture was diluted with water (Yoo) mL) and extracted with Yo + (ethyl acetate mL). The organic layer (MgS04) was dried, VO-filtered, and evaporated. The residue was purified (5:02 chromatogram and filtered with 0 770 diethyl ether (iso-hexane). The purified portions were evaporated to dryness to yield the subtitle compound as oil (1.1 g). 'H NMR 5 (CDCls) 7.60 (d, 1H), 7.51 - 7.45 (m, 1H), 7.39 - 7.33 (m, 3H), 7.32 - 7.25 (m, 4H), 4.53 (s, 2H) , 3.52 (t, 2H), 2.97 (1, 2H), 2.03 - 1.96 (m, 2H) YAAY

470” — (e) 2-{2-[3-(Benzyloxy)propyl}phenyl} propan-2-amine A suspension of cerium (II) chloride (£.01 g) dissolved in (Ja Yo) THF at full for ? Hours in Joe by «©0100886. The resulting suspension was cooled and added: 2-(3-(benzyloxy)propyl)benzonitrile ) ex. 77 7d; 0 (p>YOY) The mixture was cooled to 1 01 1 Jd© adding 0,©m methyllithium as a complex with (V0,Y0) lithium bromide mL). The mixture was maintained at -01°C for 0 minutes before being quenched by adding (AA + ammonia 01 (ml). The mixture was stirred at room temperature for 1 hour before the solids were separated by filtration (and discarded). Dilute the filtrate with water (Jo 001) and extract ethyl acetate Yo 0 ml.The organic layer (MgSO4) was dried, filtered and evaporated to yield the compound Ye subtitled as oil (0 7,0 g). ), 2.04 - 1.92 (m, 2H), 1.83 - 1.63 (m, 2H), 1.62 (s, 6H). 3.04 (f): Methyl 3-{3-[(1-{2-[3- (benzyloxy)propyl]phenyl}-1-methylethyl)amino]-5-bromo-2- oxopyrazin-1(2H)-yl}-5-fluoro-4-methylbenzoate \o The subtitle compound was prepared using the method Similar to example (RYOY) of : methyl 3-(3,5-dibromo-2-oxopyrazin-1(2H)-yl)-5-fluoro-4-methylbenzoate (example (LY oY and 2 -(2-(3-(benzyloxy)propyl)phenyl)propan-2-amine (Example '71 AH). YAAY

MS: APCI(+ve) 622 (M+H)". : (g) 3-{3-[(1-{2-[3-(Benzyloxy)propyl]phenyl}-1-methylethyl)amino [-5-bromo-2- oxopyrazin-1(2H)-yl}-N-cyclopropyl-5-fluoro-4-methylbenzamide : from (&Y oY ) The subtitle compound was prepared using a method similar to the example 8 3-{3-[(1-{2-[3-(benzyloxy)propyl]phenyl}-1-methylethyl)amino]-5-bromo-2- oxopyrazin-1(2H)-yl}-5-fluoro -4-methylbenzoate (STYY) (example see NMR § (CDCl) 7.48 (d, 1H), 7.40 - 7.07 (m, 8H), 4.57 (s, 2H), 3.59 (t, 2H), 3.16 - 3.04 (m, 2H), 2.04 - 1.92 (m, 2H), 1.83 - 1.63 (m, 2H), 1.62 (s, 6H). -[3-({1-[2-(3-hydroxypropyl)phenyl]-1-methylethyl }amino)-2- oxopyrazin-1(2H)-yl]-4-methylbenzamide : from (YOY) done Prepare the subtitle compound using a method similar to example 3-{3-[(1-{2-[3-(benzyloxy)propyl]phenyl}-1-methylethyl)amino]-5-bromo-2- Vo oxopyrazin-1) 2H)-yl}-N-cyclopropyl-5-fluoro-4-methylbenzamide AgA

— {Yo - .)g*71 (Example MS: APCI(+ve) 479 (M+H)". : (i) 3-[3-({1-[2-(3) -Bromopropyl)phenyl]- 1-methylethyl } amino)-2-oxopyrazin-1(2H)-yl]-N- cyclopropyl-5-fluoro-4-methylbenzamide °: A solution of

N-cyclopropyl-3-fluoro-5-[3-({1-[2-(3-hydroxypropyl)phenyl]- 1 -methylethyl } amino)-2- oxopyrazin-1(2H)-yl]-4-methylbenzamide +,YYY) carbon tetrabromide with (Je 01(THF) dissolved in (p>..4((example "7 H) triphenylphosphine) The resulting mixture was cooled to 0 1 before adding nitrogen g) in Atmosphere of 0 h. Then the mixture was evaporated (11 μL) then the reaction mixture was stirred at room temperature for () ethyl acetate in DCM Zo reaction and the residue was purified (chromatography 2) and filtered using (a). > LY°) for obtaining the subtitle compound as a solid 111 NMR § (CDCI3) 7.65 - 7.56 (m, 1H), 7.55 - 7.46 (m, 1H), 7.43 - 7.34 (m, 1H), 7.26 - 7.17 ( m, 4H), 6.80 - 6.71 (m, 1H), 6.64 - 6.55 (m, 1H), 3.38 (t, 2H), 3.08 - 2.82 (m, 3H), 06 2.14 (8, 3H), 1.91 (d , 6H), 1.29 - 1.18 (m, 2H), 0.91 - 0.81 (m, 2H), 0.66 - 0.55 (m, 2H): (j) N-Cyclopropyl-3-fluoro-4-methyl-5 -{3-[(1-methyl-1-{2-[3-(methylamino) ‎propyl]phenyl}ethyl)amino]-2-oxopyrazin-1(2H)-yl} benzamide

YAAY

The subtitle compound was prepared from 3-[3-({1-[2-(3-bromopropyl)phenyl]-1-methylethyl }amino)-2-oxopyrazin-1 (2H)-yl]-N- cyclopropyl-5-fluoro-4-methylbenzamide (Example 77?g) using a method similar to that described in Example (7049e).

MS: APCI(+ve) 492.4 (M+H)+. © 1H NMR 5 (DMSO-d6) 8.65 - 8.55 (m, 1H), 7.82 (d, 1H), 7.74 (s, 1H), 7.51 - 7.41 (m, 1H), 7.25 - 7.14 (m, 3H), 7.10 - 6.99 (m, 1H), 6.76 - 6.65 (m, 2H), 2.98 - 2.79 (m, 3H), 2.51 -2.39 (m, 2H), 2.31 (s, 3H), 2.10 (s, 3H), 1.91 - 1.79 (m, 6H), 1.59 - 1.47 (m, 2H), 0.81 - 0.69 (m, 2H), 0.67 - 0.55 (m, 2H). (Fv ) Example Yo

N-Cyclopropyl-4-methyl-3-[3-(2-{2-[3-(methylamino)propoxy phenyl} pyrrolidin-1 -71(- 2-0077 [71-(1)211-h6) 0 ==

N N ¢ 0 N- \

NH

/

YAAY

67L-: (1)

N-Cyclopropyl-3-{3-[2-(2-hydroxyphenyl)pyrrolidin-1-yl]-2-oxo-3 ,4-dihydropyrazin- 1(2H)-yl}-4-methylbenzamide to :

N-cyclopropyl-3-(3-(2-(2-methoxyphenyl)pyrrolidin-1 -yl)-2-oxopyrazin-1(2H)-yl)-4- 5 methylbenzamide (ex “dV 9957.1g) In (0 Jo ( DCM) £,£Y) boron tribromide mL of a 1 M solution in (DCM at 0 C) was added and the sad Jeli mixture was stirred ? hours. of £,£V) boron tribromide ml of a 1 M solution in (DCM) and the reaction mixture was stirred for ?0 hours and ice was added, followed by ele, and the aqueous layer was extracted using 4 Then WEtOAC the aqueous layer was neutralized to a pH of V pH and extracted using DCM then BIOAC and all the organic layers (Na2S04) were dried and the solvent was removed to obtain the subtitle compound as a solid (p > 0 YA). MS: APCI(+ve) 432 (M+H)". -oxopyrazin-1(2H)-yl]-N- cyclopropyl-4-methylbenzamide Solution was treated with: YAAY

N-cyclopropyl-3-{3-[2-(2-hydroxyphenyl)pyrrolidin-1-yl]-2-oxo-3,4-dihydropyrazin- 1(2H)-yl}-4-methylbenzamide (example 7 Y + 7 g) in (Je©) acetonitrile using (a> +,1£Y) potassium carbonate (Je + 804 ) 1-bromo-3-chloropropane in nitrogen atmosphere The resulting suspension was stirred at AY 1© for 10 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer (MgSO4) was dried, filtered, and evaporated to yield the sub-title compound (77, g). MS: APCI(+ve) 507 (M+H). } pyrrolidin-1-yl)-01 2-oxopyrazin-1(2H)-yl]benzamide Heated: 3-[3-{2-[2-(3-Chloropropoxy)phenyl]pyrrolidin-1 -yl}-2-oxopyrazin-1(2H)-yl]-N- cyclopropyl-4-methylbenzamide Yo (ex. 4b (Je 1) amine methyl gs (p> +, YY) in a microwave CEM in dioxane at 0 C for 10 min.The resulting solution was concentrated in vacuo and purified by preparative HPLC (X-Bridge column using 75-95 gradients of Ale 7/0.71 ammonia in acetonitrile ) to obtain the title compound as a solid (YA) 0.0 g).

