CA2984073A1 - Inhibitors of polynucleotide repeat-associated rna foci and uses thereof - Google Patents

Inhibitors of polynucleotide repeat-associated rna foci and uses thereof Download PDF

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CA2984073A1
CA2984073A1 CA2984073A CA2984073A CA2984073A1 CA 2984073 A1 CA2984073 A1 CA 2984073A1 CA 2984073 A CA2984073 A CA 2984073A CA 2984073 A CA2984073 A CA 2984073A CA 2984073 A1 CA2984073 A1 CA 2984073A1
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nn1c1
n1ccocc1
compound
cn1c
cell
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CA2984073A
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French (fr)
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Sheldon Crane
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Nuchem Sciences Inc
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Nuchem Therapeutics Inc
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/18—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to carbon atoms of six-membered aromatic rings
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    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
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    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
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    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
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    • C07D209/04—Indoles; Hydrogenated indoles
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    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
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    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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Abstract

The present invention generally relates to polynucleotide repeat disorders such as trinucleotide repeat disorders, and more particularly to compounds and uses thereof such as for the treatment of diseases associated with the presence of polynucleotide repeats, such as myotonic dystrophy.

Description

INHIBITORS OF POLYNUCLEOTIDE REPEAT-ASSOCIATED RNA FOCI
AND USES THEREOF
TECHNICAL FIELD
The present invention generally relates to polynucleotide repeat disorders such as trinucleotide repeat disorders, and more particularly to compounds and uses thereof such as for the treatment of diseases associated with the presence of polynucleotide repeats, such as myotonic dystrophy.
BACKGROUND
Polynucleotide repeat disorders are a set of genetic disorders caused by polynucleotide repeat expansions (typically trinucleotide repeat expansions). The expanded polynucleotide/trinucleotide repeats have been shown to cause the retention of transcripts .. in the nucleus, where it accumulates in numerous foci (RNA aggregates).
More and more RNA aggregates or foci have been identified in different pathologies, for example Myotonic Dystrophy type 1 (DM1) (Davis et al., 1997) and type 2 (DM2) (Liguori et al., 2001), Fragile X-associated tremor/ataxia syndrome (FXTAS) (Tassone et al., 2004), Spinocerebellar ataxia type 8 (SCA8) (Daughters et al., 2009) and Huntington's disease-like 2 (HDL2) (Rudnicki et al., 2007). All these diseases are characterized by microsatellite expansions of CNG or CCTG repeats in specific genes, leading to the accumulation of their transcripts as nuclear RNA foci (Ranum and Cooper, 2006).
Myotonic dystrophy is a chronic, slowly progressing, highly variable, inherited multisystemic disease that can affect all age groups. It is characterized by myotonia, progessive muscle weakness (especially facial muscles), excessive daytime sleepiness, cardiovascular complications, cognitive impairment, heart and respiratory problems, diabetes, low reproduction and early cataract. Because of the range of systems affected, management requires a more expansive approach than most disorders and care is best provided by a coordinated, multidisciplinary team. There are currently no approved disease .. modifying pharmacologic treatments. Most patients end up wheelchair bound requiring pacemakers, antidiabetic and sodium channel blocker drugs.
Two types of myotonic dystrophy exist. Type 1 (DM1), also known as Steinert disease, has a severe congenital form and a milder childhood-onset form. Type 2 (DM2), also known as proximal myotonic myopathy (PROMM), is rarer and generally manifests with milder .. signs and symptoms than DM1. Occurrence is rare in the general population (1/8000 births), but high in the Quebec Saguenay-Charlevoix region with 1 in 500 births. Currently an estimated 133,000 patients in the Western world suffer from the disease.
There is no current treatment for the progressive myopathy, which eventually kills the patients, highlighting the urgent medical need for therapeutics.
2 It is a multisystemic disorder (FIG. A), caused by an expansion of CUG
trinucleotide repeats in the 3' untranslated region (UTR) of the protein kinase DMPK mRNA
(Brook et al. 1992, Buxton et al. 1992, Fu et al. 1992, Mahadevan et al. 1992). The expanded CUG
repeats have been shown to cause the retention of this transcript in the nucleus, where it accumulates in numerous foci. The current toxic RNA hypothesis posits that the retention of mutant DMPK (dystrophia myotonica protein kinase) mRNAs in the nucleus alters the function of RNA-binding proteins, such as the alternative splicing factors MBNL1 and CUGBP1. As a consequence, mRNA mis-splicing has been reported for several genes in DM1 (reviewed in Wheeler and Thornton 2007). One of the mechanisms proposed is that these nuclear RNA foci sequester essential proteins that normally interact with CUG
nucleotides in mRNAs and interfere with their normal function in the cell.
Disrupting these nuclear RNA foci and promoting the nuclear export of the CUG-rich transcripts should reduce the alteration of splicing factor function and prevent the development of symptoms in patients with DM1 (Wheeler 2008).
Several academic laboratories and pharmaceutical companies have been targeting the disease at key points in the mechanism of toxic RNA as outlined in FIG. B.
These include 1. Preventing the transcription of mutant RNA, 2. Preventing the binding of MBNL
proteins to the RNA hairpin loops on mutant DMPK mRNA, 3. Enhancing degradation of mutant RNA or 4. Treating the symptoms of the disease especially myotonia.
Recent findings have shown that just blocking MBNL protein binding is not enough to prevent the downstream effects of the toxic RNA and that it is more important to reduce the levels of mutant DMPK mRNA to have an overall effect on reducing myotonia (Nguyen et al.
2015).
W02015042685 describes inhibitors of polynucleotide repeat-associated RNA foci and uses thereof.
There is a need for the development of novel strategies to inhibit the aggregation of RNA
with expanded tracts of triplet repeats, for the treatment of diseases associated with the presence of triplet repeats, such as myotonic dystrophy.
SUMMARY
The present invention relates to compounds, as well as to uses thereof, such as to treat a polynucleotide repeat disorder (such as a trinucleotide repeat disorder, such as myotonic dystrophy).
Other objects, advantages and features of the present invention will become more apparent upon reading of the following non-restrictive description of specific embodiments thereof, given by way of example only with reference to the accompanying drawings.
The present description refers to a number of documents, the content of which is herein incorporated by reference in their entirety.
3 BRIEF DESCRIPTION OF THE DRAWINGS
FIG. A shows the symptoms of myotonic dystrophy, as described on the Myotonic Dystrophy Foundation website;
FIG.B shows a generalized mode of action for toxic RNA in DM1.
FIG.0 shows Table A listing the compounds of the application. SMILES is the "C4H602"
formulation.
DETAILED DESCRIPTION
In the studies described herein, the present inventors have demonstrated that compounds having the structure of formula defined below reduce the formation of mutant DMPK
mRNA foci in DM1 patient myoblasts, have the capacity to correct the stabilization of the CUGBP1 alternative splicing factor in DM1 myoblasts, and/or correct the mis-splicing of specific mRNAs in DM1 cells. These compounds may thus be useful for the treatment of diseases associated with the accumulation of RNA foci (RNA aggregates), such as expanded polynucleotide (e.g, trinucleotide) repeat disorders.
Accordingly, in a first aspect, the present invention provides compounds as described in Table A. The present invention also provides racemates, enantiomers, and/or prodrugs of these compounds.
A library of ¨100,000 compounds was assayed in a DM1 model cell line expressing a reporter mRNA with multiple CUG-repeats. This culminated in the discovery of two potential lead structures originally referred to as compound 15 and compound 32, which have been described in WO 2015/042685 (Chartrand et al.).
Hybridization of subunits to the left and to the right of the central carbonyl of these structures led to the identification of two additional lead series of DM1 splicing correctors.
The four lead series of splicing correctors that were identified are represented by the compounds N-0210, N-0248, N-0196 and N-0444 and are shown in Figure 1.
4 Figure 1 ¨ Four lead series r ii (:), N
0 lei 'S -0 0 AN 0 0 b )LNI N
0 ilip N'N Z
H el el HN

(compound 15) (compound 32) 'Hybrids' Optimization of original hit series As part of the process of selecting the most promising chemical series to be transitioned into lead-optimization, the preliminary SAR trends were characterized through the preparation of additional analogs in each of the four lead series. Additional compounds from these four structural classes were ordered from commercial suppliers following an in-silico sub-structure search of commercially-available compound databases.
The SAR
trends that were observed are summarized in Figure 2 and Figure 3.
Figure 2 ¨ N-0196/0210 SAR Trend Summary 55 analogs 4mide and sutfonamide !
critical for activity ' ..
Large lidoohillic . , groups p.refrred i 2 (NH) or 3 =-= oi, . '14------.;.-;"
(benril, aryl, alkyl 1 sip L--; sulfornamides .
. . N _ , oicloalkyl, fused) j H \ '1, acceptable I
}
, N-benzyl 1 Cyclic" amine an option 1 r- --1 f Pyridine 1 ,e.tt oiperidine or raoroholine i amino acids Small N alkyl i 1 , 1 groups tolerated] tolerated ' ! but not Picierazine ' 1 acceptabie 1 L____ õ._õ ______ ___ _ . _1
5 Figure 3 - N-0248/0444 SAR Trend Summary , --132 analogs 1 Amide critical ¨ - f acti I
Pvrro --T or vity J le and i Amide C-Otransposable 1 .. , . õ..
nvrazole preferred i to alterate benzylic position .
beteroaromatics_ I /
- Very polar-- 1 Large lipothillic ----,, \ a v heteroaromatics arYI grouPs (..,\I-=-u-N -c-- (e.8. oyridone) .
. OKat either '142-zyix,, c i _ / not tolerated .
position or ,,-' o 1,-...
fused to het-5 _ = *, ._ õ_____ ; Replaceable by bicyclic i heteroaromatic.s Lioorthillic Small n-al-kyl gri;u.r.T571 (indOle azaindole, quinoline)1 . _. , aromatics best, I enhance activity; ' \ ---, - ¨ -- = - ----i [4-pyridine also [ethyl preferred, hut I tolerated I NIA2 also tolerated i Bis-N-alkylhenzarnide (m- or p-) --- 1---==== = = -- = = . -- 4 analogous to N-210/N. 1% l :
sulfonamide enhances activity From the initial panel of 257 compounds (187 new synthetics, 70 commercial), 12 members were chosen to broadly sample the structural diversity represented in a subset that achieved at least 40% splicing correction of MBNL2 in DM1 patient cells. These 12 compounds were submitted for ADME profiling. Based on the results, the compound class represented by compound N-0701 was identified as the most promising lead series. Based on the presence of a biaryl moiety to the left of the centrally located amide, this class of MBNL2 splicing correctors was referred to as the `biaryl series.' Optimization of N-701 series The chemistry effort commenced focusing on lead-optimization of the biaryl series. The initial focus was a study of effects of replacing the left hand side (LHS) biaryl and the right hand side (RHS) phenyl with alternative heteroaromatic groups as shown in Figure 4.
Figure 4 - SAR study around N-701 r--0 %, N) C AI 140 b A4k-r-N
xv, H
Gn HetAr 1 LIVirri ,---0 amide (----0 czb,N,_) G n so c)SN,J
sb = 0 Bicyclic re'")(11 Biaryl A
N yoj, Is b N
Gn,A-A 1 ilk ,Ar
6 Replacement of the N-phenylpyrazole in N-0701 with an indole in N-1403 (Table 1) led to the identification of the 'bicyclic series' of MBNL2 splicing correctors. N-1403 exhibited MBNL2 splicing correction and low cytotoxicity comparable to that observed with its biaryl counterpart N-0879. At this point, chemistry studies were split between the biaryl and bicyclic series. Other representative examples with comparable splicing correction and cytotoxicity profiles from both chemical series are also documented in Table 1.
Table 1 ¨ Key biaryl and bicyclic compounds Splicin Cell Correct Toxicity % PK (FVB
Cmpd Series Structure ion (% @ 2 IAM, mice) @2 TC50 EC50 ) 0,õõseN
%F 104 0%,> 0%, >16 N-0701 Biaryl N 16 IAM vtM CL 26 =T1/20.2 N
' 40%, 3%, >16 N-0879 Biaryl AL n ND
0.6 ktIVI
1111¨r 33%, 0%,>16 0.6 M %F 15 jiM
N-1402 Biaryl o' 33%, CL 136 0%,>4 0.7 T1/2 1.2 JAM*
1.1M*
47%, N-1403 Bicyclic 0%, 7 vt.M ND
26%, 0%,>16 %F >60 ), 23.360p,hM
I-LM
N-1529 Biaryl CL 16 0%,>4 \_ 0.4 T1/2 3.5 1-1M*
1-tM*
As shown in Figure 5, there were also studies in the N-0248 series following the discovery that tetrahydrocarbolines such as N-0820 could achieve a splicing correction of 20% at 2.5 1-1M.
7 Figure 5 ¨ N-0248 series g g Scaffold N/1 f N ae N,c1/ f N ae c rigidification N "
ME*

Tetra hyd roca r boll nes @10 M : MBNL2 35%, tox 0%
A total of 450 compounds were tested following the discovery of N-0701.
Examples from both of the lead chemical series were identified with splicing EC50 < 1 1,1M
including several which were close to meeting the potency criteria (alternative splicing >50% at 2 M). Following the identification of the biaryl and bicyclic series, potency was improved from 20 IAM for the original lead compound N-0701 down to EC50's of 0.4 I.AM
for N-1529 from the biaryl series and 0.7 1.1M for N-1403 from the bicyclic series.
Furthermore, representatives from both chemical series were identified that exhibited moderate passive permeability and a low Pgp efflux ratio of <6 and as such would be expected to cross the BBB and penetrate into the CNS. Compound N-1529 from the biaryl series was subsequently found to exhibit excellent pharmacokinetic properties (Figure 6a) in mice thereby satisfying the criteria of in-vivo clearance less than 30 ml/min/kg and bioavailability greater than 40%. Compound N-1529 showed good potency (EC50 ¨
0.4 p.M in M909CL2) as well as a >10-fold window between alternative splicing efficacy and cell toxicity (Figure 6b). However, N-1529 fell short of the requirement of >50% splicing correction g2uM.
Figure 6 ¨ Lead Compound A: Mouse Pharmacokinetics B:
Alternative Splicing Correction of SUIXTT
= Clearance (ml/min/kg):
15.6 N-1529-A01 7d moo = unavailability: > 60% 75 D.450 T 2: 3.5 hr 0.400 50 N-1529 4 pM
0.350 0.300 '5 25 :g ono o.no mpk) Z3 0.150 -.-DO (5 mpk) 10 = 1 -6 104 alga -25 cmpd (M) mow OLXO
-9- % splicing correction MBNL2 am 5.00 10.00 1)0 2000 25.00 30.00 -9- % toxicity lime (hrj Optimization of N-1529 N-1529 was subsequently tested in vivo at 30 and 100 mpk, qd for 7 days in the HSALR
DM1 mouse model. The compound was well tolerated and accumulated in the muscle with levels up to 30 vi.M measured 18 hrs post-dose after 7-day dosing. However, no effect was
8 seen in correction of the Clcl mis-splicing transcript and no effect was observed in improving myotonia in both male and female HSA' mice. As such, it was determined that improving splicing correction should be the main focus of the optimization campaign.
A total of 470 compounds were synthesized and screened for MBNL2 splicing correction in the DM1 M909CL2 myoblasts. The primary focus of chemistry was finding aniline replacements and amide isosteres with the goals of improving solubility, preserving the PK
profile of N-1529 and maximizing splicing correction efficacy and potency. The structural modifications that were explored are illustrated in Figure 7. Splicing correction assay results for key compounds generated during the aniline replacement and amide isostere SAR campaign can be found in Table 2.
Figure 7 ¨ Aniline replacement and amide isostere strategy I=Z;D* CF3 N
R1 Ar N
=
N

R2 o R2 o R4 R2 o R4 R5 Ny'N N R1 A = 0, CRaRb or NR
IV G = 0, C-RaRb or N-R V VI * = + HetAr analogs In the biaryl series, exchange of the RHS aniline with a benzylamine in N-2086 or replacement of the aniline amide with a benzimidazole isostere in N-2047 retained splicing correction activity comparable to their aniline counterparts while also improving solubility.
Unfortunately, N-2086 exhibited less stability in mouse microsomes. In the bicyclic series, replacing the trifluoromethyl on the indole core in N-1403 with a thiadiazole substituent led to the identification of N-1840 with EC50 of 0.25 1.tM and with a high maximum splicing efficiency of 60-70% (Figure 8). It was also found that a substantial improvement of the TC50/EC50 window could be achieved by replacing the sulphonamide with a aminoquinoline as shown in N-1537 (EC50 of 0.03 ptM, TC50>10 ktM). As 7-aminoquinolines are known to have potential to cause genotoxicity, the 6-aminoquinoline analog N-2172 was prepared as this moiety would be expected to exhibit a lower genotoxicity risk (Takahashi et al. (1987) Mutat. Res. 187:191-197). N-2172 retained the high splicing correction with reduced cell toxicity of N-1537 while offering an improvement in metabolic stability in mouse microsomes.
Table 2 - Structure, % Splicing Correction of Key Compounds Splicing Cell Compound Correction Toxicity Max Series Structure ID EC50 TC50 Splicing M909CL2 (I-1M) (1-1M)
9 aah 1 N-2047 Biaryl F,C WI 1 >>10 35 H

N-2086 Biaryl 41 rTIYLri 0 ' 0.25 >>10 ,----s 9 N-1840 Bicyclic N.Ni \ HN * S:=0 _rµl--- 0.25 >10 70 \ 0 N-N-1537 Bicyclic \ HN * / 0.03 >>10 35 Br N 0 \
i---S
N-2172 Bicyclic N \ NH: * / N 0.5 >>10 70 \
Figure 8 ¨ MBNL2 Splicing correction and Toxicity in M909CL2 myoblasts for Lead Bicyclic Series Analogs too N41340-Aal N-2172-A02_MF151214 leo 0 . AO
The i .
z vf-4 . j .
0 , 0 L ID* . lee ., WI IV 144 10 ice 104 c mµpd Rd) c nvd (M) -0- ',X, ng coirectkin MBN L2 -=- % splicing correction MEHIL2 -IF % 'code* -11- %toxlcily As part of the comparative evaluation, representatives from each lead series were evaluated for off-target activity at DiscoveRX and CEREP. The result from the DiscoveRX
screen against their 403-kinase panel is shown in Table 3. For the 5 compounds that were tested, 20 3 biaryls and 2 bicyclics, significant inhibition (>50% Alo ktM) was observed for 7 kinases out of the 403 member panel. N-1840 from the bicyclic series was found to have the best selectivity profile (>50% inhibitionAl 0 fiM for 3 out of 403 kinases) of the splicing correctors selected for evaluation.
30 Table 3 ¨ DiscoveRX Kinase Panel
10 Kinases ("Ainh*10 M) YRK
Structure CLK1 CLK4 DRAK1 DRAK2 A (D835 õ..._o_Nyi-N== F 93 78 100 100 72 80 97 =HN-0¨gs=O

s? ='/N1 = - 95 88 24 14 65 77 85 IsrN-1899 N=-) F3C HN * N

\ N-1933 F3c. akh N_41 100 89 76 83 86 81 18 N
N-2047 El The results from the CEREP screen against a panel of 14 enzymes and 40 binding assays (GPCR, ion channels) were obtained. In short, relatively few off-target activities and no 'red flags' were observed in these studies. Comparable profiles were observed for representatives from both the bicyclic and biaryl series.
Analysis of the effect of a panel of splicing correctors on mRNA levels revealed that higher activity (>50% MBNL2 correction) compounds N-1840 and N-2172 from the bicyclic series reduced DMPK mRNA levels in both normal and DM1 myoblasts. In contrast, compounds such as N-1529 from the biaryl series, which generally exhibited a significantly lower (ca 30%) correction of MBNL2 relative to the bicyclic series, had less impact on DMPK mRNA levels. Further profiling of the two higher splicing correctors revealed that N-1840 had lower metabolic stability in mouse liver microsomes with only 29%
remaining after 1 hour incubation (+NADPH) compared to N-2172 with 47% remaining.
Despite exhibiting only a moderate mierosomal stability, N-2172 confirmed a reasonable PK
profile with clearance of 4.5 ml/min/kg and bioavailability of 43% following iv and po administration in mice. However, despite its very favorable overall profile, the potential genotoxicity risk of the 6-aminoquinoline moiety in N-2172 was deemed to be unacceptable.
Optimizing N-2534 to remove genotoxicity potential Compounds containing a non-aniline, non-sulphonamide containing compounds with high MBNL2 splicing correction (>70%) and metabolic stability comparable, or superior to N-
11 =
2172 were sought. A total of 45 compounds were designed and synthesized with the intention of removing the aromatic character of the ring connected to the amide nitrogen while retaining the polar and lipophilic characteristics found in the quinoline and/or morpholine sulphonamide substructures. N-2534 was identified and achieved a maximum MBNL2 splicing correction (60-70%) comparable to N-1840 but with a 3-fold boost in potency and a concomitant improvement in the therapeutic window between splicing efficacy and cell toxicity. Based on the historical assay data and the results obtained for the analog campaign that led to the identification of N-2534 (entry 1, Table 4), the SAR
model illustrated in Figure 9 was formulated for the bicyclic series.
Figure 9 ¨ Bicyclic Series SAR model LipophEllic t = t.= toff Liisophdlic et Fe, w pooi, Jnolf A ( = N =I W=O or N
, N 0 w N ç.µ4 ¨
H '0 H W H
N ksp Or MR

= Lipophilic groups (alkyl, halogen, thioether, non-polar HetAr) preferred on indole core - loss of activity with very polar groups (alcohols amides, ureas, sulfonamides) - CH30-, CF30- acceptable in place of thiadiazole (but less active) - oxadiazole analog (0 instead of S on LHS of N-1840) is inactive = Methyl group preferred on indole nitrogen for activity - N-ethyl, N-cyclopropyl tolerated in some instances but with reduced activity - hydrogen, larger alkyl and polar groups lead to loss of activity = Reduction of activity with amide isostere analogs - e.g. oxetane, 5-membered heteroaromatics (oxadiazole, imidazole) = Highest activity splicing correctors have one or more H-bond acceptors on RHS
Additional lead-optimization of N-2534 led to the identification of several other MBNL2 splicing correctors with comparable profiles. Activity and toxicity data for several compounds within this sub-series is shown in Table 5. The notable SAR trends that were obtained from the second round of lead-optimization are as follows:
= Relocation of pyridine nitrogen diminishes MBNL2 splicing correction activity = Switching from 4- to 3-aminopyridine dramatically lowers the magnitude of MBNL2 correction = 3-aminopyrollidine linker preserves high MBNL2 correction but at the expense of potency
12 = With the 4-aminoazetidine or 6-amino-2-azasprio{3.3]heptane linker, the 4-pyridyl isomer is preferred and relocation of the pyridine nitrogen leads to loss of activity = Thiadiazole substituent is critical for high splicing correction and cycicopropyl on the thiadiazole can give a boost in potency by 2-3X
= Methyl substitution on the indole core is tolerated, larger alkyl groups diminish activity = There is a strong correlation observed between pKa, splicing correction and Pgp efflux; a pKa between 7 and 10 required to achieve high splicing correction and low Pgp efflux.
Table 4 ¨ Assay data for highest activity splicing correctors in the N-2534 series.
%Splicing i ECSO (uM) i %Splic i ing % tox % splcng %Toxicty Compound Structure uM Plateau @ 10 MBNL2 @ 10 uM @ 1 uM
MBNL2 (MBNL2) uM
N-2534-401 =
te N 0.33 59 61 66 17 41 "
N N
N-2556-401 0.62 42 65 64 17 41 f¨ 4 N-2592-401 N " 0.46 55 66 67 6 29 N-2635-401 0.22 51 53 44 77 '6 N-2568-401 ti 0.13 60 41 59 34 51 N-2654-401 0.37 77 84 11 57 N-2658-401' 0.38 41 48 5 52 ADME profiling of a selected group of N-2534 analogs was conducted with a focus on mouse microsomal stability, permeability assays, and plasma protein binding. A
summary of the results is given in Table 11. Generally speaking, most of the compounds in the N-2534 series showed good microsomal stability and low plasma protein binding.
High Pgp-efflux and low membrane permeability were observed for some of the N-analogs and as such, they would have been expected to exhibit poor pharmacokinetics. A
study of the effect of modulating the pKa of the aminopyridine moiety in N-2534 made it clear that this group was probably responsible for the increased susceptibility to Pgp efflux. Attenuation of the basicity of the pyridine nitrogen by the addition of a chlorine
13 atom in the 3-position, as in N-2654 and N-2658, reduced Pgp efflux without compromising high splicing activity. Although N-2654 had high permeability and higher splicing activity than N-2658, it had a lower microsomal stability. The lower microsomal stability manifested itself in a higher clearance (Clp = 41 mL/min/kg) comparable to the value previously observed for N-2534 (Figure 9). On the other hand, N-2658 exhibited a plasma clearance of 8.8 ml/min/kg and an oral bioavailability of 100% (Figure 9).
Table 5 ¨ ADME Profiles of most active N-2534 series DM1 splicing correctors ________________________________ PAMPA MDCK- Mouse Mouse Human Mouse 10-6 MDR1 microsomal microsomal PPB PPB efflux stability + stability -Compound %fraction %fraction cm/sec ratio NADPH NADPH
(perm unbound unbound) (perm (% (%
class) class) remaining) remaining) 01 _____ N-2534 17 11 <0. 123 93 96 (v. low) 01 _____ N-2556 15 14 <0. 84 50 38 (v. low) N-2592 18 8 <0. 97 54 20 (v. low) 01 _____ N-2635 2.8 1.6 <0. 140 50 77 (v. low) N-2568 7.9 3.5 0.09 190 60 47 (low) N-2654 0.7 0.6 4 (high) 1.6 59 85 N-2658 0.1 0.1 0. 1.0 73 93 (mod) Figure 9 ¨ Pharmacokinetics of N-2654 and N-2658 A) N-2654
14 N-2654 io.00 f. ¨.1.Crtr.27,1 IV PO IP _ N-2654, cardiac puncture male FVB mice 1 5 5 , --*(Prel) a NA 1.15 2.8 2 Leo 0.35 NA NA
c NA 1 0.25 o ale o --=-=-iv r." '..1.5t.1 = lj .iitit i. -....14-144* 05 7.4 9.4 2 c ,..
, ' FIT.-4-gun 1-5 NA NA 0 fu E. 0,01 1 NA NA
RMEIMED 61.5 NA NA
, 1 .7 0 A , 1 00 [ , .a.,,,, i 04õ,,i1 m..1. NA NA o 5 10 15 20 5.315 NA NA , Time (hr) ' i '7' rir"Tflii 100 100 1 t:' = ..soracre/o) -B) N-2658 ETV 'd 461E1 N-2658 10.00 L4.1. loonot w PO IP _ N-2658, cardiac puncture male FVB
mice r119/41)* 1 5 5 --,,. i 1 NA 2.96 3.38 g too -. .. ...... , 7..,, 1.06 NA NA u I
c NA 2 2 8 o.10 --0-1v i 71:4771/7f7% co _ =40-gft ,,,=,,, 5.3 23.8 24.4 c ¨IF¨
PO
=
,Atr).,iJ 4.7 NA NA m' 0.01 IP
E
i' 1.47=1/7 NA NA
,.,7TZM,IIMM 13.2 NA NA
- 1 1114Cµ 1,1 8.8 NA NA o 5 10 15 20 25 30 2.772 NA NA Time (hr) rack() , 1. Abio iltd 161A no no Synthesis of new analogs - coincident with the identification of N-2654 and N-2658.
1114 novel compounds were designed and synthesized, and 269 analogs were sourced from commercial suppliers for a total of 1417 compounds. A complete list is available in Table A.
The compound with a favorable overall profile for an in vivo POC study that has been identified is N-2658. Prior to the initiation of an efficacy study in HSALR
mice, a tolerance study was conducted at 60 and 100 mpk, bid by PO in male and female HSALR
mice.
Although there was some indication of toxicity (weight loss), both males and females tolerated the high dose for 7 days. An efficacy study is planned with N-2658 in HSALR
mice.
Biological Assays ¨ Primary
15 Mutant DMPK RNA remains in the nucleus of a cell as RNA foci. Ideally, treatment should reduce RNA foci and there are literature reports of compounds that do cause a reduction in RNA foci along with efficacy in mouse models of DM1 (Wojciechowska et al. 2014, Ketley et al. 2014). A 96-well RNA foci assay was developed to measure the .. reduction of foci by compounds. The foci assay was optimized using DM1 patient cells (M909) measuring foci density based on foci number, intensity and area. A
number of compounds were tested including the literature compounds C16 and Ro31-8220.
Although these compounds did reduce foci density, reduction of foci was strongly correlated with toxicity (Figure 1). Furthermore, for compounds in which alterative splicing correction was observed, no foci reduction was detected until concentrations reached cell toxic levels (data not shown). The foci assay could not be solely relied on to give an accurate representation of foci reduction compounds without the effect being due to cell toxicity.
Figure 1 ¨ %Foci in DM1 M909 myoblast cells treated with C16 and Ro31-8220 120 C16 (n) 140 Ro31-8220 (n) .111¨Foci Density/NA 120 , ¨IF¨Foci Density/NA

9 ino i) 60 e 4G

0.01 0.1 1 10 0.1 1 15 Concentration (1.1M) ConcentratRan (WV]) A 6-well, 7 day alternative splicing assay using DM1 patient myoblast cells (M909) and immortalized cells (M909-1) was developed to measure the mRNA transcript levels of several alternatively spliced genes as illustrated in Figure 2. Positive compounds were expected to reduce the level of mis-spliced transcript to normal levels. The level of 20 correction was reported in terms of% splicing correction. The level of mRNA was initially measured using classical PCR and later converted to qPCR for increased efficiency. This also allowed the assay to be conducted in a 96-well format. The splicing assay was further optimized from a 7 day assay to a 3 day assay as correction of splicing was observed within a 3 day incubation time with less cell toxicity (Figure 3) allowing a 1.5 week turnaround .. time for n=2 assays per compound.