MS: APCI(+ve) 502 (M+H)+. 'H NMR § (DMSO-d) 8.14 (s, 1H), 7.77 (d, 1H), 7.65 - 7.56 (m, 1H), 7.42 - 7.31 (m, 1H), 7.10 (t, 1H), 6.92 - 6.77 (m, 4H), 6.57 - 6.57 (m, 1H), 5.97 - 5.94 (m, 1H), 4.13 - 4.03 (m, 3H), 3.93 - 3.77 (m, 1H), 3.01 (s, 4H), 2.87 - 2.81 (m, 1H), 2.65 (t, 2H), 2.28 (s, 3H), 2.09 (s, 1H), 1.88 - 1.79 (m, 5H), 0.70 - 0.64 (m, 2H), 0.58 - 0.53 (m, 2H) © (vv 1) eg (VYo) eg (R)-N-Cyclopropyl-4-methyl-3-(3-(2-(2-(3-(methylamino)) propoxy)phenyl)pyrrolidin-1- yl)-2-oxopyrazin-1(2H)-yl)benzamide and (S)-N-Cyclopropyl-4-methyl-3-(3-(2-(2-(3) - (methylamino)propoxy)phenyl)pyrrolidin-1-yl)-2-oxopyrazin-1(2H)-yl)benzamide «Chirobiotic V chiral (HPLC column B (YY£) The racemic mixture was purified from an example Ve in acetic acid 11:MeOH in triethylamine (Zo) Xu tA and filtered using to obtain two unspecified monoisomers. ) methanol : ( \ ) MS isomer: APClI(+ve) 502.2 (M+H)+.

Chiral Purity 95.5% © 220nM by HPLC 0 and YAAY

1. :) ) MS isomer: APCI(+ve) 502.2 (M+H)+.

Chiral Purity 97.1% @ 220nM by HPLC (*Y V) Example N-Cyclopropyl-4-methyl-3-[3-(2-{2-[2-(methylamino)ethoxy]phenyl} pyrrolidin-1-yl )-2- © oxopyrazin-1(2H)-yl]benzamide Trifluoroacetate salt 0 eh Ho) r=

N > | CY~: NH

Jpol: ()

Benzyl 2-(2-(1-(4-(5-(cyclopropylcarbamoyl)-2-methylphenyl)-3-oxo-3,4- dihydropyrazin-2-yl)pyrrolidin-2-yl)phenoxy)ethyl(methyl) carbamate Ye : To a solution of (a> +, YVE) Cesium carbonate was added

N-cyclopropyl-3-{3-[2-(2-hydroxyphenyl)pyrrolidin-1-yl]-2-oxo-3,4-dihydropyrazin- 1(2H)-yl}-4-methylbenzamide in (J++ 47) benzyl 2-chloroethyl(methyl)carbamate g) 08 (example; “a”

DCM hour. added VY (; ml); The reaction mixture was heated at 960 °C for 0 acetonitrile and the solvent was removed in an incubator medium. after (Na2S04) and water; extraction of the organic layer; And dry it expensive

4711—Purification (Si02 chromatography and elevation with EtOAc 755-70 in 0014) Subtitle compound obtained as YY oil (g). MS: APCI(+ve) 622 (M+H)". (b): N-Cyclopropyl-4-methyl-3-[3-(2-{2-[2-(methylamino)ethoxy]phenyl } pyrrolidin-1-yl)-2- 6 oxopyrazin-1(2H)-yl]benzamide Trifluoroacetate salt A solution of benzyl 2-(2-(1-(4-(5-(cyclopropylcarbamoyl)) was heated. -2-methylphenyl)-3-oxo0-3,4- dihydropyrazin-2-yl)pyrrolidin-2-yl)phenoxy)ethyl(methyl)carbamate 0 (ex. 77 ?; 177 g) in (Jo 01) ethanol through a PA/C cartridge at a rate of 1 ml/min. Cast maximum pressure hydrogen at 60 m on a cubic hydrogen generator []. Solvents were evaporated. After purification with preparative HPLC ( Xbridge column and filtering with graded amounts of acetonitrile in 11/7 (vol/v) aqueous TFA) the title product was obtained as a solid (©; mg). MS: APCI(+ve) 488 (M+H)+.\o 1H NMR 6 (CD30D) 7.78 (dt, 1H), 7.70 - 7.38 (m, 1H), 7.34 (d, 1H), 7.28 - 7.18 (m, 1H) , 7.03 - 6.90 (m, 4H), 6.67 - 6.63 (m, 1H), 6.36 - 6.28 (m, 1H), 4.49 - 4.27 (m, 2H), YAAY

4.24 - 4.07 (m, 1H), 3.97 - 3.79 (m, 1H), 3.44 - 3.33 (m, 2H), 2.90 - 2.79 (m, 1H), 2.55 - 2.37 (m, 4H), 2.22 - 1.54 (m , 6H), 0.85 - 0.75 (m, 2H), 0.66 - 0.56 (m, 2H). (vv A) Example N-Cyclopropyl-3-fluoro-4-methyl-5-[3-{[(1R,2S)-2-methyl-1-phenyl-3-pyrrolidin-1- ylpropyl] amino}-2-oxopyrazin-1(2H)-yl]benzamide©

ANY 1 z z m

N No: N.S

H 0 =

F

(2R,3R)-3-Amino-2-methyl-3-phenylpropan-1-ol (1): stirred

N-[(1R,2R)-3-{[tert-butyl(diphenyl)silyl]oxy}-2-methyl-1-phenylpropyl]-2- methylpropane-2-sulfinamide Yo mol £) hydrogen chloride then Add (Ja V +) methanol g) in 0.456 (eg 7b hours and then concentrate it in medium Vm for a period of Vo ml). The reaction mixture was stirred at (10) dioxane in ether for two days and then pulverized in vacuo toluene. The crude product was azeotropicly distilled using 'H NMR 5 (DMSO-dg) 8.51 (s, 2H), 7.71 - 7.67 (m, 1H), 7.49 - 7.35 (m, 4H), 4.18 - 4.14 © (m, 1H) , 3.24 - 3.07 (m, 2H), 2.14 - 2.10 (m, 1H), 0.97 (s, 3H)

YAAY

(b) : Methyl 3-[5-bromo-3-{[(1R,2R)-3-hydroxy-2-methyl-1-phenylpropylJamino}-2- oxopyrazin-1(2H)-yl]- 5-fluoro-4-methylbenzoate to methyl 3-(3,5-dibromo-2-oxopyrazin-1(2H)-yl)-5-fluoro-4-methylbenzoate (Example 1, YY © g ) in (Je ¥) THF added : (2R,3R)-3-amino-2-methyl-3-phenylpropan-1-ol (ex. Lafer 4, ; g) and Hunig base YY E ) , + ml) and the Jeli mixture was stirred at 00 C. A sad hours. The reaction mixture was diluted with ethyl acetate and washed with aqueous 11011003. The organic layers (504p0/8) were dried and concentrated in vacuo to leave the crude product, which was then pulverized overnight in iso-hexane 1:1 diethyl ether [0_0] to obtain the subtitle compound. After purification of the filtrate (chromatograph 2 and filtration with diethyl ether 7100-80 in iso-hexane) the subtitle compound was obtained again (total AY g). MS: APCI(+ve) 506 (M+H). (c): Methyl 3-[5-bromo-3-{[(1R,2R)-3-hydroxy-2-methyl-1- phenylpropyl]amino}-2- Yo oxopyrazin-1(2H)-yl]-5-fluoro-4-methylbenzoate The subtitle compound was prepared from: YAAY

Ere — — methyl 3-(5-bromo-3-((1R,2R)-3-hydroxy-2-methyl-1-phenylpropylamino)-2- oxopyrazin-1(2H)-yl)- 5-fluoro-4-methylbenzoate (Example 1778b) using a method similar to that described in Example (0849?b). MS: APCI(+ve) 426 (M+H)+.:)( *

N-Cyclopropyl-3-fluoro-5-[3-{[(1R,2R)-3-hydroxy-2-methyl-1-phenylpropylJamino } -2- oxopyrazin-1(2H)-yl]-4-methylbenzamide The subtitle compound was prepared from: 3-fluoro-5-[3-{[(1R,2R)-3-hydroxy-2-methyl-1-phenylpropyl]Jamino }-2-oxopyrazin- 1(2H) -yl]-4-methylbenzoate 01 (YA example of it using a method similar to that then described in the example) (LY oY . MS: APCI(+ve) 451 (M+H)+. (e) : N-cyclopropyl-3-fluoro-4-methyl-5-[3-{[(1R,2R)-2-methyl-3-o0xo0-1-phenylpropyl] amino }-2-oxopyrazin-1( 2H)-yl]benzamide Yo J slaw of Dess-Martin Periodinane (52+ g) in (Je A) DCM was added dropwise to a solution of:

— © 7 N-cyclopropyl-3-fluoro-5-[3-{[(1R,2R)-3-hydroxy-2-methyl-1-phenylpropyl]Jamino } -2- oxopyrazin-1(2H) -yl]-4-methylbenzamide (ex. 5774 VE, + g) in (Jo A) DCM at 77 °C. The resulting mixture was stirred at YYC for 0 min. The reaction mixture was quenched by adding 11025203 saturated aqueous 5 saturated aqueous NaHCO3 and stirred for another yo min then extracted in DCM The organic extracts were collected and dried (MgSO4) and concentrated in vacuo to obtain the subtitle compound as a substance

0.1 (g) solid. MS: APCI(+ve) 449 (M+H)+.(f): N-Cyclopropyl-3-fluoro-4-methyl-5-[3-{[(1R,2S)-2-methyl N -cyclopropyl-3-fluoro-4-methyl-5-[3-{[(1R,2R)-2-methyl-3-oxo-1- phenylpropyl]amino}-2-oxopyrazin-1(2H)- yl]benzamide Yo (ex. Hf OLY g); (711) pyrrolidine ml) and (Je E80 V) Hunig's base in DCM (Vo) ml) 0. The resulting suspension was stirred at YY C for 2 hours. The reaction mixture, Loe ls, was made by adding a saturated sodium bicarbonate solution before extraction using DCM. The collected organic phases were concentrated in vacuo and the residue was purified by a preparative HPLC (Phenominex YAAY column).

using a graded 1758-7 of ammonia 707 aqueous in acetonitrile as an eluting solution). The fractions containing the desired compound were evaporated to dryness to obtain the title compound as a solid (0 , 1 £). :

MS: APCI(+ve) 504 (M+H)+. 'H NMR 5 (DMSO-dq) 9.14 (dd, 1H), 8.52 (dd, 1H), 7.77 - 7.62 (m, 2H), 7.36 - 7.24 (m, ~~ ° 5H), 6.75 - 6.65 (m, 2H), 5.07 - 5.05 (m, 1H), 2.85 (q, 1H), 2.56 - 2.53 (m, 4H), 2.45 - 2.37 (m, 3H), 2.01 (s, 2H), 1.95 (s, 1H) , 1.73 (t, 3H), 0.79 (d, 3H), 0.69 (t, 2H), 0.58 - 0.54 (m, 2H). (¥ Ya ) Example N-Cyclopropyl-3-fluoro-4-methyl-5-[3-{[(1R,2S)-2-methyl-1-phenyl-3-piperidin-1- Vo ylpropyl] amino}-2-oxopyrazin-1(2H)-yl]benzamide

Chiral 0 to A x 1 2

N NT YN rr

F

: The title compound was prepared from

N-cyclopropyl-3-fluoro-4-methyl-5-[3-{[(1R,2R)-2-methyl-3-0x0-1- Vo phenylpropylJamino }-2-oxopyrazin-1(2H)-yl] benzamide a

717 - (Example (—aYYA) and papyridine using a similar method as described in Example (74?g). MS: APCI(+ve) 518 (M+H)+. 'H NMR 5 (DMSO -dg) 9.30 (dd, 1H), 8.52 (dd, 1H), 7.78 - 7.74 (m, 1H), 7.65 (d, 1H), (m, 5H), 6.69 (dd, 2H), 5.08 - 5.05 (m, 1H), 2.84 (s, 1H), 2.54 - 2.45 (m, 2H), 7.22 - 7.36 (m, 7H), 1.74 - 1.64 (m, 2H), 1.62 - 1.53 (m, 2H) ), 1.41 - 1.34 (m, 2H), 0.86 - © 1.88 - 2.23 (m, 3H), 0.72 - 0.67 (m, 2H), 0.58 - 0.54 (m, 2H). 0.75 Example (YY) 4-Chloro-N-cyclopropyl-3-[3-[(1-methyl-1-{2-[2-(methylamino)ethoxy] phenyl} ethyl)amino]-2-oxopyrazin-1(2H) )-yl]benzamide H yy the A and “Cl 01 Methyl 3-amino-4-chlorobenzoate () A solution of (a> ) +) methyl 4-chloro was treated -3-nitrobenzoate dissolved in acetic acid (Je 001) using iron powder (p 0177) in a nitrogen atmosphere. The reaction mixture was stirred vigorously at 70 C for 2 hours. The reaction mixture was filtered through a cellite The filtrate was evaporated to YO dryness to obtain a crude product.The residue was diluted with an aqueous sodium bicarbonate solution (de 001) and extracted with YO (dichloromethane ml). The organic layer was separated, dried (MgSO4), filtered, and evaporated to yield the subtitle compound AEY (g). YAAY

NMR 5 (CDCl) 7.47 (s, 1H), 7.37 - 7.24 (m, 3H), 4.29 - 3.95 (m, 2H), 3.90 (s, 3H) {' Methyl 4-chloro-3-{[ ethoxy(oxo)acetyl]amino} benzoate (=) a suspension of methyl 3-amino-4-chlorobenzoate (ex. sol AE g) dissolved in ethyl acetate (0 mL) was treated with (Je © 9,497 (triethylamine) in nitrogen atmosphere The resulting mixture was stirred at zero 5 before adding (©,0V) ethyl oxalyl chloride ml) dropwise for 0 minutes. The resulting mixture was stirred for an hour. The reaction mixture was diluted with Palma (Jo 001) and extracted with ethyl acetate. The organic layer was washed with Molar Y hydrochloric acid and then with a saturated sodium bicarbonate solution. The organic layer (MgSO4) was dried, filtered and evaporated to obtain Crude product The solid was pulverized with diethyl ether to yield compound 0 subtitle 11.7 (g).'H NMR § (CDCl3) 9.92 (s, 1H), 9.12 (s, 1H) , 7.81 (d, 1H), 7.70 - 7.56 (m, 1H), 7.50 (d, 1H), 4.44 (t, 1H), 4.00 (s, 3H), 3.54 (t, 2H), 3.48 (s , 6H) Methyl 4-chloro-3-{[[(2,2-dimethoxyethyl)amino](oxo)acetyl]amino} benzoate : (z) a solution of methyl 4-chloro-3-{ was treated [ethoxy(oxo)acetyl]amino} benzoate (eg 1.7 “FY. 9 g) in A+ (ethyl acetate mL) using aminoacetaldehyde dimethyl (Jo 0, A) acetal under atmosphere 0100880. The resulting mixture was stirred at Yo C for * hours. The reaction mixture was diluted by adding (Je 001) diethyl ether and stirred at room temperature overnight. The formed solid was separated by filtration and dried in vacuo to yield the subtitle compound (£1 g). YAAY tre 'H NMR 5 (CDCls) 9.92 (s, 1H), 9.12 (s, 1H), 7.81 (d, 1H), 7.70 - 7.56 (m, 1H), 7.50 (d, 1H), 4.44 ( t, 1H), 4.00 (s, 3H), 3.54 (t, 2H), 3.48 (s, 6H) methyl 4-chloro-3-(2,3-dioxo-3,4-dihydropyrazin-1(2H)- yl)benzoate : (2) : (eg methyl 4-chloro-3-{[[(2,2-dimethoxyethyl)amino](oxo)acetylJamino} benzoate © has been treated in (Je Ae) trifluoroacetic using (Je Y1) acetic acid in (p>Ao zYY) for ¥ hours. 1 VY atmosphere from «©010086. The resulting mixture was stirred at, and the resulting solid was separated by filtration to obtain a compound (Ja 0 ( mixture quenched with water) H NMR 5 (DMSO-d) 8.13 - 8.01 (m, 2H), 7.84 (d, 1H), 6.52 - 6.40 (m, 2H), 3.93 01 (s, 3H) ) methyl 3-(3-bromo-2-oxopyrazin-1(2H)-yl)-4-chlorobenzoate (—=) : a suspension of

A FY. (eg methyl 4-chloro-3-(2,3-dioxo-3,4-dihydropyrazin-1(2H)-yl)benzoate

Y,4¢)oxalyl ml) and +,YY+)N,N-dimethylformamide using (Ja A+) DCM in (pa 1° nitrogen mixture was stirred ml) dropwise for © minutes at room temperature in an atmosphere of an hour. The reaction mixture was returned and evaporated to obtain a product. 17 m for 71 minutes yield at

YAAY

— E41 — After purifying (Si02 chromatograph) and filtering with diethyl ether / Ye in (dichloromethane) to obtain the subtitle compound (6.77 g). 'H NMR 5 (DMSO-dg) 8.28 (s, 1H ), 8.10 (d, 1H), 7.90 (d, 1H), 7.77 (d, 1H), 7.32 (d, 1H), 3.83 (s, 1H) © and: Methyl-3-[3 -({1-[2-(benzyloxy)phenyl]-1-methylethyl } amino)-2-oxopyrazin-1(2H)-yl]- 4-chlorobenzoate. A solution of: methyl 3- was treated. (3-bromo-2-oxopyrazin-1(2H)-yl)-4-chlorobenzoate (ex. 1H ¥ —( 01 dissolved in (Je 10) toluene using (Je Y,99) N- ethyldiisopropylamine and 2-(2-(benzyloxy)phenyl)propan-2-amine (Ex. 148 Pd 110.7 g) in a nitrogen atmosphere, and the resulting mixture was stirred at 15 m for A hours. In a sealed tube. The reaction mixture was diluted with water (+10 (Jo) and extracted with YOu) ethyl acetate mL). The organic layer (MgSO4) was dried, filtered, and evaporated to yield a crude product. After purification (V0 chromatography 58:02 and filtered with Low diethyl ether in ('hexane' obtained subtitle compound Y, YY.) g). YAAY

“H NMR § (DMSO-d) 8.10 - 7.99 (m, 2H), 7.85 (d, 1H), 7.43 - 7.27 (m, 5H), 7.23 - 7.15 (m, 1H), 7.03 (d, 1H), 6.95 - 6.82 (m, 2H), 6.73 - 6.64 (m, 2H), 5.16 (s, 2H), 3.92 (s, 3H), 1.81 (d, 6H) : (g) 3-[3- ({ 1-[2-(Benzyloxy)phenyl]-1-methylethyl }amino)-2-oxopyrazin-1(2H)-yl]-4- © chloro-N-cyclopropylbenzamide : methyl-3-[ was processed 3-({1-[2-(benzyloxy)phenyl]-1-methylethyl }amino)-2-oxopyrazin-1(2H)-yl]- 4-chlorobenzoate (JeY,Y1Y) amine cyclopropyl with (Ja ¥+) THF dissolved in (pa 1.17 0 (ex. 01 Molar .nitrogen) 7 ml was stirred in an atmosphere of 1 C ammonium chloride Isopropylmagnesium chloride for 2 hours. The reaction mixture was diluted With the resulting solution at 71 ml the dichloromethane (YOu) layer was dried, extracted with aqueous V0, filtered and evaporated to yield the subtitle compound (7.4 g). (MgSO4) Organic 'H NMR § (DMSO-d) 8.61 - 8.54 (m, 1H), 7.99 - 7.93 (m, 2H), 7.81 - 7.75 (m, 1H), Yo 7.38 - 7.28 (m, SH), 7.25 - 7.16 (m, 1H), 7.09 - 7.02 (m, 1H), 6.94 - 6.84 (m, 2H), 6.73 - 6.66 (m, 2H), 2.90 - 2.83 (m, 1H), 1.86 (s, 6H ), 0.74 - 0.66 (m, 2H), 0.60 - 0.53 (m, 2H)