Figure 2 ¨ Alternative Splicing Transcripts in M909 DM1 patient cells
16 Alternative splicing (%) ice a 90 M908 (WT) 7 80 .1 M909 (DM1) E 70 M M909-1 (DM1) = 60 -, fi so ...i 20 1 10 .
I , Ii 1 III

MENL1 MBNL2 TNNT2 SERCA1 INSR hoRNPA281 ex7 Ind ex6 Ind ex5 lad ex22 excl ex11 excl ex2 Inc!
Figure 3 ¨ Comparison of 3 day versus 7 day splicing correction assay csi -J = 96 well 7days RTq PCR
Z 80- ISE 96 well 3days RTq PCR 80 CO

.is 60- 60 o .Pg .s 20-o 1 4 - i II -Li 11,111 ii S 0 111 g 40 I¨

= 2 2 M 2 E E M E
in a ata"
I I I I
-20- EI r=-i vi .1 ;-.' -20 ,,,i El 2 ,si 5 Further refinement involved changing the cells from a pool of immortalized cells to a specific clone (c1one2, M909c12) of immortalized cells to more closely match the growth rate, myotube formation and the toxicity sensitivity of the immortalized cells to the primary cells. A comparison of M909, M909-1 and M909c12 is given below:
10 Table 2 ¨ Characteristics of M909 . atient cells and immortalized cells Cells Myotube Growth MBNL1 MBNL2 Cell formation Rate relative to relative to toxicity WT +++ ND ND ND ND
M909-1 ++ 2.8 ND ND +d¨F
=ool il .,1-:''," "0'. ''' = ':i.i . .
Ni...:-. . i 1.= '. ' Clone 2 was chosen to replace the immortalized pool M909-1cells as it closely matched the primary cells in terms of growth rate and sensitivity to toxicity.
Cell toxicity was also optimized from measuring cell density to a more accurate determination of cell viability with the Mitotracker orange assay measuring cell redox state.
17 Prestoblue was also included as a confirmatory assay of cell toxicity as this assay was found to be less sensitive to interference by compound precipitation compared to the Mitotracker method.
Biological Assays ¨ Secondary Other genes known to be mis-spliced in DM1 patient cells compared to normal cells were studied with key compounds. These transcripts included MBNL1 exon 7, MBNL2 exon 7, TNNT2 exon 5, SERCA exon 22, INSR exon 11, and COPZ2 exon 9b. These particular exons were selected because they show a large alternative splicing change between DM1 and wt human myoblast lines. Exons in transcripts that are not affected by DM1 and that were used as controls include HnRNPAB1 exon 2, MAP4K4 exon 23, ECT2 exon 3 and HMGCS1 exonl. Compounds such as N-1529, N-1840, N-2534 and N-2658 showed various levels of correction of DM1-dependent genes while having no effect on the alternatively spliced exons not regulated by MBNLI and CUGBP I . Examples are shown in Figure 4.
Figure 4 ¨ Splicing Correction of various DM1-dependent transcripts by N-1840
18 N-1529 48w M909c12 >
_Li A _4 1,4 # "11 T , ____________ tli.=========,e--4 = ===
la! = look *10 10, cmpd (M) %splicing correction MBNL2 .A %splicing correction MBNL1 -iv %splicing correction SERCA1 %splicing correction TNNT2 %splicing correction INSR
% splicing correction COPZ2 N-1840 48w M909c12 t 1-v4 = =
= f 0 _______________ ¨ __ -i- 10-8 10', 10-6 10-5 cmpd (M) %splicing correction MBNL2 A %splicing correction MBNL1 %splicing correction SERCA1 %splicing correction TNNT2 =-=-- %splicing correction INSR
% splicing correction COPZ2 Furthermore, the splicing correction was independent of the patient myoblast cells used with similar EC50's and toxicity obtained in three DM1 patient myoblast lines:
M909 with 1250 CUG repeats, M1610 with 1300 CUG repeats and DM15 with 3200 CUG repeats (embryonic origin) are shown in Figure 5.
19 Figure 5 ¨ Splicing correction (as % activity) by N-1840 in different DM1 patient cell lines.
N-1840 48w M909c12 N-1840 48w M1610 N-1840 48w loo 100 100 50. ; 50 = i ,O1 *
i I 10-0 lit 10! T 1O5 ________ -icro 10-7 lot 10 5 cmpd (M) cmpd (M) cmpd (M) ==== %splicing correction MBNL2 = % splicing correction MBNL2 %
correction MBNL2 U - %toxicity a % toxicity = % toxicity MBNL2 corr@1 M MBNL2 corr@1 M
MBNL2 corr@1 M
5 32% 4 50% 12 62% 9 DM1 myoblasts have also been reported to have an increase in CUGPB1 protein levels and other small molecules have been shown to reduce CUGBP1 levels when toxic RNA
is reduced. Studies with N-1840 showed that the compound restored CUGBP1 levels to that 10 of wt cells (Figure 6).
Figure 6 ¨ CUGBP1 protein levels of DM1 myoblasts (M909) treated with N-1840 CUGBP1 protein blot a 0) cci .! 1_ CCI

=

gee-exN.
15 For the screening assay, the DM1 myoblast cells were incubated for 72h in the presence of compounds. At the highest doses tested it was observed that the live cell number (Mitotracker positive cells) was reduced for some compounds. To investigate the mechanism of this toxicity, we used assays to detect cell death (apotosis or necrosis) or cell cycle arrest. Figure 7 shows that with compound N-1840, a partial cell cycle arrest in G2M
20 was observed, but not with the other active compounds tested. Other specific assays were run to detect caspase and PARP cleavage at early and late timepoints but no significant apoptotic cell fraction was detected (data not shown).

Figure 7 ¨ Cell cycle assay SubGi ail Si 111. S
&52M

PI ao 4' 80 4) ao 2,..3i 60 2 60 2 60 >, >, li; 7.1 1 = . lt tiµ . ki% lt' 4, 0 c)", c,', . 4, . .
NV 4µ tt . O'S r,'' 4, 4, . 4, 4- . . 44, 0 cs...3 cp.
co,õ,õ..,,,, ,.../_._. ,,=.c,,,,,Z.43 clz .0 tp4 4,,,q,0 ,,,4 ,,,,/ ,..,4 ,4,544, Z 80 ' ii 80 80 a a a 04, 6 ty 60 040 6 7, 7, >, >, . 20 1 .e= " . 20 .1-, ILLtLILt . . . . . 4- 4' . µ,0 cc, c,'` µ,4µ," "µ 44' st si'lµ 4.) , ' )'s =
4, . . 4, 4- 4, . 0 pµb N
5 Figure 8 illustrates a time-course experiment with compound N1840, showing that the splicing correction effect is observed at 24 hours, but that cell toxicity, i.e. lower numbers of cells, gradually increases after each day of incubation, thus pointing to slower cell growth as a main component of toxicity.
10 Figure 8 ¨ Time-course of activity/toxicity compound N1840
21 loo = 72 his -o- 48 his 24 hrs **3 50 0.
1 k43 1. -7 104 104 cmpd (M) 100 72 his -4.- 48 his -o- 24 hrs SO
/
T --0 _ 1Q-8 t 1:*7 4 104 10-s cmpcitIVI) RNAseu studies Several RNAseci studies were conducted. These included mRNA from muscle tissues of the DM1 mouse models DMSXL and HSALR, and DM1 myoblast cells treated with N-1840 and N-1529. For the DMSXL samples, very few genes were found to have different expression or different splicing compared to wild type samples, such that no gene with clear splicing changes could be used as a marker during in vivo studies.
Furthermore, none of the reported human DM1 splicing deficits were found in the mouse mRNA and the DMSXL mouse was dropped from the program. Follow up studies showed that the level of the transgene human DMPK was very low (0.004) compared to the endogenous mouse DMPK (0.11) in muscle mRNA from DMSXL mice, accounting for the lack of splicing phenotype. It is possible that this particular mouse strain has lost so much transgene hDMPK expression that it has reverted to the wt phenotype.
An RNAseci study on HSALR gastrocnemius and vastus muscle identified Tnnt3 exon 32 as a splicing event with significant difference between wild-type and HSALR
mice. Other known transcripts were identified and are listed in the table below:
Table 3 ¨ Spliceopathy in HSALR muscle Transcript F VB % HSALR % Window inclusion inclusion Cid 4 36 9 mTTN 62 98 1.6
22 MBNL2 6 29 4.8 MBNL1 4 51 12.7 SERCA1 100 31 3.2 TNNT3 7 89 12.7 A final RNAseq study was conducted for looking at gene expression and mis-splicing events between different DM1 patient myoblast cells treated with N-1529 and N-compared to wild type myoblast cells. Analysis of the RNAseq data was able to identify genes that were known to be up or down regulated between DM1 patient and non-patient cells. With the analyzed RNAseq data, it was possible to identify potential toxicity markers for the compounds to be used for future optimization. The main toxicity pathway induced was found to be p53-dependent signalling, with transcripts TNFRSF1OB (TRAIL-R2), CDKN1A (p21 cipl) and MDM2 being chosen for validation. It was confirmed by qPCR
quantification that all these genes were induced by the more toxic compound N-1840, but not by the low cell-toxic compound N-2172.
Other mis-spliced transcripts affected by the compounds DMPK mRNA reduction Other potential genes that could be affected by the compounds focusing on genes known in the literature to be either MBNL dependent or independent were explored.
All MBNL-dependent genes studied (MBNL1, MBNL2, TNNT2, SERCA1, INSR, ITGA6, COPZ2) were found to be normalized to varying degrees by compounds such as N-2291 and N-2172 (Figure 9a). Splicing events that were not dependent on MBNL or CUGBP1 such as hnRNPA2B1, MAP4K4, HMGCS1 and PPP3CB were unaffected by compound treatment up to 10 M (Figure 9b).
Figure 9 ¨ Effect of compounds on a) DM1 affected alternative splicing events (as `)/0 correction) and b) control transcripts (as `)/0 inclusion) (Dec 2015 JRT) a) b) N-2172-601 48w M909c12 N-2172-1301 48w M909c12 100-75 *Ns no an.
1-%
= =A. 5o =-=
I __________________________________________________ 4-1 177 e 2 5 -e 25 . 0 -0 __________________________________________ 4, - 10a 10-7 106 10-5 18 1 -1 1 108 cmpd (M) ceipd (M) -25 % ndusion hriRNPA2B1 A % correction MBNL2 %
% correction MBNL1 inclusion MAP4K4 % correction TNNT2 % inclusion HMGCS1 % correction SERCA1 =% inclusion -v- % correction INSR 0 % toxicity % correction IT6A6 % correction COPZ2 %toxicity
23 It was also found that some compounds could reduce the amount of the DMPK mRNA
in both wt and DM1 myoblasts. A clear correlation was found with max splicing correction efficiency and DMPK mRNA reduction such that compounds that could only reach 35%
max splicing (open dots-Figure 10) were found not to decrease DMPK gene levels whereas compounds that could reach splicing levels above 60% were able to decrease DMPK gene levels (blue dots-Figure 10). This suggested that the two groups of compounds were working by a different mechanism of action. Being able to reduce DMPK mRNA
levels along with MBNL binding in DM1 has been shown by others in the field to be required to achieve in vivo efficacy (Zimmerman et al, 2014, 2016). Further studies are underway to investigate the hypothesis that DMPK transcript levels are reduced due to decreased transcription from the DMPK promoter in N-1840-treated cells.
Figure 10 ¨ Maximum splicing correction versus maximum DMPK reduction =
(,) 1840.
60 =
= =
=
a_ x 20 ea 0 0 =