YAAY

: (h) N-(sec-butyl)-4-chloro-3-[3-{[1-(2-hydroxyphenyl)-1-methylethylJamino} -2-oxopyrazin- 1(2H)-yl] benzamide : a solution of 3-[3-({1-[2-(benzyloxy)phenyl]-1-methylethyl }amino)-2-oxopyrazin-1(2H)-yl]-4-chloro-© was treated

N-cyclopropylbenzamide ml A, £Y) boron tribromide with (Je ¥+) DCM dissolved in (p> 7.17 0 (eg the resulting solution was stirred hydrogen at zero in an atmosphere of (molar DCM in 1 of a ml solution) and extract it using Yoo) at 0°C for an hour, then dilute the reaction mixture with water

La ads and its nomination “(MgSO4) ml). The organic layer (YO +) dichloromethane 0 mL) was dried to yield 0+) diethyl ether to obtain the title product. The raw product was crushed using PEN VY, Ve ) on the subtitle compound “TH NMR § (DMSO-dg) 9.59 - 9.50 (m, 1H), 8.62 - 8.53 (m, 1H), 8.03 - 7.94 (m, 2H), 7.84 - 7.75 (m, 1H), 7.29 - 7.20 (m, 1H), 7.10 - 7.01 (m, 2H), 6.83 - 6.69 (m, 4H), 2.96 - 2.82 (m, 1H), 1.93 (s, 6H), 0.77 - 0.67 (m, 2H), 0.64 - 0.54 (m, 2H) Yo : (i) 4-Chloro-3-[3-({1-[2-(2-chloroethoxy)phenyl]-1- methylethyl ( amino)-2-oxopyrazin-1(2H)-yl]-N-cyclopropylbenzamide

YAAY

A solution of: N-(sec-butyl)-4-chloro-3-[3-{[1-(2-hydroxyphenyl)-1-methylethylJamino} -2-oxopyrazin- 1(2H)-yl was treated ]benzamide (ex. 0 H (p>) dissolved in (Je V+) acetonitrile using potassium carbonate (0 ),¥ © >) and (Je 0.897) 1-bromo-2-chloroethane In an atmosphere of “© 010086. The resulting suspension was stirred at Vo C for 10 hours. The reaction mixture was evaporated to dryness, diluted with water (+ Yo ml) and extracted by 1.. Then the layer i guia all was separated dried, filtered and evaporated (MgSO04) to obtain the crude product. The crude product was crushed using 7860 ether in

iso-hexane to yield the subtitle compound 0.001 (g). 'H NMR 5 011980-00 8.61 - 8.52 (m, 1H), 8.02 - 7.93 (m, 2H), 7.78 (d, 1H), 7.39 - Yo (m, 2H), 6.97 - 6.88 (m, 3H), 6.65 (d, 2H), 4.24 - 4.15 (m, 2H), 3.98 - 3.89 (m, 2H), 7.30 (m, 1H), 1.89 - 1.81 (m, 6H), 0.74 - 0.65 ( m, 2H), 0.62 - 0.53 (m, 2H) 2.81 - 2.90 (J)

4-Chloro-N-cyclopropyl-3-[3-[(1-methyl-1-{2-[2-(methylamino)ethoxy ‎]phenyl}ethyl)amino]-2-oxopyrazin-1(2H)- yl]benzamide Vo

A solution of: 4-chloro-3-[3-({1-[2-(2-chloroethoxy)phenyl]-1-methylethyl ( amino)-2-oxopyrazin- 1(2H)-yl was treated ]-N-cyclopropylbenzamide

‎YAAY

— ttt — aqueous amine methyl 8 mL) with ¥) acetonitrile g) dissolved in YY YY. (Example: 1 hour in a sealed tube. 11 m for 100 mL). The resulting mixture was stirred at 174° using a preparative Phenominex Gemini (HPLC column, filtration of the reaction mixture and purified by a filter solution). The aqueous acetonitrile fractions 70.7 in ammonia were evaporated in a gradient of 5-508/5. (a > 0, AY) containing the required compound to obtain the title compound ©

MS: APCI(+ve) 496 (M+H)+. 'H NMR 5 (DMSO-d) 8.62 - 8.52 (m, 1H), 8.02 - 7.92 (m, 2H), 7.78 (d, 1H), 7.33 (d, 1H), 7.19 (t, 1H), 6.99 - 6.85 (m, 3H), 6.71 (s, 2H), 4.03 - 3.89 (m, 2H), 2.91 - 2.76 (m, 3H), 2.31 (s, 3H), 1.87 (s, 6H), 0.74 - 0.65 ( m, 2H), 0.60 - 0.51 (m, 2H) using a similar method as described (V0 (PFE Table) to (FT) The following examples were prepared Ve : using YY. In an example 4-chloro-3-[3-({1-[2-(2-chloroethoxy)phenyl]-1-methylethyl } amino)-2-oxopyrazin- 1(2H)-yl]-N-cyclopropylbenzamide Appropriate. [ethoxy} phenyl)-1- methylethyl]amino}-2-oxopyrazin-1(2H)-yl]benzamide

YAAY

— $80 —

Example (YY a) 4-Chloro-N-cyclopropyl-3-[3-({1-[2-(2-{[(2R)-2-hydroxypropyl]amino} ethoxy)phenyl]- 1-methylethyl }amino)-2-oxopyrazin-1(2H)-yl]benzamide

( "7 ) Example 4-Chloro-N-cyclopropyl-3-[3-[(1-{2-[2-(ethylamino)ethoxy]phenyl }-1- © methylethyl)amino]-2-oxopyrazin -1(2H)-yl]benzamide

(* Example) T-3-[3-({1-[2-(2-Aminoethoxy)phenyl]- 1 -methylethyl }amino)-2-oxopyrazin-1(2H)-yl]-4- chloro- N-cyclopropylbenzamide

Expensive

(Yo) 1H NMR table. § (DMSO-d6) [M-+H]+ R Example m/z 8.66 - 8.56 (m, 1H), 8.07 - 7.96 526 ry (m, 2H), 7.84 (d, 1H), 7.38 (d, 1H), 7.24 (t, 1H), 7.06 - 6.89 (m, H 3H), 6.76 (s, 2H), 4.43 (t, 1H), Ny OH 4.08 - 3.95 (m, 2H), 3.52 - 3.38 OD (m, 2H), 3.01 - 2.88 (m, 3H), 2.73 - 2.60 (m, 2H), 1.94 (s, 6H), 0.82 - 0.69 (m, 2H), 0.68 - 0.55 (m, 2H 8.65 - 8.56 (m, 1H), 8.06 - 7.97 540 ry (m, 2H), 7.82 (d, 1H), 7.37 (d, 1H), 7.23 (t, 1H), 7.05 - 6.88 (m, 3H), 6.67 (s, 2H), 4.45 - 4.36 (m, H 1H), 4.10 - 3.93 (m, 2H), 3.74 - NOH 3.57 (m, 1H), 3.01 - 2.85 (m, 3H), >< 2.52 - 2.45 ( m, 2H), 1.85 (s, 6H), 1.04 (d, 3H), 0.78 - 0.71 (m, 2H), 0.65 - 0.59 (m, 2H 8.68 - 8.57 (m, 1H), 8.07 - 7.96 510 or ( m, 2H), 7.83 (d, 1H), 7.39 (d, 1H), 7.24 (t, 1H), 7.07 - 6.91 (m, H 3H), 6.76 (s, 2H), 4.10 - 3.93 (m, NN 2H), 3.01 - 2.84 (m, 3H), 2.67 - ] 2.56 (m, 2H), 1.93 (s, 6H), 0.95 (t, 1 3H), 0.81 - 0.70 (m, 2H), 0.66 - 0.56 ( m, 2H) 8.58 (d, 1H), 7.99 - 7.92 (m, 2H), 482 op 7.77 (d, 1H), 7.33 (d, 1H), 7.18 (t, H 1H), 6.99 - 6.85 (m, 3H), 6.65 (s, Hh

OH), 3.95 - 3.79 (m, 2H), 2.95 - ] 2.79 (m, 3H), 1.78 (s, 6H), 0.77 - 3 0.65 (m, 2H), 0.59 - 0.50 (m, 2H)

YAAY rr. Physical image data: Detailed data on measuring devices:

PANalytical Cubix PRO data was collected using the XRPD mechanism

PANalytical Gubix PRO - XRPD 07 in Figure 6-20 Over the scan range PANalytical Gubix PRO data were collected using the © mechanism from 7" to 46 by exposure 01 sec per 1.07 device. Radiation generated X by means of a long copper micro-focal tube operating at 56 kV 50 mA The wavelength of the copper X-rays was 1.418 angstroms 0 The data were collected on background zero barriers on which about ? mg of the compound The barrier was made from a single 0 crystal of Allg silicon that was cut along a diffraction-free plane and then polished on an optical flat polish The X-rays incident on that surface were discarded by a Bragee vanishing Measurement of DSC thermographs using a TA 01000 Differential Scanning “Calcorimeter with aluminum pots and perforated lids. Sample weights changed from 1.5 to © mg. The procedure was carried out under a flow of [Je © + gas] (nitrogen min) and the temperature was studied from No ©? to 00°C at a constant rate of temperature increment of 10°C per minute.Then 5 forms were measured using a Dynamic Vapor Sorption DVS-1 and the solidified sample was applied It is about 1-5 mg in Au glass and the weight of the sample was recorded during the double cycle step method (relative humidity Er RH) to 90 to zero to 90 to zero; In their respective stages (RH 701 YAAY

EA — — Free Base Preparation in Example (VY) N-Cyclopropyl-4-methyl-3-[3-[[1-[2-[2-(methylamino)ethoxy] phenyl]cyclopropyl] amino]-2-oxo-1(2H)-pyrazinyl]-benzamide A Crystalline Form © Processed: 3-(3-(1-(2-(2-Chloroethoxy)phenyl)cyclopropylamino) -2-oxopyrazin-1 (2H)-y1)-N- cyclopropyl-4-methylbenzamide (example OH© (p>) dissolved in (Je V0) dioxane using V0) methylamine mL by weight solution in water). The resulting suspension was stirred at 100 C for ; hours in 0 autoclave the solution was evaporated to dryness. The crude product (chromatograph $102) was purified and filtered using a 10:1 94 (vol/v) mixture of :triamine ethyl : methanol dichloromethane, respectively). The product-containing fractions were evaporated in vacuo and purified by RPHPLC (Xterra column 75-90 gradient of +/,Y aqueous ammonia in acetonitrile as mobile phase). Product-containing fractions were collected, aggregated, and VO lyophilized to leave a solid. After pulverization with diethyl ether 5 by drying in vacuum overnight and then obtaining the title compound as a white powder (p> ve. 1H NMR consistent with that described above in Ghala

tea — — Example MS: APCI(+ve) 474 (M+H)+. : VV free base analysis in example (VY) N-Cyclopropyl-4-methyl-3-[3-[[ 1-[2-[2-(methylamino)ethoxy]phenyl] cyclopropyl] amino ] -2-oxo-1(2H)-pyrazinyl]-benzamide © crystallized form A A sample of crystallized form A in Example (No 1) generated by the procedure described above was analyzed by DSC “XRPD” and 0175 The melting temperature of the crystallized form m in the example (VY) as determined by Ala DSC gave a singular endothermic; occurring at 6751°C (+ ¥ ofp with a water absorption of 71 (Loy) 0 between RH between 07 and 7850 as measured by 0178. The XRPD diffraction pattern in the crystalline form is shown in Example (7/1) in Figure (1). Preparation and analysis of the free base in Example (VY) N-Cyclopropyl-4-methyl-3-[3-[[1-[2-[2-(methylamino)ethoxy]pheny]] cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl] -benzamide VO crystalline form 3. A sample of crystalline form 3 in Example (VY) was obtained by converting the crystalline form M. dioxane (TY) at room temperature (about Yom) and Analyzed by (1. The XRPD diffraction pattern of the crystalline image 3 in example (No. 1) is shown in the form of (Y). the

— © for the free base preparation in example (Yo) N-Cyclopropyl-3-fluoro-4-methyl-5-[3-[[1-[2-[2-(methylamino)ethoxy]phenyl] cyclopropyl}amino]-2-oxo-1(2H)-pyrazinyl]- benzamide Crystalline form © A Processed: 3-[3-[[1-[2-(2-chloroethoxy)phenyl]cyclopropyl [amino]-2-oxo-1(2H)-pyrazinyl]-N- cyclopropyl-5-fluoro-4-methyl-benzamide (ex. 4d (pa 01) in (Je Yo) dioxane using (V0) amine methyl (ml of 740 wt. aqueous solution). The resulting mixture was stirred at 100°C for 1 hour VT in a sealed tube. 0 The reaction mixture was cooled, filtered, and the solvents removed in vacuo to yield a crude product (approximately 0 g). The crude product (approximately A g) was purified by RPHPLC (Column (Waters X-Bridge 1-90 gradient of 8.7 7 aqueous ammonia in acetonitrile as mobile phase). The product-containing fractions were collected and evaporated. and crushed with diethyl ether overnight.The white solid 0 was collected by filtration and dried in vacuo to yield the title compound (£18 g). The NMR data is consistent with what is described in the example MS: APCI(+ve) 492 (M+H).". (Y04). Elemental Analysis - Present (Calculated): (14.3) %C:65.9 ( 66.0); %H:6.1 (6.2); %N:14.2 Free Base Analysis in (VY) YAAY Example

01 — N-Cyclopropyl-3-fluoro-4-methyl-5-[3-[[1-[2- [2-(methylamino)ethoxy]phenyl] cyclopropyl] amino]-2-oxo- 1(2H)-pyrazinyl]-benzamide crystalline form A A sample of the crystalline form A in example (Yod) generated by the procedure described above was analyzed by © DSC “XRPD 075”. The melting temperature in Crystalline form A in example (Yd) as determined by DSC is a single endothermic state; occurring at 1011 m (* Y”); with an absorption of 1/7 ela (< 20.7) The RH is between zero and 780 as measured by 0175. The XRPD diffraction pattern is shown in the crystalline form e in example 1 v) ( in Fig. 9 (0). Free base preparation in Yi. ) Joe ( : N-Cyclopropyl-3-fluoro-5-[3-[[1-[2-[2-[(2-hydroxyethyl)amino] ethoxy] phenyl]cyclopropyl]amino]-2-oxo -1(2H)-pyrazinyl] -4-methyl-benzamide Heated: 3-[3-[[1-[2-(2-chloroethoxy)phenyl]cyclopropyl]amino]-2-oxo-1 (2H )-pyrazinyl]-N- cyclopropyl-5-fluoro-4-methyl-benzamide \o (ex. mL) in a sealed tube for 1 hour VT. YAAY

After filtering using preparative HPLC (column 8 and filtering it with a gradient of acetonitrile in 7 (vol/v) of it «0» e_hydr) the title compound (90, ¥ (pa) was obtained after removing the solvent in vacuo and pulverizing it with (Je 860 0:1( diethyl ether / iso-hexane) MS: APCI(+ve) 522 (M+H)+. 1H NMR 6 (DMSO0-d6) 8.46 (1H, d), 7.73 ( 1H, d), 7.61 (1H, s), 7.51 (1H, d), 7.43 (1H, © s), 7.19 (1H, t), 6.95 (1H, d), 6.92 - 6.80 (2H, m ), 6.74 (1H, d), 4.44 (1H, s), 4.06 (2H, 1), (2H, 1), 2.69 l (2H, m), 3.42 - 3.30 (1H, m) , 2.97 (2H, 0. 2.90 - 2.77 (1H, 3.43- 3.51 (3H, s), 1.27 - 1.01 (4H, m), 0.75 - 0.63 (2H, m), 0.57 - 0.50 (2H, m) 1.97 Elemental Analysis - Existing (Calculated): ..(13.4) C:63.8 (64.5); H:6.3 (6.2); N:13.0% 0 Free Base Analysis in Example (770): N -Cyclopropyl-3-fluoro-5-[3-[[1-[2-[2-[(2- hydroxyethyl)amino]ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)- pyrazinyl]-4- methyl-benzamide crystalline form A Yo and then analyze a sample of the crystalline form A in Example (0) produced by the procedure described above by GVS 3 DSC “XRPD”. The melting temperature in the crystalline form.8 in the example (YO) as determined by Alla DSC gave a single endothermic; Occurring at 1167 m (+ op Y with water absorption) 7 YAAY

017 - (< (£0) between RH between zero # and 7280 as measured by 01778. The XRPD diffraction pattern in the crystallized image is shown in example VV) in the form of (¢). Image preparation The A crystallization of the free base in example: (16) N-Cyclopropyl-4-methyl-3-[3-[[ 1-methyl-1-[2-[2-(methylamino)ethoxy]phenyl]ethy ] Jamino]-2-oxo-1(2H)-pyrazinyl]-benzamide © crystallized form A to: N-cyclopropyl-3-(3-(2-(2-hydroxyphenyl)propan-2) -ylamino)-2-oxopyrazin-1(2H)-yl)-4- methylbenzamide Yo (ex. (p > 4,9 14 in (Je ©) acetonitrile Y,At added ) potassium carbonate g) followed by the addition of benzyl 2-chloroethyl(methyl)carbamate (74,¥ g) and the reaction mixture was heated at Ao mm for NT hours in a nitrogen atmosphere after cooling to a temperature the room; The mixture was evaporated to dryness and the residue was divided between (71 da (elo and 0014 Yo) mL). The hydrate was separated and then extracted in DCM (Yo XY ml). The combined organic layers were evaporated to remain crude: benzyl 2-(2-(2-(4-(4-(5-(cyclopropylcarbamoyl)-2-methylphenyl)-3-oxo0-3,4- dihydropyrazin-2-ylamino)propan -2-yl)phenoxy)ethyl(methyl)carbamate YAAY

— 06 - Y,0. ) g) as a resin. 1) Pd/C (Ja Yo.) ethanol 11 g of © %) was added and the reaction mixture was stirred under an atmosphere of Y (H2 bar) for ; hours. Ladi was then filtered through celite (Jue filler was filtered using portions of ethanol and the combined filtrate was evaporated leaving 1.7 (g) crude product. Recrystallization from ethyl acetate gave title product 1 0.10 g) as a white solid©. MS: APCI(+ve) 476 (M+H)+

Analysis of the A crystalline form of the free base by example (VY) N-Cyclopropyl-4-methyl-3-[3-[[ 1-methyl-1-[2-[2-(methylamino)ethoxy]phenyl ethylJamino]-2-oxo-1(2H)-pyrazinyl]-benzamide

0 crystallized image m. The due of the crystallized form A by example (¥) generated by the procedure described above was analyzed by means of an XRPD (measured using DCC “Phillips X-Pert MPD” and 01778. The crystallized form was slurried in propylacetate, Toluene and Methyl tertiary-butyl ether unchanged in the crystalline form.