% Maximum splicing correction 15 In Vivo studies Two transgenic mouse models were first proposed: DMSXL and HSALR. The DMSXL
mouse contains the expanded human DMPK gene with >1000 CTG repeats resulting in a mouse with muscle, heart and brain DM1 mis-splicing (Huguet et al., Plos Genet 2012;
Hernandez-Hernandez et al., Brain 2013). The HSALR mouse contains a mutant human 20 alpha-actin gene with ¨250 CTG repeats affecting skeletal muscles only (Mankodi et al., Science 2000). Muscle and brain tissue from the DMSXL mouse was analyzed and shown to have none of the splicing defects expected for a DM1 mouse model. On the other hand, RNAseq analysis on the HSALR muscle tissue showed the expected mis-splicing of key gene transcripts including those coding for the chloride channel Clc-1, the calcium reuptake 25 pump Serca-1 and the alternative splicing factor Mbnl 1 . All in vivo studies were conducted using this mouse model of DM1, also known to display myotonia (Mankodi et al., Science 2000). One gene product most relevant to myotonia in the HSALR model is the chloride channel Clc-1. Mis-splicing that results in inclusion of exon 7a (E7a) in its mRNA leads to premature termination of translation and synthesis of a protein devoid of channel activity 30 in skeletal muscles such as the vastus and the gastrocnemius (Lueck et al., 2007).
Reduction of this mis-splicing should translate into milder chloride channelopathy and ultimately in improvement in myotonia. To measure myotonia, the MP150 hardware with
24 EMG100C electromyogram amplifier module from Biopac Systems was purchased. A
concentric needle electrode is inserted directly into the gastrocnemius of an anesthetized mouse and the electrical activity of the muscle recorded and translated into graphs and sounds using specialized software. An example of the muscle electrical response to the needle insertion obtained from a wild type FVB mouse compared to an HSALR
mouse displaying a myotonic discharge is shown in Figure 11.
Figure 11 ¨ EMG traces from gastrocnemius muscles of WT FVB and Tg HSALR
mice FVB HSALR
In an experimental protocol, the electrode is inserted twenty times into the muscle of each HSALR mouse and the occurrence of a myotonic discharge examined within each trace, after which the rate of occurrence of the discharge is calculated. The average rates between the compound-treated group and the vehicle-treated group are then compared using the statistical t test to determine if a compound lowering effect is significant (p>0.05). A list of compounds studied in the HSALR mice and the results is summarized in table 4.
Table 4 ¨ Summary of in vivo studies and results with HSALR
Cmpd Dose/ frequency/ # animals Toxicity Cmpd Mis-EMG
route/ duration/ per cmpd in splicing Myotonic age of mice treatment muscle Clc-1 discharge group 18 hr correction post dose N-0196 40 mpld qd/ 6 males No BW ND No effect ND
IP/ 7 days/ change similar 1.8 months to vehicle Hept- 30 mpk/ qd/ 6 males 5 out of 6 ND ¨89% ND
amidine IP/ 7 days/ animals died splicing 4.2 months day 4 correction N-1529 5, 10 mpk/ qd/ 1 male, 1 Minor BW 3-4 Nil ¨39% ND
PO babyfood/ 7 female increase 8 hrs correction in days/ (tolerabilit similar to females only 4.2 months y study) vehicle N-1529 10 mpk/ qd/ 7 males, 3 Minor BW 1-4 tiM No effect No effect PO babyfood/ 14 females increase days/ similar to 3.6-3.9 months vehicle N-I529 25,50 mpk/ qd/ 2 males, 2 No BW 5-18 p.M ND ND
PO babyfood/ 7 females change similar days/ (tolerabilit to vehicle 8.6-9.1 months y study) N-1529 30, 100 mpk/ qd/ 8 males, 7- Minor BW 6-26 tiM No effect No effect PO babyfood/ 7 9 females increase @ 100 days/ mpk
25 3.4-4.4 months similar to vehicle N-2534 30,50 mpk/ qd/ 2 males, 2 Significant 0.6 1\4 ND
ND
PO gavage/ 7 days; females BW loss by @ 50 5,15 mpk/qd/ FVB IP, minor BW mpk IP/ 7 days (tolerabilit decrease by 3-4 months y study) PO
N-2534 25 mpk/ bid/ 10 males, Minor BW 0.2-0.7 No effect No effect PO gavage/ 7days/ 10 females decrease 4-4.5 months N-2082 10, 20, 30 mpk/qd/ 2-4 males, 75% died at 0.7-1.7 89-100% 26%
IP/ 7days/ 2-4 day 4-7 at >20 p,M correction at decrease @
3.8-4.0 months females mpk. All mice 10 mpk lowest dose 10 mpk (tolerabilit survived at 10 y study) mpk N-2082 1,5 mpk/ qad/ 2-4 males, No adverse 4-14 M ¨70%
Up to 60%
IP/ 11 or 21 days/ 2-4 effect on @ 5 correction at decrease 4.6-5.5 months females behavior; 4 mpk, 21 5 mpk, 21 (average mice with days days 33%) ¨12% BW
loss N-2658 60, 100 mpk/ bid/ 2 males, 2 Significant 0.09-0.2 >40%
24-44%
PO gavage/ 7days/ females BW loss but I.A.M correction in decrease in 4.5 months (tolerabilit similar to 50% of mice 50% of y study) vehicle mice N-0196 was tested in the HSALR mouse as a training exercise for the biology group. An oral feeding method in which the drug was ejected into the mouth using a pipetman at the same time as a drop of blueberry-flavoured baby food placed on the tip was being licked by the mouse. This method works very well for compounds such as N-1529 that are highly soluble in DMSO (i.e. > 50 mg/ml) and can be concentrated enough in vehicle to allow for small volumes to be administered.
The first good compound with splicing correction in DM1 myoblasts with an EC50 below 1 M and good pharmacokinetic properties was N-1529 (EC50 ¨ 0.4 M). Although N-1529 gave high micromolar levels of compound (up to 26 M) in the muscle of the HSALR
mouse after a 7-day dose by baby food oral method, no effect was observed on correcting the mis-splicing of the chloride channel mRNA in this tissue. Not surprisingly, without gene splicing correction, no effect on myotonia was observed. N-1529 could correct splicing to a maximum effect of 35% in DM1 myoblasts and had no important effect on reducing DMPK mRNA. The lack of in vivo efficacy suggested that higher splicing correction was needed and perhaps a different MOA, too. Compound N-2534 has an of 0.3 M with maximum splicing correction of 70% and had activity in decreasing DMPK
mRNA in myoblasts. It was then decided to conduct the tolerability study at 50 mpk for 7 days with N-2534 prior to obtaining the pharmacokinetic data. The mice tolerated the 50 mpk dose but showed low muscle levels at trough of 0.2 M. The PK data which arrived after the tolerability study, also suggested it was needed to have bid dosing to get good coverage and ideally high dose. Being limited to a total dose of 50 mpk from the tolerability study, the in vivo efficacy study was conducted at 25 mpk bid for 7 days.
However, the muscle trough drug levels were still very low after 7 days reaching only 0.4 1_11\4. No effect was observed in the correction of the chloride channel mutant transcript,
26 nor on myotonia. For the next compound to be studied in vivo, it was wanted to have improved pharmacokinetics profile compared to N-2534 while maintaining the high splicing correction and DMPK mRNA reduction MOA. At the close of the program, N-2658 best met these criteria and the PK compared to N-2534 is shown in Figure 12 below:
Figure 12 ¨ Pharmacokinetic Profiles of N-2534 and N-2658 woo N-2534, cardiac puncture male FVB mice at.
o ¨11P¨P0 Ar IP

aco o 5 10 15 20 25 30 Time (hr) 10.00 1 N-2658, cardiac puncture male FVB mice Jo 6 0.10 ¨411¨P0 0.01 0,00 Time Ihr) A tolerability study with N-2658 was conducted at 60 and 100 mpk bid for 7 days by PO
dosing. All mice showed minor to severe weight loss. Since vehicle-treated mice also lost significant weight, the losses might have been mainly related to the gavage technique rather than to some toxicity of the compound. Although the goal of this study was to see whether the mice would tolerate the highest dose, tissue collection and EMG
measurements were performed on this small cohort. Splicing corrections for the Clc-1 transcript ranged from 14 to 82% with half the mice showing more than 40% rescue. Interestingly, this was accompanied by amelioration in the myotonia as reflected by a decrease in both the frequency (23%) and duration (-60%) of myotonic discharges (Figure 13a-b). An in vivo efficacy study in which 20 mice are treated with compound N-2658 was planned to confirm these preliminary findings.
Figure 13 ¨ Myotonia alleviation after treatment with compound N-2658 for 7 days at 60 and 100 mpk b.i.d.
a)
27 Myotonia in gastrocnemius N-2658 tolerability study p= 0.0016 if100- *AT*, =
Male Female up 6- 80- 00 60 mpk b.i.d.
= MN 100 mpk b.i.d.
60- =
=
=

o 20-o 0 __________________ Vehicle N-2658 b) Myotonia in gastrocnemius N-2658 tolerability study p= 0.00031 Male ch 7000-E Female oc - 6000 _ 00 60 mpk b.i.d.
ta:= 0.100 mpk b.i.d.
-a 5000-to 4000-A' c 2000-o 4} 1000"
tO) 0 ___________________ Vehicle N-2658 The two compounds heptamidine and furamidine have been reported to correct mis-splicing in HSALR mice but both have been shown to be relatively toxic in vivo (Coonrod et al. 2013; Siboni et al. 2015; Wenzler et al., Antimicrob Agents Chemother 2009). It was possible to reproduce the splicing correction for Clc-1 in two control studies with the first one conducted early in the program with heptamidine on a few animals, then later with furamidine on a larger cohort. In the tolerability study with furamidine given i.p. once daily at 10, 20 and 30 mpk for 7 days, RNA mis-splicing was virtually corrected for Clc-1 (89-100%) at all doses. With this correction, small but significant reductions in the myotonic discharge frequency were observed in 7 out of the 8 recorded mice, irrespective of dose (a 26% and 21% decrease at 10 mpk and 20-30 mpk respectively; t-test p=0.0427 and p=0.0009, respectively). It was hypothesized that normalization of the skeletal muscle pathology, which is dependent on the accumulation of functional Clc-1 proteins, might require more time than to rescue the splicing deficits. Thus, by increasing the length of
28 treatment to 3 weeks it was hoped to reduce the myotonia further. However, since two-thirds of the mice that received the highest doses died during the tolerability study and adverse effects were also observed in the animals dosed at 10 mpk the dosing regimen needed to be modified. Therefore the efficacy study with furamidine was conducted at the lower doses of 1 and 5 mpk, dosing every other day by IP (terminal elimination half-life [
i.p.] = 22 hr, Yang et al. Antimicrob Agents Chemother 2014) to help reduce toxicity. The treatment duration was also split into 2 time periods ¨ an 11-day and a 21-day regimen. At 1 mpk, no effect was observed on the Clc-1 mRNA mis-splicing or on myotonia even after 21 days. However, at 5 mpk, a significant decrease in Clc-1 E7a inclusion was observed in females (n=2) after 11 days and in both gender after 3 weeks [67-71%
correction, n=8]
(Figure 14). Myotonia was reduced only slightly after 11 days but significantly after 21 days with an average of 67% of the insertions leading to myotonic discharges [p=0.0035;
range = 10-60% decrease, n=8] (Figure 15a). Furthermore, the duration of the discharges was 73% shorter on average compared to vehicle-treated mice (Figure 15b).
This study with furamidine demonstrated that it was possible to correct the chloride channel mRNA mis-splicing in the mouse model and, with a longer exposure time, that myotonia could be significantly alleviated using a dose regimen that was tolerated by the animals.
We have previously shown that this compound can correct the mis-splicing of mRNA in DM1 myoblast cells with an EC50 of 0.8pM and a MOA that leads to a decrease in DMPK mRNA in both normal and DM1 patient cells suggesting that a similar mechanism may be involved in vivo.
Figure 14 ¨ Clc-1 mRNA E7a mis-splicing in Gastrocnemius muscle after treatment with furamidine (N-2082) or vehicle for 11 or 21 days at 1 and 5 mpk q.a.d.
Clc-1 mRNA mis-splicing in Gastrocnemius N-2082 efficacy study 80 I **
****
70- r ______________ Male g 60. = Female =

AT
"
ate, A : p = 0.0027 .-ikjA GO "" : p< 0.0001 P., 30- II : p= 0.0424 Lig =
==-.. 20-=
0 õ , , I
11/21 11 21 11 21 - days (q.a.d.) 0 1 1 5 5 -mpk N-2082 HSALR FVB
Figure 15 ¨ Myotonia alleviation after treatment with furamidine (N-2082) for or 21 days at 1 and 5 mpk q.a.d.
a)
29 Myotonia in gastrocnemius N-2082 efficacy study Zze-LI 100- *11.11afr .6611,A A2A
Male = =
= Female o **: p = 0.0035 Cr) =
=¨=
=
gs 60-a) .
.c = 40-u ._ 20-.9 >, 0 ______________ .=
2 11/21 11 21 11 21 11"¨ 111 days (q.a.d.) 0 1 1 5 5 ¨ mpk N-2082 HSALR FVB
b) Myotonia in gastrocnemius N-2082 efficacy study ***.
1) 8000-=
Male A
O A. Female , *:p=0.0346 13 **** P 0.0301 A
= 4000-1:41 =
"F.
= 2000-=
a o = =
(1) 0 _________________________ 11/21 11 21 11 21 days (q.a.d.) 0 1 1 5 5 mpk N-2082 HSALR
ADME/PK profiling Key compounds were profiled for their ADME properties. A list of the assays conducted is given in table 5 Table 5 ¨ List of ADME assays
30 Assays Protocol microsomal stability Mouse liver microsomes +/- NADPH incubation lhr. Measure remaining compound by LC-MS/MS
= Typical test dose 1 M
Metabolite profiling Mouse liver microsomes +/- NADPH incubation 1 hr Full mass spectral scan (ESI positive and negative and mass extraction (EIC, extracted ion chromatogram) is performed to look for metabolites = Typical test dose 3 M
Plasma protein Incubated in plasma (human or mouse) (n=2) in binding a Rapid Equilibrium Dialysis (RED) device and dialyzed against PBS.
= After 4 hr, each side is analyzed for the test agent by LC/MS/MS
= Typical test dose 5 M
Chemical stability Incubated compound at 37 C for 0 to 2 hr in (half-life SGF (simulated gastric fluid, pH 2.2) and determination) FaSSIF (fasted-state simulated intestinal fluid, pH 6.0 buffers. Stop reaction with cold methanol/PBS and analyze supernatant by LD-MS/MS. Fit to first-order decay model to determine half-life.
= Typical test dose 5 M
Kinetic solubility Titrate compound in PBS and DMEM/15% FBS
in 96-well plate. Measure light scattering using BMS Nephelostar. Solubility estimated at break in segmental regression fit.
= Typical test dose 250 M, 2 fold serial dilution Thermodynamic 24hr in buffer, measure compound in solute by solubility HPLC/UV
= Typical test dose 2.5 mg CYP induction Human AhR, and CAR3 nuclear receptor activation using stable cells transfected with nuclear receptor and corresponding response elements in a 96-well plate. 6 conc of compound incubated with cells for 24 hr (human AhR) or 48 hr (human CAR3) and determine cell viability and reporter gene activity.
= Typical test dose (30 nM ¨ 10 M) for
31 Assays Protocol CYP inhibition Incubated with human or mouse liver microsomes and a pool of isotype-specific probe substrates for 7 CYPS:
CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. Measure by LC-MS/MS
= Typical test dose 3 pM and 10 p.M
LogD HPLC based water/octanol partitioning assay at fixed pH, performed at Sirius MDCK-MDR1 MDCK-MDR1 cells in 96-well Caco-2 plate add permeability compound to apical side (A) and amount of permeation on the basolateral side (B) was determined after 2 hrs for A to B. Inverse was conducted for B to A and permeability Papp calculated as rate of permeation/initial concentration x area of monolayer (0.11 cm2).
Efflux ratio Er is Papp(B to A)/ Papp(A to B) = Typical test dose 5 p,M
PAMPA permeability Pre-coated PAMPA plates (BD bioscience) with 300 jil of compound solution in PBS added to donor well and 200 pl of PBS added to accepter well. After 5 hrs amount of compound in each section was determined.
= Typical test dose 5 M
Ames genotoxicity 24-well mini Ames:5-histidine-requiring strains of Salmonella typhimurium +I- (S-9 rat microsomes) N-1858 @250 jig/m1 N-2067 @ 250 jig/ml Phototoxicity Balb/c 3T3 Neutral Red Uptake Phototoxicity Assay N-1868 @ 100 jig/m1 N-1870 @31.6 g/m1 hERG CHO cells expressing the hERG channel are dosed with test agent at 6 concentrations for 5 minutes.
Membrane currents are measured using an automated patch clamp system (IonWorksTM
HT instrument, in a specialized PatchPlateTM).
= Typical test dose (30 nM ¨ 10 M) IC50 determined Kinase panel 468 kinome scan = Test dose 10 pM
32 Assays Protocol CEREP panel 35 radioligand binding assays, 14 enzyme assays = Typical test dose 10 M
PgP-substrate Screen Same general protocol as MDCK-MDR1 permeability LLCPK1-MDR1, assay to determine Efflux ratio with 2 hr incubation LLCPK1-Mdrla time = Typical test dose 1 uM
Pharmacokinetic FEW mice, 3 per dose/route/time point, IV, PO, IP, 8 study time points up to 24 hrs: 5, 15, 30, 60, 120, 240, 480, and 1440 min post dosing, cardiac puncture. For muscle and brain tissues, sacrificed at requested time (usually 2 hrs post dose). Tissue was extracted, homogenized and crashed with 3 volume methanol including internal standard, centrifuged and drug levels analyzed by LC-MS/MS compared to calibration curve prepared in mouse blank tissue homogenates.
= Typical test dose 1 mpk for IV, 5 mpk for PO, IP
Table 6 lists some of the compounds tested in various ADME assays.
Table 6 ¨ Compounds tested in various ADME assays Chem = LEC-PKE
Microsome= Metabolic Cyp MDCtK Photo.
stability Therm Plasma Kinase PgP PAMPA Logo Ames bERG CEREP PK
Stability Profile inhils perm. toxicity FaSSIF/ Solubility binding Panel substrate ; S6f N-0701 N-0701 N-0701 N-0701 N-0701iN-0701 N-N-1402 N-1402' N.1529 N-1529 N-1529 N-1529 N-1529 N-1529 N-1529 N.1529 N-1529 _ N-1840 N-1840 ______________ N-1840 N-1840 N-1840 N-2534 i N-2534 N-2534 N-2534 ______________ N-2534.N-2534 N-2534 N-2534 N 2658 1 N2658 _N= 2654 N=2658 N-Table 7 lists several compounds tested in various ADME assays.
33 Chem Microsomal Metabolic MDCLK LLC-PK1 PgP Photo- Therm Plasma Cyp inhib PAMPA LogD Ames hERG stability S CEREP
Kin''e PR
Stability Profile perm. substrate toxidty olubility binding Panel FaSSIF/ SGF
N-0196 N-0196 N-0196 8-01% N-0196 N-0196 N-0196 N-01% 8-01%
N-01% N-0196
34 Chem Mictosomal Metabolic cyn inhib MDCLK LLC-PK1PgP
PAMPA Logi) Ames Pimth- hERG
stability FaSSIF/ SOP Them' CEREP Ki"" PK
Stability Profile perm. substrate toxicitY
Solubility binding Panel 5-2604 ____________ N-2604 __ 5-2604 ___________________ 5-2604 Although the present invention has been described hereinabove by way of specific embodiments thereof, it can be modified, without departing from the nature of the subject invention as defined in the appended claims.
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II Structure Database name SMILES

CC1=C(C=NN1C1=CC=CC=C1)C(=0)N (CC1=CC=CS1)CC1=CC=CC=C1 \N-CõHõN305 _______________ F
N

FC(F)(F)C1=C(C=NN1C1=CC=CC=C1)C(=0)N(CC1=CC=CS1)CC1=CC=CC=C1 -N

C23H,.F3N305 N

COC1=CC=CC=C1C1CCN(CC1)C(=0)C1=C(C)N(N=C1)C1=CC=CC=C1 Cy.
N¨N
C23H,5N30, CCCN(CCC)5(.0)(=0)C1=CC=C(NC(.0)C2=C(C)N(N=C2)C2=CC=CC=C2)C=C1 o C2,1-6N,035 /

CCCN(CCC)S(=0)(=0)C1=CC=CiNC(=0)C2=C(C)N(N=C2)C2=CC=CC=C2)C=C1 C231-1,,,N,035 6 0%

CCCN(CCOS(=0)(=0)C1=CC=C(NC(=0)C(CC)C2=CC=CC=C2)C=C 1 ,S
Th\l"

(CCC)S(=0)(=0)C1=CC=C(NC(=0)C(CC)C2=CC=CC=C2)C=C 1 co3oN2035 CCCN(CCOS(=0)(=0)C1=CC=CiNC(.0)[C@H](CC)C2,-CC=CC=C2)C=C1 C221130N,035 9 0% 10 CCCN(CCC)S(=0)(=0)C1=CC=C(NC(=0)[C@HI(CC)C2-CC-CC-C2)C-C1 A

C22H3oN2035 N.

N-0000212 CCCN(CCC)S(=0)(=0)C1=CC=C(NC(r.0)(C@@HI(CC)C2=CC=CC=C2)C=C1 H
Cul-130,03S
CE) N
If11 N-0000212 CCCN(CCC)5(=0)(=0)C1=CC=CiNC(=OHC@@HHCC)C2=CC=CC=C2)C=C1 ) 0 C2,1102035 N =12 N-0000213 CN(CCC1,CC=CC=C1)C(=0)C1=C(C)N(N=C1)C1=CC=CC=C1 CzoH030 13 N-0000214 CC 1=C(C=N N 1C1=CC=CC=C1)C(=0)N
(CC1=CC=CC=C1)CC1=CC=CC=C1 04N oh ¨N

Nr1/AN
N-CC1=C(C=NN1C1=CC=CC=C1)C(=0)N1CCC(CC1)C1=CC=CC=C1 CuH23N30 OI N-0000216 CC1=C(C=N N 1C1=CC=CC=C1)C(=0)N 1CCCCC1C1=CC=CC=C

Nc.¶.
N ________ ¨

C,21-123N30 16 Y Fl -f( N-0000217 CC1-C(C-NN1C1-CC-CC-C1)C(-0 )NCC1-Nr1)-"--.1( NTh CC1=C(C=NN1C1=CC=CC=C1)C(=0)N1CCOCC1 N-CIsHoN302 CC1=C(C=NN1C1=CC=CC=C1)C(=0)N1CCCCC1 CC1=C(C=NN1C1=CC=CC=C1)C(=0)N1CCC2=C1C=CC=C2 CI,H,7N30 20 \N- N-0000221 CC1-C(C-NN1C1-CC=CC-C1)C(.0)N1C=CC=C1 CIsH13N30 CCCN(CCOS(=0)(=0)C1=CC=C(NC(=0)C(C)(C2=CC=CC=C2)C2=CC=CC=C2)C=C1 C,71132N,03S
CI

CCCN(CCC)S(=0)(=0)C1=CC=C(NC(=0)C2(CCC2)C2=CC=C(COC=C2)C=C1 C,31-129CI N2035 CCCN(CCC)5(=0)(=0)C1.CC=CiNC(.0)C2(CC2)C2=CC=CC=C2)C=C1 c,2110203s 401 N-0000240 CCCN(CCC)5(,-0)(=0)C1=CC=C(NC(=0)CC2=CC=C3C=CC=CC3=C2)C=C 1 C,41-10,035 CCCN(CCC)5(.0)(=0)C1=CC=C(NC(=0)CC2=CC=C(C1 )C=C2)C=C1 CI
NH

Cz0HCIN2035 CCCN(CCC)5(=0)(=0)C1=CC=C(NC(=0)C(C)C2=CC=C(CI)C=C2)C=C1 CI
NH

C2,H,7CIN203S
CI
27 N-0000243 CCCN(CCC)5(=0)(=0)C1=CC=Ci NC(=0)C(C(C)C)C2=CC=C(CI)C=C2)C=C1 N

C,31-13,0 N2035 r 0 Oa CI
NH

CCCNICCCIS(.0)(=0)C1=CC=CINC(=0)C(C2=CC=C(CI)C=C2)C2=CC=C(Cl)C=C2/C=C1 CI
C261-128Cl2N2035 CCCN(CCC)5(.0)(=0)C1=CC=C(NC(=0)C(C2=CC=CC=C2)C2=CC=CC=C2)C=C1 C261-130N,035 r 0 0' CCCN(CCC)5(=0)(.0)C1=CC=C(NC(=0)C(C2=CC=CC=C2)C2=CC=CC=C2)C=C1 C261'102035 CI
NH

CCCN(CCC)5(.0)(=0)C1=CC=CINC(.0)C(0C2=CC=C(COC=C2)0C2=CC=C(C1)C.C2)C=C1 0\\
) N

C26112021420,5 32 11110 N"Y11\ N-0000247 CC1=C(C=NN1C1=CC=CC=C1)C(.0)NC(C1=CC=CC=C1)C1=CC=CC=C1 \N¨

c,A,N30 CCCC1=C(C=NN1C1=CC=CC=C1)C(.0)N(CC1=CC=C51)CC1=CC=CC=C1 \N-C2sH2,N305 =

CCCC1=C(C=NN1C1=CC=CC=C1)C(=0)N(CC1=CC=C51)CC1=CC=CC=C1 S
N\
N -C2sH25N,05 =

CCCC1=C(C=NN1C1=CC=CC=C1)C(=0)N(CC1=CC=C51)CC1=CC=CC=C1 = S
N\
N
C25E10'1305 36 N-0000249 CCCC1=C(C=N N1C1=CC=CC=C1)C(=0) N (CC 1=CC=CC=C1)CC1=CC=C(OC)C=C1 N
0 *
N -
37 * N-0000250 CCCC1-C(C-NN1C1-CC-CC-7C1)C(-0)N(CC1=CNC2=CC=CC=C12)CC1=CC=CC=C1 CHNO
38 * N-0000250 CCCC1=C(C=NN1C1=CC=CC=C1)C(.0)N(CC1=CNC2=CC=CC=C12)CC1=CC=CC=C1 C,91-1640 N
\V
39 0 CCC(Ci=0)NC1=CC=C(C=C1)5(.0)(.0)N1CC(C)0C(C)C1)C1=CC=CC=C1
40 N-0000252 CCCC1-C(C-NN1C1=CC=CC=C1)C(.0)N(CC1=C5C2=CC=CC=C12)CC1,-CC=CC=C1 Cõ1-12,N3OS
41 N-0000253 CCCC1=C(C=N N1C1=CC=CC=C1)C(=0)N (CC1=CC=CC=C1)CC1=CC=C(C=C1)C(F)(F)F
N
0 *
\N ¨
C2.H26F,N30
42 0\µ

CCCN(CCC)S(=0)(=0)C1=CC=C(NC(=0)C(OC)C2=CC=CC=C2)C=C1 ) N

C,11-12aN,045 r 0 N
43 N-0000255 CCCN(CCC)S(=0)(=0)C1=CC=C(NC(=0)C2=CC=C3C=CC=CC3=C2)C=C 1 c231-10,035 N NN
44 N-0000257 COC1=CC=C(C=C1)N1N=CC(C(=0)N(CC2=CC=C52)CC2=CC=CC=C2)=C1C(F)(F)F

/

V N
45 CI N-0000258 FCIFIIFIC1=C(C=NN1C1=CC=CC(CI)=Cl)CI=OIN(CC1=CC=C51)CC1=CC=CC--,C1 -N

N, N
46 N-0000261 FC1=CC=CC=C1N1N=CC(C(=0)1,1(CC2=CC=C52)CC2=CC=CC=C2I=C1C(F)IFIF

C23N0F,N305 N, N
47 N-0000263 CC1=CC=C(C=C1)N1N=CCIC(=0)N(CC2=CC=CS2)CC2=CC=CC=C2)=C1C(F)(F)F

C.) /N
CHoFaNOS

N, N
48 N-0000264 [0-j[N+](=0)C1=CC=C(C=C1)N1N=CCIC(=O)N(CC2=CC=C52)CC2=CC=CC=C2)=C1C(F)( FIE

C231-1,7F3N,03S
49 111111 N 9-0000265 CC1=C(0=0)N(CC2=CC=C52)CC2=CC=CC=C2)C(=NN1C1=CC=CC=C1)C1=CC=CC=C1 \ 0 N
C291-12,N305
50 N 9-0000266 NC1=C(C=NN1C1=CC=CC=C1)C(=0)N(CC1=CC=C51)CC1=CC=CC=C1 S

N ________ -N
1,1".
N-N
51 N-0000273 C C(=N
NC(.0)C1=CC=CC=C1)C1=C(C)N(N=N1)C1=CC=CC(=C1)[194](101)=0 \O"
C186,6N503
52 0. I