DSC as determined by (167) gave the melting temperature of the crystalline form m eg 1 m (second start) YY double endothermic; occurring at 100 m (first start) Ala 7 (0.7 £ 0.7) ) RH ZA by weight over (w/w 7) at 75 GVS give a determination. (” Y + (). (°) In the example (¥ 1) in figure A of the XRPD crystalline image, a diffraction pattern is displayed.

‎YAAY

- 00 Preparation of the crystalline form 3 of the free base by example (VY) N-Cyclopropyl-4-methyl-3-[3-[[ 1-methyl-1-[2-[2-(methylamino)ethoxy] phenyl] ethyl]amino]-2-oxo- 1(2H)-pyrazinyl]-benzamide Photoresolved B © Processed: 3-[3-[[1-[2-(2-Chloroethoxy)phenyl] -1-methylethyl[amino]-2-oxo-1(2H)-pyrazinyl]-N- cyclopropyl-4-methyl-benzamide (Ex. A) 4e; (p= 11.5 in 0 (dioxane mL) using 06 amine methyl solution (50 mL) under atmosphere of “©010086.” The resulting suspension was heated in a sealed system at 1000 °C for 0 4 h. After cooling to room temperature, the solution was evaporated to dryness. Aan the crude product was chromatograph Aan (Si02) ; Methanol filtration solution 0 in dichloromethane and 71 (triethyl amine) and evaporation was given to the relevant parts until dryness and crushing of the remaining solid in diethyl ether was separated by filtration and dried to give the title compound PEN 11) as a yellowish-white solid. MS: APCI(+ve) 476 (M+H)+. : ( 1 ¥) by example 3 all of base B crystallized image analysis VO

N-Cyclopropyl-4-methyl-3-[3-[[ 1-methyl-1-[2-[2-(methylamino)ethoxy]phenyl] ethyl]amino]-2-oxo-1(2H)-pyrazinyl] -benzamide

B crystallized image

YAAY

to". The crystallized form 3 in Example (VIF) as determined by DSC has a dual endothermic state; it occurs at 71 C and 7758 C. The GVS determination was given as 74.7 wt© increment (wt/Toss) at 786 (LX 2) RH The XRPD diffraction pattern of the crystalline form B in Example (¥ 5) is shown in figure ( ). Preparation of the crystalline form C of the free base in Example 9 7 : N-Cyclopropyl-4-methyl- 3-[3-[[1-methyl-1-[2-[2-(methylamino)ethoxy] phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide Yo The crystalline form C. has been processed: 3-[3-[[1-[2-(2-Chloroethoxy)phenyl]-1-methylethylJamino]-2-oxo-1(2H)-pyrazinyl]-N- cyclopropyl-4-methyl-benzamide (ex. 948 17.5 a) g) in (Ja©+) dioxane using 7400 amine methyl solution (+0 VO _ml) in atmosphere of nitrogen The resulting suspension was heated in a sealed system, Jill at 1000 C for hours After cooling to room temperature; The solution was evaporated to dryness. The crude product was purified by flash chromatography Si02) methanol filtrate 701 in dichloromethane (triethyl amine 1 ). After evaporating the relevant fractions to dryness and pulverizing the residue in YAAY ether

— 1e — diethyl solid was obtained which was separated by filtration. The filtrate was collected and evaporated. Said residue was purified using preparative HPLC (Waters X-Terra column using 6-08/gradient of dla ammonia 71:07 in acetonitrile as filter solution). Sections containing the desired compound were evaporated to dryness. After further purification with preparative HPLC© (ammonia %+,Y column (Phenomenex 45 in acetonitrile as filter solution) the relevant fractions were freeze-dried to yield a solid. The lyophilized material was readily dissolved in Je 71 ethyl acetate at room temperature and after stirring for 1 hour some solids precipitated. The mixture was then heated to Ao C for 1 hour to cause dissolution and then cooled and stirred at 0°C for 1 week. The solid was separated by filtration And dried in vacuo at 50 m: to obtain the title compound (PEN d). Analysis of the crystallized form © of the free base by example: (177) N-Cyclopropyl-4-methyl-3-[3-[[1-methyl- 1-[2-[2-(methylamino)ethoxy] phenyljethyl]amino]-2-oxo0-1(2H)-pyrazinyl]-benzamide Ve crystalline form C. A sample of the crystalline form was analyzed © (VY) JBL generated by the procedure described above via XRPD (measured using .GVS 3 DSC “(PANalytical CubiX PRO” YAAY)

C0 - gave the melting temperature of the crystallized form © in example (1167) as determined by DSC Alla dual endothermic; occurring at 117 C and 7758 C. The GVS determination of “0, wt over (wt / (Cos at 77860 .,Y +) RH 7) The XRPD diffraction pattern of the © crystallized image of Example Viv ( is shown in Figure (V). © Preparation of the free base © crystallized image of the example 1767:( N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2- [2-(methylamino)ethoxy] phenyl]ethyl]amino]-2-oxo -1(2H)-pyrazinyl]-benzamide crystalline form D and then crystalline form 3: N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2- [ 2-(methylamino)ethoxy[phenyl] Vo ethylJamino]-2-oxo-1(2H)-pyrazinyl]-benzamide as a slurry in 32d ethyl acetate for 1 week.The solid was separated by filtration and dried in medium Vacuum at 460 m to obtain the title compound. A sample of the AD crystallized form example (¥ 1) was analyzed following the procedure described above by means of 0 XRPD (measured using PANalytical CubiX PRO). A diffraction pattern is shown. XRPD of the example AD crystalline form (¥ yi ) in Figure (A). Preparation and analysis of crystalline form A of saccharide salt by example: (16) YAAY

— 09 - ‎N-Cyclopropyl-4-methyl-3-[3-[[ 1-methyl-1-[2-[2-(methylamino)ethoxy]phenyl] ethyl]amino]-2-oxo-1 (2H)-pyrazinyl]-benzamide The A crystalline form of the saccharide salt: dissolved: N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[2] -(methylamino)ethoxy[phenyl]© ethyl[amino]-2-oxo-1(2H)-pyrazinyl]-benzamide in methanol; treated with 1 (saccharide equivalent); fumigate to dryness and slurry in acetonitrile (0,+ ml) for one week. The mixture was centrifuged and the solid was separated by filtration to obtain the title compound. Then analyze a sample of crystalline form 0 A of the saccharide salt by crystallization example (VY) following the procedure described above by XRPD (measured using a Philips X-Pert MPD and 080. Melting temperature of the crystalline form A of the saccharide salt in example (V1) as determined gives ?endothermic states; occurring at 144 °C, 77 °C, and 17 °C (+7 °C).The XRPD diffraction pattern of the m-examined image of the salt is shown. saccharide by example (VY) in form 0 (3) preparation and analysis of a crystalline form A of tosylate salt by example: (16) N-Cyclopropyl-4-methyl-3-[3-[] 1-methyl-1-[2-[2-(methylamino)ethoxy]phenyl] ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide YAAY

414.0 — Crystalline form A of saccharide salt : dissolved: N-Cyclopropyl-4-methyl-3-[3-[[ 1-methyl-1-[2- [2-(methylamino)ethoxy]phenyl] ethyl] amino]-2-oxo-1(2H)-pyrazinyl]-benzamide© in methanol; treated with 1 ( p-sulfonic toluene equivalent); fumigate to dryness and slurry in sal (Ja +,0) acetonitrile for a week. The mixture was centrifuged and the solid was separated by filtration to obtain the title compound. A sample of crystalline form A of salt 60 was analyzed by example crystallization (V17) following the procedure described above by XRPD (measured using a DSC “Philips X-Pert MPD” and 0175. Ve melting temperature of the crystalline form A for the tosylate salt of Example (117) as determined gives Alls an endothermic one; occurring at 0707°C (2 7°C). Determination of GVS gives 701 wt plus (wt/(Fads) at RED (+ 0.7 7). The XRPD diffraction pattern of crystalline form A of tosylate salt in Example 1767 is shown in Figure (01). Ye preparation and analysis of crystalline form B of tosylate salt by example: (167) N-Cyclopropyl-4-methyl-3-[3-[[ 1-methyl-1-[2-[2-] (methylamino)ethoxy] phenyl ‎Jethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide Crystalline form B of Tosylate salt : YAAY

Dissolved: N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2- [2-(methylamino)ethoxy]phenyl] ethylJamino]-2-oxo0-1(2H) )-pyrazinyl]-benzamide at 0076018001; treated with 1 acid (p-sulfonic toluene equivalent); evaporated to dryness and slurred in THF (b)Ja for a week. The mixture was centrifuged and the solid was separated by filtration to obtain the heading compound 0. A sample of the crystalline form A of the tosylate salt was analyzed By example crystallization (¥ 1) following the procedure described above by XRPD (measured using GVS_ DSC “(Philips X-Pert MPD). The melting temperature of the crystalline form 3 of the tosylate salt in Example 9 1 as then determined gives 0 One endothermic state, occurring at AA, 167oM and lala1oM (a YE) Diffraction pattern 704870 of the crystalline form tosylate lal A of Example 167 is shown in Figure 1 ( .:(Y1¥) by Example hydrochloride Salt A preparation and analysis of a crystalline form

N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[2-(methylamino)ethoxy]phenyl]ethyl

Jamino]-2-oxo-1(2H)-pyrazinyl]-benzamide Vo The crystalline form A of the hydrochloride salt : dissolved: YAAY

N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[2-(methylamino)ethoxy]phenyl] ethyl]amino]-2-oxo-1(2H) -pyrazinyl]-benzamide in methanol; and process it with 1101; standard in dioxane (excess); evaporate to dryness and slurry in THF (5 mL) for one week. The mixture was centrifuged and the solid was separated by filtration to obtain the title compound. A sample of polymorph A of the HCI salt by crystallization example (¥ 7) was analyzed following the procedure described above by XRPD (measured using a DSC 5 “Philips X-Pert MPD as determined). ) by example HCL of salt A Melting temperature of polymorph (aX +) endothermic states; occurring at 47 µm, 6 µm and not 1 µm (VY) in Fig. 1 by example HCI of salt A For polymorphic XRPD Ye diffraction model is displayed Pharmacological analysis: Using the bioassay p38 kinase to inhibit the enzyme (1), the ability of the compounds of the following formula can be determined: p38 alpha enzyme test Done Perform enzyme tests in polypropylene plates 976 eyes.The following solutions were added to each well: 01 µL of compound dilutions in test buffer 85 mM Yo) pH 4,/” containing 01 mM magnesium acetate « 5 (w/v) Tween 01 Yom mM (DTT contains 71 (w/v)

YAAY

0 or Test Buffer Solution containing 71 (vol/v) DMSO alone; Ve μl of a test buffer solution containing nanomolar YU substrate (biotin-treated (ATF2-) and 10 μl in an appropriate diluent of 380-611:9M recombinant labeler. Depending on the batch of 038, the appropriate dilution was typically with nanomolar © solution to obtain a final enzyme concentration of 0 nM.At this point, the eyes of the primary control also received 0 μl of 0 mM AlphaScreen (HEPES Na) quench buffer solution, pH 4, containing no 100 mM EDT 7007 (w/v) bovine serum albumin).The plate was coated;initially incubated for 2 hours at PV C and the activation of the enzymatic reaction was initiated by the addition of 01 μl;1 mM ATP After incubating for another £0 min at cp YY 0 the reaction was stopped by adding 50 µL chemical reaction quenching agent Jing 00 µL of reaction quenching mixture to a sterile plate; white of 41 cultures was added. Chemical reagent; Yo μl of 10 mM HEPES Vif pH containing 100 mM EDTA; 7507 (w/v) bovine serum albumin; Fg, + nanomolar body Anti-ATF2 phosphorylated 5 YO μg/mL of AlphaScreen A receptor protein and squishy beads to each 0_eyes in a darkened room; The dish is sealed and left in the dark between © &;? An hour before taking AlphaScreen readings using a Perkin Elem EnVision dish reader, iB compounds showed ≥ 0.75 inhibition of 38 M and/or 808 at concentrations less than 10 micromolar.

YAAY

The following table shows the values of 1050 m for the compounds of the present invention. Oh, Bhas Sat A Se ae YAAY

B YAAY

Safe [ae oe [a ee ee

YAAY

gay — — Tar Jere] we fer * The standard deviation of the p38 inhibition test is between 07 and 71 logarithmic units. The pIC50 values in the above table represent a means of repeating determinations within the range XY standard deviation AY between each (Hla /40)

YAAY

Claims (1)