CCCN(CCC)S(=0)(=0)C1=CC=C(NC(=0)C(CC)C2=CC=CC=C2)N=C1
53 N-0000290 CCOC(.0)C1=CC=C(NS(=0)(=0)C2=CC(C)=CC=C2C)C=C1 NH
C,71-1,9N045 0 rc
54 CCCC1=C(C=NN1C1=CC=CC=C1)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CC(C)0C(C)C1 HN
*

NS
o 0 N-0000293 CCCN(CCC)5(.0)(.0)C1=CC=C(NO=0)C2=C(CCON(N=C2)C2=CC=CC=C2)N=C1 N
C,41.13,N ,03S
0=S=0 = N/

0)(=0)C1=CC=C(N=C1)N(C(=0)C1=C(CCC)N(N=C1)C1=CC=CC=C1)0=0)C1=C(CCON(N=C1) N¨N
=
CO-1070.5 =

=
ozs., /

CCCN(CCC)C(=0)C1=CC=C(N5(=0)(=0)C2=CC(C)=CC=C2C)C=C1 ______ \ NH
N)_ NH
\"O

CCCN(CCC)C(=0)C1-,CC=C(N5(=0)(.0)C2=CC(C1)=CC(C1)=C20)N=C 1 CI
C181-1,1C12N3045 59 0% Ol 0 N-0000315 CCCN(CCC)5(=0)(=0)C1=CC=Ci NC(=0)N (CC)C2=CC=CC=C2)C=C1 NS%

C2,1-1203035 CCCN(CCC)5(=0)(.0)C1=CC=C(NO=0)N (C)CC2=CC=CC=C2)C=C1 cõH2,N30,s OC(=0)C1=C(NC(.0) C=C C2=CC=C52)5C=C1C1=CC=CC=C1 C.1-1,3N0352 r 0 NH

CCCN(CCC)S(.0)(=0)C1=CC=C(NC(=0)C2=NN=C(02)C2=CC=CC=C2)C=C1 C21HNN40¾5 01 *
NH

CCCN(CCC)5(.0)(.0)C1=CC=C(NC(=0)C2=C5C(=N2)C2=CC=CC=C2)C=C1 N
CO24430,52 C) CC1CN(CC(C)01)C(=0)C1=CC=C(N5(=0)(=0)C2=CC(C)=CC=C2C)N=C1 C20,5143045 1 * 0 N-0000338 CCCN(CCC)5(=0)(=0)C1=CC=C(NO=0)C2=C(C)C(=NN2)C2=CC=CC=C2)C=C1 c231-10403S

CC1=C(C=NN1C1=CC=CC=C1)5(=0)(.0)N(CC1=CSC2=CC=CC=C12)CC1=CC=CC=C1 \
NI

HN

CC1=CIC=NN1C1=CC=CC=C1)C(=0)NC(C)(C)C1=CC2=CC=CC=C251 N

C221-12,N1305 N

68$ N-0000362 CC1=C(C=CN1C1=CC=CC=C1)4=0)N(CC1=CSC2=CC=CC=C12)CC1=CC=CC=C1 C2,0-10205 CCCNICCC)S(r.0)(=0)C1.,CC=C(C=C1)C(=0)NC(C1=CC=CC=C1)C1=CC=CC=C1 HN

CCCC1=C(C=NN1C1=CC=CC=C1)C(.0)N(CC1=CC2=CC=CC=C2S1)CC1=CC=CC=C1 N

=
CaH271,605 N

71 * N-0000372 CCCC1=C(C=NN1C1=CC=CC=C1)C(=0)N(CC1=CNC2=NC=CC=C12)CC1=CC=CC=C1 /
c.H27N,0 oss s 72 * 0 N-0000373 EN(CCC)5(=0)(=0)C1=CC=C(CN(CC2=CC=CC=C2)C(.0)C2=C(CCC)N(N -C2)C2-CC-CC-C2)C--N¨N
=
CH40N40,S
ONO

73 N-0000374 ..
CCCC1=C(C=NN1C1=CC=CC=C1)C(=0)N(CC1,-C2C=CC=CC2=NN1)CC1=CC=CC=C1 co2,N,0 =====,..õ
o=s=0 74 5-0000375 IN(CCC)Sfr-0)(=0)C1.---CC=C(CN(CC2-CC-CC-C2)C(-0)C(C2-CC-CC-C2)C2-CC-CC-C2)C-( Culia.N20,5 /

CCCN(CCOS(=0)(=0)C1=CC=C(NC(=0)C(C2=CC=CC.-.C2)C2=CC-2CC=C2)N =C1 o CõHõN,03S

S ON

CC(.0)N(C(C)=0)C1=C(C=NN1C1=CC=CC=C1)0=0)N(CC1=CC=C51)CC1=CC=CC=C1 ¨N

C0,4N4035 *

CC(=0)NC1=C(C=NN1C1=CC=CC=C1)C(.0)N(CC1=CC=C51)CC1=CC=CC=C1 ¨N
C,41-122N4025 \
= N I -N
\N"

0=C1N(CC2=C1C=NN2C1=CC=CC=C1)C1=CC=CC=C1 Col-11030 CC1=CC=C(C=C1)C1,-CC=C(N1C=C)C(=0)N(CC1=CNC2=CC=CC=C12)CC1=CC=CC=C1 c301427N3o 80 = N-0000409 CCCN(CCC)5(=0)(=0)C1=CC=C(CNC(=0)C(CC)C2=CC=CC=C2)C=C1 NH

C23110,035 /

CCCN(CCC)5(=0)(=0)C1=CC=C(CNC(=0)C(C2=CC=CC=C2)C2=CC=CC=C2)C=C1 =

CCCN(CCC)S(=0)(=.0)C1=CC=C(CNC(.0)C2.-C(CCC)N(N-C2)C2-CC-CC-C2)C-C1 N -N

µ./

CCC(C(.0)NCI=CC=C(C=C1)5(=0)(=0)NC(C)(C)C)C1=CC=CC=C1 CCCN(CCC)5(=0)(=0)C1=CC=C(NC(r-0)C2C3=C(0C4=C2C=CC=C4)C=CC=C3)C=C1 0=S=0 #
0# 0 CCCN(CCC)S(=0)(=0)C1=CC=C(NC(.0)C2=CC3=C(0CO3)C=C2)C=C1 co0,05s H

NH
86 N-0000426 CCCCNS(.0)(=0)C1=CC=Ci NC(=0)C(CC)C2=CC=CC=C2)C=C 1 C,01-10,0,5 0 \\ N-0000427 CCC(C)N5(=0)(=0)C1=CC=C(NC(.0)C(CC)C2=CC=CC=C2)C=C1 S
HN

C20E1261,1,035 N-0000428 CCC(C(.0)NC1=CC=C(C=C 1)S(=0)(=0) N
1CCCCC1)C1=CC=CC=C 1 c21H020,s 89 N-0000429 CC1CN(CC(C)01)C(=0)C1=CC=C(N5(=0 )(=0)C2=CC(C)=CC=C2C)C=C1 C2,H,6N20,S

90 N-0000430 CCC(C(-0)NC1-CC-C(C-C1)5(-0)(-0)N (C)CC1-,CC-CC-C1)C1-CC-CC=C1 co0203, CCCN(CCC)5(-,0)(=0)C1=CC=C(NC(.0)CC2=-CC=CC=C2)C=C1 NH

C2oHNN2035 0 %0 CCC(C(=0)NC1=CC=C(C=C1)5(=0)(.0)N1CCN(C)CC1)C1=CC=CC=C1 C1-1,N303S
0====

HN, I(C(=0)NC1=CC=C(C=C1)5(=0)(.0)NC12C[C@ H13C[C@ FIRM@ Hj(C3 )C1)C2)C 1=CC=CC=C

C2sHazNAS

CCCN(CCC)S(=0)(=0)C1=CC=C( NC(=0)CCC2CCCC2)C=C1 0/ n):>
c20HõN203, CCCN(CCC)S(=0)(=0)C1=CC=C(NC(=0)C2=CN=CC=C2)C=C1 N)-1 C.H23N3035 N N
96 \N __ N-0000436 CCCC1-,C(C=NN1C1=CC=CC=C1)C(,-0)N1CCC(CC1)C1=C(OC)C=CC=C1 =

CC1=C(C=NN1C1=CC=C(CI)C=C1)C(.0)N(CC1=CC=CS1)CC1=CC=CC=C1 CI
N

N ¨

oi7N7N7o 98 N-0000438 NC(=N
)C1=CC=C(OCCCCCOC2=CC=C(C=C2)C(N)=N )C=C 1 =0 OC(=0)CCN1C2=C(CIC@@HHCC2)N5(.0)(=0)C2=CC=C(F)C=C2)C2=CC=CC=C12 HOO
C2,H2,FN,O,S
ONO

NC1=NC(=CC2=C(CNN)C(=NC(N)=C12)N1CCCC1)N1CCCC1 N N

C,,Hz1N7 \

101 # N-0000441 CCN1C(=CC=C1C1=CC=C(C)C=C1)C(=0)N(CC1=CNC2=CC=CC=C12)CC1=CC=CC=C1 C301-1,9N30 *

CCCC1=C(C=NN1C1=CC=CC=C1)C(=0)N(CC1=CNC2=CC=CC=C12)CC1=CC=NC=C1 ONO
103 N-0000443 CCCC1=C(C=NN1C1-CC-CC-C1)C(=0)N(CC1=CNC2=CC=CC=C12)CC1=CC=CN=C1 c20,27N,0 0$

0=C(C(C1=CC=CC=C1)C1=CC=CC=C1)N(CC1=CNC2=CC=CC=C12)CC1=CC=CC=C1 C301-1,A0 0 *

CCCC1=C(C=NN1C1=CC=CC=C1)C(=0)NN(C1=CC=CC=C1)C1=CC=CC=C1 \N _________ NH

0=C(N(CC1=CNC2=CC=CC=C12)CC1=CC=CC=C1)C1=C2C=CC=C N2 N=C1 N
co2oN4o e -s HN

CCCN(CCC)5(=0)(.0)C1=CC=C(C=C1)C(.0)NCC1=C(CCC)N (N=C1)C1=CC=CC=C1 N-N
=
C261-134N40,5 N
108 \N N-0000463 CCCC1-C(C-NN1C1=CC=CC=C1)C(=0)N(CC1-CC-CC-C1)CC1-CC-CN-ClOC
\
C,H20402 0 *
N
\N-CCCC1=C(C-NN1C1=CC-CC=C1)0=0)N (CC1=CC=CC=C1)CC1=CC=CC(OC)=N1 N N
0\

ril N

CCCC1=C(CNC(=0)C2=CNC3=CC=CC=C23)C=N N 1C 1=CC=CC=C1 NN
C2211,2N40 N

CCCC1=C(CNCC2=CNC3=CC=CC=C23)C=NN1C1,CC<C=C1 HN
CHN

CC1=C(SC(=C1)C(=0)N(CC1=CNC2=CC=CC=C12)CC1=CC=CC=C1)C1=CC=CC=C1 cHo2os CCCC1=C(C=NN1C1=CC=CC=C1)C(N)=0 \N _____________ NH2 CI3H,s1430 HN

1110 114 __________________ N\N N-0000472 CCCC1=C(C=NN1C1=CC=CC=C1)C(=0)N(CC1=CC=CC(=0)N1)CC1=CC=CC=C1 NcD

0=C(N(CC1=CNC2=CC=CC=C12)CC1=CC=CC=C1)C1,-NN(CC2=CC=CC=C2)C2=CC=CC=C12 CHNO
HN

N \ N
116 * N-0000477 CC1=C(N=NN1C1=CC=CC(=C1)C(F)(F)F)C(.0)N(CC1=CNC2=CC=CC=C12)CC1=CC=CC=C1 =
C,71-1,2F,N,0 S \ N

CC1=C(SC(=N1)C1=CC=CC=C1)C(=0)N(CC1=CNC2=CC=CC=C12)CC1=CC=CC=C1 Cz7H2,N3OS

0=C(N(CC1=CNC2=CC=CC=C12)CC1-CC=CC-C1)C1-C2C-CC-CC2-NN1CC1-CC-CC-C1 \

0=C(N(CC1=CNC2=CC=CC=C12)CC1=CC=CC=C1)C1=CC=C(S1)C1=CC=CC=C1 C,FinN2OS

o N
120 \N __ CCCC1=C(C=NN1C1=CC=CC=C1)C(=0)N(CC1=CC=CC=C1)CC1=CC=CNC1=0 coz6N402 N
121 N-0000486 CCCC1=C(CN
(CC2=CNC3=CC=CC=C23)C(=0)C2=CC=CC=C2)C=NN1C1=CC=CC=C1 QN

122 N N-0000487 0=0 N
(CC1=CNC2=CC=CC=C12)CC1=CC=CC=C1)C1=CN (N=C 1)C 1=CC=CC=C1 c26.2,N,o /

123 111 N-0000488 0=C( N(CC1=CNC2=CC=CC=C12)CC1=CC=CC=C1)C1=CSC(C1)C1=CC=CC=C1 c27,-,22N,os o 1110 124 N-0000489 0=C( N
(CC1=CNC2=CC=CC=C12)CC1=CC=CC=C1)C1=CC=C(C=C1)C1=CC=CC=C1 C291124N a0 125 * N-0000492 0=C( N
(CC1=CN C2=CC=CC=C12)CC1=CC=CC=C1)C1=CC=NC(=C1)C1=CC=CC=C1 Czn1-123N30 CCCCI=C(C=N N 1C1=CC=CC=C1)C(=0)N(CC1=CC=CC=C1)CC1=CC=C2C=CC=CC2=N 1 CI /

CCCC1=C(C=N N 1C1=CC=CC=C1)C (=0)N (CC1=CC=CC=C1)CC1=CC=NC(C1)=C1 -N
C,61-125CIN40 128 el N-0000495 CCCC1=C(C,-N N1C1=CC=CC=C 1)C(=0)N (CC1=CC=CC=C1)CC1=CC=CC2=C10CO2 C286,7N303 129 ,, N-0000496 0=C(N(CC1=CNC2=CC=CC=C12)CC1=CC=CC=C1)C1=CC(=CC=N1)C1=CC=CC=C1 CHNO

CCCC1=C(C=NN1C1=CC=CC=C1)C(=0)N(C)CC1=CN(N=C1)C1=CC=CC=C1 \N ______ ¨

C1-1N,0 131 * N-0000498 CCCC1=C(C=NN1C1=CC=CC=C1)C(=0)N(CC1=CC=CC=C1)CC1=C2C=CC=CC2=CC=N1 N
C3oHN40 =

N
132 ¨N
\ N N-0000499 11C1¨CC¨CC¨C1)C(-0)N(CC1¨CN¨C2C¨CN(C¨C12)C(-0)C1¨C(CCC)N(N¨C1)C1¨CC¨CC¨C1) N/
=
C.1113,N,02 =
133 N-0000500 CCCC1¨C(C¨NN1C1¨CC¨CC¨C1)C(-0)N(CC1=CC=NN1)CC1=CC=CC=C1 NZ/

NH
\ 0 N¨

C241-12sN,0 =

CCCC1=C(C=NN1C1=CC=CC=C1)C(=0)N(CC1,-CC=CC=C1)CC1=CC=C(F)C(C)=C1 *
N¨

C281-12aFN30 CI
135 H N-0000508 CIC1=CC=C2NC(C(,-0)N(CC3=CNC4=CC=CC=C34)CC3=CC=CC=C3)=C(C2=C1)C1=CC=CC=C1 HN
C311-1,4CIN30 CCCN(CCC)5(=0)(=0)C1=CC=0CN(CC2=CC=CC=C2)C(=0)CC2=CC=CC=C2)C=C1 C28HuN20,5 0=6=0 68CCOS(=0)(=0)C1=CC=C(CN(CC2=CC=CC=C2)C(=0)C(C2=CC=CC=C2)C2=CC=C(OC)C=C2)C
DI
C3,H40N2045 (E) ===,) 0 138 0\\ N-0000513 CCN(CCC)S(.0)(.0)C1=CC=C(NC(.0)[C@@H](NC(=0)0CC2=CC=CC=C2)C2=CC=CC=C2)C=C

zS
C2aF133N,0,5 0=S=0 139 * N-0000514 :CN(CCC)5(=0)(=0)C1=CC=C(C=C1)N(CC1=CC=CC=C1)C(=0)C1=C(CCON(N=C1)C1=CC=CC., C:
C321-13,N4035 0=S=0 CCN(CCC)S(=0)(=0)C1=CC=C(C=C1)N (CC1=CC=CC=C1)0=0)C(C1=CC=CC=C1)C1=CC=CC=C

N

CN(CC1=CN(N=C1)C1=CC=CC=C1)C(=0)C1=CNC2=CC=CC=C12 C2oHIõN40 /
" 0 CCCN(CCOS(=0)(.0)C1=CC=C(NC(.0)[C@@HI(N )C2=CC=CC=C2)C=C1 NH

CzoHNN303S
\

CCCC1=C(C=NN1C1=CC=CC=C1)C(=0)N(CC1=CC=CC=C1)CC1=CC=C(OC)N=C1 NN No *
\N -C271-1281µ.402 =
144 N-0000519 CCCC1=C(C=NN1C1=CC=CC=C1)C(=0)N
(CC1=C(C)N=CN1)CC1=CC=CC=C1 \N ¨
C251-127Ns0 145 N-0000520 CCCC1=C(C=NN1C1=CC=CC=C1)C(=0)N
(CC1=CNC2=CC=NC=C12)CC1=CC=CC=C1 / N
C.H27N,0 N

146 N-0000521 CC1=C(C=CN1C1=CC=CC=C1)C(=0)N
(CC1=CNC2=CC=CC=C12)CC1=CC=CC=C1 c.HõN30 =
N
147 (30) N-0000522 CC1=CC(=NN1C1=CC=CC=C1)C(=0)N(CC1=CNC2=CC=CC=C12)CC1=CC=CC=C1 c2,H24N,o 148 110 N-0000523 ..
0=C(N(CC1=CNC2=CC=CC=C12)CC1=CC=CC=C1)C1=C5C(=N1)C1=CC=CC=C1 CCCC1=C(C=NN1C1=CC=CC=C1)C(=0)N(CC1=CC=CC=C1)CC1=CC=C(C=C1)5(C)(=0)=0 N
N\ NV\ cso N¨

C281-12,N3035 N

¨N N-0000525 CCCCI=C(C=NN1C1=CC=CC=C1)C(=0)N(CC1=CC=CC=C1)CC1=CC=C(C1)C=C1F
CI
C,HCIFN30 N N

.NN1C1=CC=CC=C1)C(=0)N (CC1=C(C)N(C=N1)C(=0)C1=C(CCC)N(Nr.C1)C1=CC=CC.,C1)CC1 V N

:=NN1C1-CC-CC-C1)C(-0)N (CC1-C(C)N-CN1C(-0)6-C(CCC)N (N-C1)C1-CC-CC-C1)CC1-N\N----- =

o 153 N-0000528 COC1=CC=C2CCCC(C(.0)N(CC3-CNC4-CC-CC-C34)CC3=CC=CC=C3)C2=N1 /0 =

yJ

ICN(CCOS(.0)(.0)C1=CC=C(NC(=0)1C@ @ Hj(NCC2=CC=C(F )C(C)=C2)C2=CC=CC=C2)C=C:

C,01-134FN3035 a CCCN(CCC)5(.0)(.0)C1=CC=C(NC(=0)[C@@Hj(NCC2=CC=C(OC)N=C2)C2=CC=CC=C2)C=C1 NNAo C1-134N40,5 ==õ, 156 0% $ N-0000534 CCCN(CCC)S(=0)(.0)C1=CC=C(NC(=0)[C@@H]NCC2=CC=C(C1)C=C2F)C2=CC=CC=C2)C=C1 NrS%
C271-13,CIFN,0,5 =

N(CCC)S(.0)(=0)C1=CC=C(NC(=0)(C@@HIINCC2=CC=C(C=C2)5(C)(=0)=0)C2=CC=CC=C2)( ,S

0 =
N
\N

CCCC1=C(C=NN1C1=CC=CC=C1)C(=0)N(CC1=CC=CC=C1)CC1=CC=CC(=C1)C(=0)0C

Br _____________________________________________________________ 159 N-0000538 CCCC1=C(C-NN1C1=CC=CC=C1)C(=0)N(CC1-CC-CC-C1)CC1-CC-CC(130-C1 C/N *
¨N
C271-1,613rN30 160 9-0000539 CCCC1=C(C=NN1C1=CC-CC=C1)C(-0)N(CC1=CC=CC=C1)CC1=CC=C(C=C1)C8N
Nr\rko CHNO
N
Nr0 CCCC1=CC(=NN1C1=CC=CC=C1)C(.0)N (CC1=CC=C(C=C1)N(C)C)C1=CC=C(C=C1)C(C)C
----N
C3,H3eN40 NH

162 /'S
N N-0000541 CCCN(CCC)5(-0)(=0)C1=CC=C(NC(=0)C2=CNC3=CC=CC=C23)C=C1 C2,H2sN3035 \
NO
163 N-0000542 CCCC1-C(C-NN1C1-CC-CC=C1)C(-0)N(CC1=C2C=CC=CN2N=C1)CC1=CC=CC=C1 N
CH2,N50 =
164 N-0000548 CCCC1=C(C=NN1C1-CC-CC-C1)C(-0)N
(CC1=CC=CC=C1)CC1=CC=C(C=C1)C(N )=0 110 *
N
C20'120402 N

165 10 N-0000549 CCC1=C(C=NN1C1=CC=CC=C1)C(-0)N
(CC1-CN (C2=CC-CC-C12)5(C)(=0)=0)CC1=CC=CC=C
oj C30H30N403s N

(CCC)5(=0)(=0)C1=CC=C(C=C1)N(C)C(=0)C(C1=CC=CC=C1)C1=CC=CC=C1 veNN7N, //

0/ * 0 N-0000551 CCCN(CCC)5(=0)(=0)C1=CC=C(C=C1)N
(C)C(.0)C1=C(CCC)N (N=C1)C1=CC=CC=C1 N
Cal-10403S
a V

:N(CCOS(=0)(=0)C1=CC=C(NC(=0)[C@@H](NCC2=C3C=CC=CC3=CC=N2)C2=CC=CC=C2)C.

NVS%o HO
NH
o CCCC1=C(C=NN1C1=CC=CC=C1)C(=0)N(CC1=CC=CC=C1)CC1=CC=CC(=C1)C(.0)NCCO
N
0 =
N ¨
C3oH32N403 170 * N-0000554 CCCNC(.0)C1=CC=CC(CN(CC2=CC=CC=C2)C(=0)C2=C(CCC)N(N-C2)C2-CC-CC-C2)-C1 N ¨N

N
N I
NH

I1=C(C=NN1C1=CC=CC=C1)C(.0)N(CC1=CC=CC=C1)CC1=CC=CC(=C1)C(=0)NCC1=CC=CN.
=
N

:CCN(CCC)C(=0)C1=CC=CC(CN(CC2=CC=CC=C2)C(=0)C2=C(CCC)N(N=C2)C2=CC=CC=C2)=C
N

CõH40N,O, CCCC1=C(C=NN1C1=CC=CC=C1)C(=0)N(CC1=CC=CC=C1)CC1=CC=CC(=C1)C(=0)N(C)C
= N\
N-174 110 N-0000560 CCN1C=C(C=C10=0)N(CC1-CNC2-CC-CC-C12)CC1=CC=CC=C1)C1=CC=CC=C1 1\-1 c2,HõN30 CCCN(CCC)5(=0)(=0)C1=CC=0NC(=0)C2=C0=CN2CC)C2=CC=CC=C2)C=C1 C2sH3114303S
NH

CCN1C=C(C=C1C(=0)NCC1=CC=CC=C1)C1=CC=CC=C1 CCC1=C(C=NN1C1=CC=CC=C1)C(=0)N (CC1=CC=CC=C1)CC1=CC=CC(=C1)0-,0)NC1=NC=CS
N¨

C3,H2,N50,S

CCC1=C(C=NN1C1=CC=CC=C1)C(=0)N (CC1=CC=CC=C1)CC1=CC=CC(=C1)C(.0)NC1=NC=C5 *
N¨

C3,HõN502S

179 N-0000564 CCCC1=C(C=NN1C1=CC=CC=C1)C(=0)N
(CC1=CC=CC=C1)CC1=CC=CO=C1)C(=0)N1CCOCC1 Nc.
N¨

NH

0=C(N(CC1=CNC2=CC=CC=C12)CC1=CC=CC.C1)C1=CC=C(N1)C1=CC=CC=C1 CCCN(CCC)5(=0)(=0)C1=CC=C(NC(=0)C2=CN(CC3=CC=CC=C3)C3=NC=CC=C23)C=C 1 / I
C,H3oN4035 CCN1C(=CC=C1C1=CC=CC=C1)C(=0)N(CC1=CNC2=CC=CC=C12)CC1=CC=CC=C1 c291-12,N3o N

CCC1=C(C=NN1C1=CC=C(C)C=CHC(=0)N(CC1=CNC2=CC=CC=C12)CC1=CC=CC=C1 N

CCCC1=C(C=NN1C1=CC=CC=C1)C(=0)N(CCO)CC1-CC-CC=C1 HO
Cz2H,,N302 O
185 N-0000576 CCCN1C(-CC=C1C1=CC=CC=C1)C(=0)N(CC1=CNC2=CC=CC=C12)CC1=CC=CC=C1 \NO

CC1=C(C=NN1C1=CC=NC=C1)C(.0)N(CC1-,CNC2=CC=CC=C12)CC1=CC=CC=C1 co23N,0 )=C(N(CC1=CNC2=CC=CC=C12)CC1=CC=CC=C1)C1=CC(=CN1CC1=CC=CC=C1)C1=CC=CC=C:
C34NNN,0 õ../N
188 * N-0000580 CCCC1=C(CN(CC2=CNC3=CC=CC=C23)CC2=CC=CC=C2)C=NN1C1=CC=CC=C1 N

:CCN(CCC)C(=0)C1=CC=C(CN(CC2=CC=CC=C2)C(=0)C2=C(CCC)N(N=C2)C2=CC=CC=C2)C=C

ON
=

(NO

CCCC1=C(C.NN1C1=CC=CC=C1)C(.0)N(CC1=CC=CC.C1)CC1=CC=C(C=C1)C(.0)N1CCOCC1 = *
=
N-CO.N.,03 çi 191 9-0000584 CCCC1=C(C=NN1C1=CC=CC=C1)C(=0)N
(CC1=CC=CC=C1)CC1=CC=CW-C1)C(N)=0 =
N¨

C.H.N402 N,s/N---\\

192 = 9-0000585 CN(CCC)S(=0)(=0)C1=CC=C(CN(CC2=CC=CC=C2)C(=0)C(CC2=CC=CC=C2)C2=CC=CC=C2)C=

=
C3,H0,035 193 * N-0000586 CCCN1C(=CC=C1C1=CC,C(C)C=C1)C(=0)N (CC1=CNC2=CC=CC=C12)CC1=CC=CC=C1 \N

194 # N-0000587 CCCC1=C(C=NN1C1=CC=CC=C1)0=0)N(CC1=CN (C)C2=CC=CC=C12)CC1=CC=CC=C1 C30H30N,0 =
I /

CC1=NN(C(C)=C1CC(=0)N(CC1=CNC2=CC=CC=C12)CC1=CC=CC=C1)C1=CC=CC=C1 CHNO

CC(N1C=NC=C10=0)N(CC1=CNC2=CC=CC=C12)CC1=CC=CC=C1)C1=CC=CC=C1 C.H.N40 \

197 * N-0000595 CC1=C(C=NN1C1=CC=CC=N1)C(=0)N(CC1=CNC2=CC=CC=C12)CC1=CC=CC=C1 Cz6F123NO
198 N-0000615 JR=0)C1=CC--,C(C=C1)N(CC1=CN(C(=0)0C(C)(C)C)C2=CC=CC=C12)C(.0)C1=C(CCON(N=C1 N

=
><0io C3,H47N50,5 *
N

CCCC1=C(C=NN1C1=CC=CC=C1)C(=0)N(CC1=CC=CC=C1)C(C1=CC=CC=C1)C(F)(F)F
N¨

F
CõHõF3N30 N

CC1=C(C=NN1C1=CC=CC=C1)C(.0)9C1.CC=C(C=C1)5(=0)(=0)N1CCOCC1 N N

N¨

0=C(NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1)C1=CC=C2C=CC=CC2=N 1 N

0=s=0 0=C(NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1)C1=CC=C(51)C1=CC=CC=C1 S N
O.