M477 - Claims 1-1 A compound of formula (ol) according to the present invention M BAB "A A 8 H B 0 8 in which: “CF3 “halo alkoxy (C1-C6) alkyl (C1-C6)” 11 and 02 choose separately from 1818 81 ¢ for 0;0 4 183 and 64 JS selects separately from 1 “alkoxy (C1-C6) alkyl (C1-C6) tweezers “OH caryl “CN” CF3 018889 vy heteroaryl aryl and 0011810811; Whereas, the said (01-06) alkyl C6) and the said (01-06) alkoxy; Each separately has a substitution with 1b "or ? 4 groups are selected separately from S(0)pR55 01812813 alkoxy (C1-C3) OH thalos 0 «cycloalkyl (C3-C7) ¢heterocycloalkyl < heteroaryl aryl 1 waiting from 15 yy ¢OR16 s CH2R16 «SO2NR16R17 «S(O)pR16 «(CR14R15)mNRI6R17 BD (C3-C7) «cycloalkyl (C3-) C7) “alkoxy (C1-C6) “alkyl (C1-C6) ¢H choose from R6+1 mentioned can be alkyl (C1-C6) where taryl and heteroaryl “alkyl (C1-) C6) cycloalkyl yib “OH halo is optionally substituted by yo and ½” cycloalkyl (C3-C7) “alkoxy (C1-C6) “alkyl (C1-C6) choose from 11; 287 with which they are connected to form a ring of ; to 7 atoms; nitrogen or 86 and 27 with a y atom and optionally containing another hetero-atom selected from 00818 8 and 0; yo YAAY -gna- (C3-C6) «alkoxy (C1-C6) «alkyl (C1-C6) and 89 select each of the RE 1 7 rings of ; to US of which nitrogen and 1019 are conjugated with an R8 atom or “cycloalkyl 0 atoms; It optionally contains another heteroatom selected from 00819 8 and 0;1” to which it carbon bonds with the R155 4 atom or “alkyl (C1-C6) and 2815 selected from 11 and 814 YY (and 0c ); Cua 0” X x”? says that said cycloalkyl (C3-C7) can have an optionally substituting Ya with a taryl group vy 7 choosing from 1 (C3-C7) 5 heterocycloalkyl < heteroaryl » aryl < alkyl (C1-C6) cycloalkyl YA where said alkyl (C1-C6) can have an optionally substituted with YO Y4 or * individually selected groups of “cycloalkyl (C3) -C10) “alkoxy (C1-C6) cheterocycloalkyl 00 heteroaryl aryl and (NR20R21 R22 5 choose from heterocycloalkyl 12229130 “OH” alkoxy (C1-C6) “alkyl (C1-C6) ) < H carly TT where said alkyl (C1-C6) can have an optional substitution with 1 ? or ? vv groups (R28) since said aryl can have Optional substitution with 1?or ve individually selected groups of CF3 «halo «alkoxy (C1-C6) «alkyl (C1-C6) ¢OH 4 Yo 1 223 choose from talkkyl (C1-C6) s H TV or R235 R22 with the carbon atom they are attached to form a cycloalkyl (C3-C7) or ¢theterocycloalkyl ring YA #4 is a bond or group ((CR24R25 )n ‎YAAY .p — 0 1224 and 8225 select each separately from (OH «alkoxy (C1-C6) «alkyl (C1-C6) H heterocycloalkyl ~ ¢) and 01839840; Or R25 5 R24 with the carbon atom to which they bond to form a â€Y' ring sheterocycloalkyl EY dehi aryl ada or Cua cheteroaryl be with the aryl ring or the heterocyclic aryl ¢ ¢ replace with ¢R27 3 R26 go 226 coagulation of 1 —O “aryl “OH” alkoxy (C1-C6) “alkyl (C1-C6) row <halo <heterocycloalkyl —O c< heterocycloalkyl 7 aryl < heteroaryl —O “heteroaryl” “CONR34R35 5 NR34R35 “S(O)pR34 “cycloalkyl —O » alkyl 49 where (C1-C6) 48 tola or alkoxy (C1) -C6) mentioned can have an ms substitution? or? 4; Separately select groups of heterocycloalkyl “OH” or 11834835 0 827 choose from 11 halo and (01-06) Cus calkyl that said alkyl (C1-C6) has 1 optionally substituent b 1; or? groups; © or R27 4 R26 together form a dioxymethylamine group 01161171606010 where OY is bonded to the adjacent carbon atom of the aryl ring or the heterocyclic aryl; JS of occurrence of R28 selects separately from: “OR36 alkoxy (C1-C6) “heterocycloalkyl 023” CH2CF3 halo 0 oo ¢ “SO2NR37R38 ys CONR31R32” COOR42 ©1 R305 R29 oY selects JS separately from 11; SO2R41 «cycloalkyl (C3-C7) »alkyl (C1-C6) OA 0(841);Cus that said alkyl (C1-C6) has an optional substitution of OH NR56R57©4 or theterocycloalkyl R325R31 0 select each separately from the alkyl (C1-C6) (H) and “cycloalkyl (C3-C7) or R31 11 and 0832 with the nitrogen atom attached to it forming a ring It has from 1 to 1 atoms containing in the form of YAAY - a - 7 optional on the heterogeneity atom of 010823 8 and 0; cycloalkyl «cycloalkyl (C3-C7) «alkyl (C1-C6) choose separately from 1 to R355 R34 AY 4 is related to C and (0)0(0)01-06 calkyl where said alkyl (C1-C6) has a substitution te optionally with C(O)OH (NR58R59 “alkoxy (C1-C6) ¢halo”OH and “heterocycloalkyl” or R355R34 17 with a nitrogen atom to which they bond to form a ring with ; to 1 atoms; R36 TV is chosen from cheterocycloalkyl s alkyl (C1-C6) ¢H where the said alkyl (C1-C6) theterocycloalkyl can be optionally substituted by a TA group R41 R40 “R39 + 38 3733” R21 “R20” R19 “R18 (R13” R12 “R11 R10 4) alkyl (C1-C6), H, 842; You choose separately from Vo (1 zero or am V) VY “is J”; VY in each occurrence why did you choose each separately from 1 hea or ?; aryl is a non-aromatic carbon ring; Optionally combined with the 1/4 cycloalkyl group VO where the said cycloalkyl ring optionally contains; when possible; On up: 7 to two double bonds; and where; unless otherwise stated; It could be pal cycloalkyl VY mentioned is an optional substitution by 1 or ? From the replacement groups you choose each (NR43R44 5 halo «CF3 «CN «OH «alkoxy (C1-C6) alkyl (C1-C6) separately from VA V4 The heterocycle cycloalkyl is a non-aromatic monocyclic or dicyclic of? to 9 atoms 0 bonded to © or (N) optionally combined with an aryl group or a heterocyclic aryl Cus cheteroaryl 1 that the heterocycloalkyl ring contains: 1 AY or ? corn 01845 or Ns 3 AY one; or ‎YAAY -¢VY- Af is one N atom and one 1845; or Ao [1 key]; 11845 one and 5(0)0 or atom©0; or Al one [1] atom and 8(0)0 or ©0 atom; or AY one atom 8; or AA 5,0 0 one; AS includes (Las) when applicable; 1 or ? double bond It has an optional substitution 0 with one or two separately selected substitution groups of (C1-C6) alkyl (C1-C6) halo «CF3 «CN «OH «alkoxy 1 and 111846847 -OCH2CH20 substitution group. bivalent 4Y Cua) that the terminal oxygen atoms are bonded to the same carbon atom of the ring); and the AY group substituting -CH2NHCH2- divalently (as the terminal carbon atoms are bonded to the same carbon 4 atom of the ring); caryl g ctetrahydro-1,1-dioxido-3-thienyl wherein (01-06) alkyl 5 mentioned may have an alkoxy group substitution (C1-C6) “aryl or 011; Whereas, each aryl group may optionally have an alkoxy (C1-C6) substituted (which in turn 7 can have a thalo_s CF3 «OH »alkyl (C1-C6) »(NR34R35) substituted aryl 4A is an aromatic ring containing 1 or 10 carbon atoms; where; unless otherwise stated 4 that; Could the aryl in question be an optional substitution of 1a? or ¥ substitutions select each 0 separately from (C1-C6) atole; «OH «alkoxy (C1-C6) forceps ¢NR48R49 5 CF3 «CN 01 The aryl congener is an aromatic ring with ©; 5 9 or 10 atoms; and contain 1 or ? N 550 017 and optionally one 00850 atom or one 10850 atom and one 8 atom or <O or one 8 atom or one 0" 0 atom where, unless otherwise noted, the heteroaryl aryl can be substituted 04 Optional with 1 1 or ?replacement groups selected from alkoxy (C1-C6) “alkyl (C1-C6)” OH 0 mm ¢ (NR51R52 5 CF3 “CN ‎YAAY - except - aryl 5 alkyl (C1-C6) 0)0(0 «alkyl (C1-C6) C(O) «alkyl (C1-C6) <H choose from R45 5 (C1-C3) mentioned is has an optionally substituted with a selection of an alkyl group (C1-C6) wherein 01" alkyl (C1-C6) C(0)O and where <(NR29R30 5 heterocycloalkyl ¢halo «OH »alkoxy 0 A taryl) is said It has an optional substitution of a 01 alkyl group (C1-C6) wherein the alkyl (C1-C6) C(0)O 5 alkyl (C1-C6) ¢H is chosen from 0 650 (OH «alkoxy (C1- Said C3) can be optionally substituted by a selection of 111 {NR53R54 5 cycloalkyl (C3-C6) ¢halo 00 R58 (R57 “R56” R55 R54 (R53 “R52” R51 (R49 (R48 (R47 (R46 R44))) (R43 17 calkyl (C1-C6)s H can be selected separately from the mentioned R59, 4. The alkyl (C1-C6) is possible, since calkyl (C1-C6) 5 11 can be selected separately from 658 V)o (OH 5 alkoxy (C1-C3) to have optionally substituted with a selection of IN or a pharmaceutically acceptable salt thereof. 117 1 7 - compound of claim (1); or its salt Acceptable liane where 1818 is H and 81 " choose from 11, 7 and 82 choose from Fy alkyl (C1-C4) .11 compounded according to claim (1); or its pharmaceutically acceptable salt. where 1803 and 1844 are -* 1 41 - a compound according to any of the claims (1) to (7); or its acceptable salt ana where "85 choose from 11 caryl aryl heterocyclic cheteroaryl 11816117 and .heterocycloalkyl YAAY -4 no 4 - 1 « - compound according to the claim (;); or its pharmaceutically acceptable salt. where 1816 is RZ RZ “Xz 1 R27 3 R26 has an aryl substitution and 72 is the X ring or its pharmaceutically acceptable salt ;. where 816 is ot) is a composite of the - +1 claim 2 V stand AN Z “ is an aryl ring with a substitution — R26 and is heterocycloalkyl R28 1 7 — a compound of claim (1) of formula (1A) or Pharmaceutically acceptable salt: R* v 23g RZ 2 0 SOOTY H H rR' (1A) rds R1 $ and 1012 choose each over 82a of 11 ¢F 5 alkyl (C1-C4) © 1822 and 8223 JS selects separately from H and talkkyl (C1-C6) 1 or 822 R235 with the carbon atom of which lagi yy forms cycloalkyl ( C3-C4) v 826 is an alkoxy (C1-C6) which can be optionally substituted with (NR34R35 and R355 834 A) selecting separately from 11 alkyl (C1-C6) 5s Whereas, the alkyl (C1-C6) mentioned 4 may have an optionally substituted with 011. 1 + - lh compound of the oY protectant) selected from: N-Cyclopropyl-4-methyl-3 -[3-[[1-methyl-1-[2-[2- Y ‎(methylamino)ethoxy]phenyl]ethyllamino]-2-oxo-1(2H)-pyrazinyl]-benzamide ¥ YAAY — SLA - N-Cyclopropyl-4-methyl-3-[3-[[1-[2-[2- ¢ (methylamino)ethoxy]phenyl]cyclopropylJamino]-2-oxo-1(2H)-pyrazinyl] -benzamide© N-Cyclopropyl-3-fluoro-5-[3-[[1-[2-[2-[(2-hydroxyethyl)amino]ethoxy]phenyl]-1- 1 methylethylJamino]-2-oxo-1 (2H)-pyrazinyl]-4-methyl-benzamide 7 N-Cyclopropyl-3-fluoro-5-[3-[[1-[2-[2-[[(2R)-2- A hydroxypropyl]amino]ethoxy [phenyl]-1-methylethyl[Jamino]-2-oxo-1(2H)-pyrazinyl]- 1 4-methyl-benzamide 01 N-Cyclopropyl-3-fluoro-5-[3-[[1-[2- [2-[[(2S)-2-hydroxypropyl]amino] 1 ethoxy]phenyl]-1-methylethylJamino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide VY N-Cyclopropyl-3- fluoro-4-methyl-5-[3-[[1-[2-[2- Ww (methylamino)ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]- VE benzamide Ve N -Cyclopropyl-3-fluoro-5-[3-[[1-[2-[2-[(2-hydroxyethyl)amino] 5 ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl ]-4-methyl-benzamide VY 3-[3-({1-[2-(2-Aminoethoxy)phenyl]-1-methylethyl } amino)-2-oxopyrazin-1(2H)-yl]-YA N- cyclopropyl-5-fluoro-4-methylbenzamide 4 3-[3-({1-[2-(2-Aminoethoxy)phenyl]cyclopropyl }amino)-2-oxopyrazin-1(2H)-yl]-N- Y. cyclopropyl-5-fluoro-4-methylbenzamide 7 , N-Cyclopropyl-3-fluoro-5-[3-{[1-(2-{2-[(2-hydroxyethyl)(methyl)amino] vy ethoxy} phenyl)cyclopropyl]amino}-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide or a pharmaceutically acceptable salt thereof. Yo YAAY -{vi- 1 1 - a compound of formula (1) according to any of the claims (1) to (A) or its pharmaceutically acceptable salt Y for therapeutic use. 011 = use of a compound of formula (1) according to any of the claims (1) through (8/); or its salt “_ pharmaceutically acceptable; in the manufacture of a drug used in the treatment of chronic obstructive pulmonary disease (COPD) 11 1 = use of a compound of formula (I ) according to any of the claims (1) to (4); or its salt “_ pharmaceutically acceptable in the manufacture of a drug used in the treatment of asthma 11 1- Using an effective amount of a compound of formula (I) As determined in any of protective elements Y (1) to (A) or its pharmaceutically acceptable salt; in the manufacture of a drug for the treatment of chronic obstructive pulmonary disease (COPD) in an animal with blood ld such as 1” 1 - A pharmaceutical composition comprising a compound of formula ( ) according to any of the claims (1(7) to (A) its pharmaceutically acceptable salt; and a pharmaceutically acceptable adjuvant, diluent, or carrier. 141 - a pharmaceutical composition comprising in ids an active ingredient that is a compound of formula (I) Y according to any of the claims (1) to (A) or its pharmaceutically acceptable salt; And at least one other active ingredient selected from: £ . phosphodiesterase enzyme. © B2 receptor cofactor. 1 chemokine receptor function modifier. ‎YAAY Lalay-1 is a protease inhibitor. A glucocorticoid receptor antagonist. 4 anticholinergic agent methylxanthines Jil. Vo is a non-steroidal glucocorticoid receptor antagonist. 11 1 - Process for preparing a compound of formula (1); according to claim (1); or its pharmaceutically acceptable salt "; by the reaction of a compound of formula (ID) rR? RI (R2 RI Ss and 85 be as specified in the claim Wis (1) be , a leaving group; of ;4: with a compound of formula (IV) 3 R SNH 7 Rov) v YAAY