NH

N1C(C(C)C)=C(C(=0)NC2=CC=C(C=C2)5(=0)(=0)N2CCOCC2)C(=C1C1=CC=CC=C1)C1=CC=CC

=

0' \
N

CN1C(=CC2=CC=CC=C12)0=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 0 N¨S NH
II

CzoHaN,O,S

0=C(NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1)C1=CN=C2C=CC=CC2=C1 N

Cz0Hl9N3045 OH
NH
206 N-0000760 OC(=0)[C@@1-1]1CC2=C(NC3=CC=CC=C23)1C@@HI(N1)C1=CC=C(CI)C=C1C1 CI
CI
OH
NH

OC(=0)[C@@H]1CC2=C(NC3=CC=CC=C23)[C@HI(N1)C1=CC=C(COC=C1C1 CI
CI
C181-1,4C12N202 NH

OC(r.0)(C@HOCC2=C(NC3=CC=CC=C23)[C@H](N1)C1=CC=C(C8C=C1C1 CI.
CI

$. OH
NH

OC(=O)[C@HHCC2-C(NC3-CC-CC-C23)[C@@HI(N1)C1=CC=C(COC=C1C1 CI
CI

0=C(NC1=CC=C(C=C1)9(=0)(=0)N1CCOCC1)C1-CC(-CS1)C1-CC-CC-C1 S N

o = 8-0000766 0=C(NC1=CC=C(C=C1)S(=-0)(=0)N1CCOCC1)C1=CSC2=CC=CC=C12 HN

II

0=C(NC1=CC=C(C=C1)5(.0)(=0)N1CCOCC1)C1=NN2C=CC=CC2=C1 II

NN

0=C(NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1)C1=CN=C2C=CC=CC2=N1 N

C191-11.N4045 HN

CN1N=C(C(=0)NC2=CC=C(C=C2)5(.0)(.0)N2CCOCC2)C2-CC-CC-C12 =
0-j 0-=S=0 0=C(NC1=CC=C(C=C1)S(.0)(.0)N1CCOCC1)C1-CN-CN1C1-CC-CC-C1 NZ) C,0H20N404S

o., ___________________________________________________________ N
I
0=S=0 S

0=C(NC1=CC=C(C=C1)5(.0)(.0)N1CCOCC1)C1=CN(C=N1)C1=CC=CC=C1 ..,..õ,' NVk)N
\\N
C,0F1,0N,045 =
.0) __________________ CN

/ _____ \
217 0 N-SII NH N----N'N._,,-------7. N-0000772 0=C(NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1)C1=CN2C=CC=CC2=N1 C,0-61µ1404S
.N, I
0=S=0 0=C(NC1=CC=C(C=C1)5(.0)(=0)N1CCOCC1)C1=C5C(=C1)C1=CC=CC=C1 N
\ S
/\

..õ..--o=-.......
I
(:)=S=0 . N-0000774 0=C(NC1=CC=C(C=C1)9(.0)(.0)N1CCOCCHC1=CSC=C1C1=CC=CC=C1 N
\ S
C.H.N20,S, r0 ,N................õ, 0 \NO
HN

0.0CC1=04=CN1CC1=CC=CC=C1)NC1=CC=C(C=C1)5(.0)(=0)N1CCOCC1 o NV') 0 \---N

221 i \N ll # NH \N $ N-0000777 0=C( NC1=CC=C(C=C1)5(.0)(.0)N1CCOCCHC1=NC2=CC=CC=C2S1 C.9 ,N304S, \
N
\
HN

* N-0000778 CN
1C=C(C(=0)NC2=CC=C(C=C2)5(.0)(.0)N2CCOCC2)C2=CC=CC=C 12 0 ----......
------S

rN \
\)---1 C20H2,N3045 ----o COC1=CC2=C(CN(CC2)C(=0)C2=CNC3=CC=CC=C23)C=C10C

NC(=0)C1CC2=CC=CC=C2CN1C(=0)C1=CNC2=NC=CC=C12 225 N-0000781 0=C(N
1CCC2=C(C1)C.CC=C2)C1=C2C=CC=CC2=NN 1 ONQ
C,71-1,5N30 NC(=0)C1CC2=CC=CC=C2CN10=0)C1=CC=CC2=CC=NN12 CI8616N402 , gFA

10C1=CC=C(C=C1)[C@HII[C@H](C(=0)N2CCCCC2)C2=CC=CC=C2C(=0)N1CC1=CC=C(F)C=C
0 Oss C2,H2,FN203 'O'Ni"H"D

=3(30)D=DD=TAZTD=D3=DD=ZD(0=b(ZD=D(i)J=DD=ZDJ)NgH@@DIT[H@Ji(0)3(3)N3D

'O'Nd"H"J
o HN 0 .D(i))=33=IDDIN(0=)DZJ=JD=J7.13(Z33033ZNJDN(0=)J)iH@DITIH@DI(I3=3)3=J3=T:

0 *
zO'N"H"J
=0 ID=DD=JD=TD(TD=3D=33=IDDIN(0=)D(EZD=DD=33=E3D.)DZN)iTD(TJJ3DDIDN)D=0 'ONJ'H'D

T7=3(J)3=D3=TDDIN(0=)DZD=JJ.DD=ZD(0=(0)3)3T3(ID=D)D=DJ=IDOD
b8L0000-N 8ZZ

Eg COC1=CC=C(C=C1)C1C(C(=0)NC2=NOC(C)=C2)C2=CC=CC=C2C(=0)N1CC1=CC=C(F)C=C1 \ 0 C,HõFN304 \ I

CC1=CC=C(C=C1)C1=NOC(=N1)C1CC2=C(CN1C(=0)C1=CC=C(F)C=C1)NC=N2 \N
N
C2,1-1.FN502 0=C1N(CC2=CC=CC=C2)C(C2=CNC3=CC=CC=C23)C2=CC=CC=C12 HN
C,3H,eN20 N
\ _____________ 0 CC1(C)CC2=C(C=NN2C2=CC=CC=C2)C(=0)N(CC2=CC=CC=C2)C1=0
55 N
236 N-0000794 CC1=CC=C2NC3=-C(CN(CC3)C(=0)C3=C(C4CC4)N (N=C3)C3=CC=CC=C3)C2=C1 C2sHuN40 V NNN

CC(C)CC1=NC=C2CN(CC2=N1)0=0)C1=C(C)N(N-C1)C1-CC-CC-N1 N

CzoH,A0 238 N-0000796 COC1=CC=C2CC(N(CC2=C1)C
(=0)CC1=NOC=C1)C1=CC=CC=C1 \o Cz,H2oN203 0=C1N(CCC2=CC=CC=C2)C(C2=CNC3=CC=CC=C23)C2=CC=CC=C12 HN
Cz4H20N,0 CC1=C2C(N(CCC3=CNC4=CC<C=C34)C(=0)C2=N N1)C1=CC=CC=C 1 HN
\
\ NH

0=C(NC1CCCCC1)C1(CN2C(=CC3=CC=CC=C23)C(=0)N1CCC1=CC.CC=C1)C1=CC=CC=C1
56 242 0 N-0000801 0=C(N
1CC(C2=CC=CC=C2)C2=CC=CC=C2C1)C1=C2C=CC=CC2= N N1 A

(2.' 0 aki 0 243 N-0000802 COC1=CC(=CC(OC)=C1OC)C1N(CC2-CC-C(F)C-C2)C(-0)CN2N -NN-C12 F
C2F120FN,04 \

COC1=CC2=C(C=C10C)C( N(CC2)C(.0)C 1=C(C)C2=C(CC(C)(C)CC2=0)N 1)C1=CC=CS1 \o COC1=CC2=C(C=C100C(N(CC2)C(=0)C1=CNC2=CC=CC=C12)C1=CC=C51 c,4H22N203s COC1=CC2=C(C=C10C)C(N(CC2)C(=0)C1=CC2=NNN=C2C=C1)C1=CC=C51 S N
57 \

s 0=C(N1CCC2=C(C=C52)C1C1=CC=C51)C1=CNC2=CC=CC=C12 C,0F11,N,052 0=C(N1CCC2=C(C=CS2)C1C1=CC=CS1)C1=CC2=CC=CC=C2N 1 CzA6N205, 0=C(N1CCC2=C(C=C52)C1C1=CC=CC=C1)C1=CC=C(C=C1)5(.0)(.0)N1CCOCC1 o/7 N
C.H24N20452 250 S" N-0000909 0=C(N1CCC2=C(C=CS2)C1C1=CC=C51)C1=CC=CC(=C1)5(=0)(=0)N1CCOCC1 < I

C22F-1,2N20453 CC1=C[N12=CiNC(=C2)C(...0)N2CCN3C=CC=C3C2C2=CC=CN=C2)C=C1 -C20-1,0N50. =
N----\

0=C(N1CCN2C=CC=C2C1C1=CC=CN=C1)C1=C2CCCCN2N=C1 C201-12,N,0
58 = 0 253 N-0000812 CC 1=CC=NC2=N C(=N N 12)C(.0) N
1CCN2C=CC.C2C1C1=CC=CC=C1 N N
N¨

C20H,A0 =

CN1N=C2CCCCC2=C1C(=0)N1CCC2-C(NC3-CC-CC-C23)C1C1-CC-CC-C1F
N
C.H2,FN40 FC1=CC=C(C=C1)C1N(CCC2=C1NC1=CC=CC=C21)C(=0)C1=CSC=C1 C2,H oFN 205 CN1C=CC=C1C1=NNO=C1)0=0)N1CCC2,-C(NC3=CC=CC=C23)C1C1=CC=CC=C1F
C,6H22FN,0 FC1=CC=CC=C1C1N(CCC2=C1NC1=CC=CC=C21)C(=0)C 1=C2 N =CC=CN2N =C1 F HN
59 CC1=NC2=CC(=NN2C(C)=C1)C(=0)N1CCC2=C(NC3=CC=CC=C23)C1C1-CC=C(F)C.C1 CõHuFN50 =

CC1=C(N2C=C5C2=N1)C(.0)N1CCC2=C(NC3=CC=CC=C23)C1C1=CC=C(F)C=C1 zNyN
C241-11,FN405 260 N-0000819 FC1=CC=CC=C1C1N CCC2=C1NC1=CC=CC
C0=C21 = C1=CC=C51 ) ) S
C22H,7FN,05 N

CCN1C=C(C=N1)C(.0)N1CCC2=C(NC3=CC=CC=C23)C1C1=CC=CC-C1F
N/

CCN1C=C(C=N1)0=0)N1CCC2=C(NC3=CC=CC=C23)C1C1=CC=CC=C1F
CBH.FN40
60 CN1N=CC=C1C(=0)N1CCC2=C(NC3=CC=CC=C23)C1C1=CC=C(F)C=C1 N/
Czz1-1,,FN40 HN

CIC1=CC=C(C=C1)C1N(CCC2=C1NC1=CC=CC=C21)C(.0)C1=CC2=CC=CC=C2N1 CI
C2,H.CIN,0 CCC1=NC=C2CN(CC2=N1)C(=0)C(C1=CC=CC=C1)C1=CC=CC=C1 CnE121N30 CC1CN(CC(C)01)5(=0)(=0)C1=CC=CC(=C1)0=0)N1CC(C2=CC=CC=C2)C2=CC=CC=C2C1 C.H.N204S
61 o s,-CIC1=CC=C(CC(=0)N2CC(.0)NC3=CC(=CC=C23)5(=0) (=0)N2CCCCC2)C,C 1 CI
C,11-1CIN30,5 CI

CICI=CC=C(CCfrON2CCC3=CC(=CC=C23)5(=0)(=0)N2CCCCC2)C=C1 C,11-1,3CIN203S

0=C(N1CCC2=CC(=CC=C12)5(=0)(=0)N1CCCCC1)C1(CC1)C1=CC=CC=C1 CHNOS

,C(CC1=CC=CC=C1) N1CCC2=CC(=CC=C 12)5(=0)(=0)N 1CCOCC1 C2oHnN2045
62 CIC1=CC=C(CC(=0)N2CCCC3=CC(=CC.C23)5(.0)(.0)N2CCCCC2)C=C1 C2,F12,CIN20,5 vs N

CC1=C(CC(=0)N2CCCC3=C2C=CC(=C3)5(=0)(.0)N2CCCC2)N C(01)C1=CC=CS1 C231-125N304S, CC1=C(SC(=N1)C1=CC=CC=C1)C(=-0)N1CCC2=C1C=CC(=C2)5(=0)(=0)N1CCCCC1 Of/
Cmliz5r1303S2 so 0=C(N1CCC2=CC(=CC=C12)5(=0)(=0)N1CCCCC1)C1=CSC(=N1)C1=CSC=C1
63 275 N-0000833 0=Ci N1CCC2,-C
1C=CC(=C2)5(=0)(=0)N 1CCCCC1)C1=CC=CS 1 0=C(N1CCC2,-CC(=CC=C12)5(=0)(=0)N1CCOCC1)C1=CC=C(C=C1)C1=CC=CC=C1 KjO1, Cni-124142045 CC1=CC=C(C=C1N1C=CC=C1)C(,-0)N1CCC2=CC(=CC=C12)5(=0)(=0)N1CCCCC1 C2,H,N303S
=

0=C(N1CCC2=C1C=CC(=C2)5(=0)(.0)N1CCCCC1)C1=CC(=NN1C1=CC=CC=C1)C1CC1
64 CC1=NN(C(C)=C1)C1=CC=C(C=C1)C(.0)N1CCC2=CC(=CC.C12)5(=0)(.0)N1CCCCC1 OU

s 0=C(N1CCC2=CC(=CC=C12)5(=0)(=0)N1CCCCC1)C1=C5C(=N1)C1=CC=CS1 /

FC1=CC=C(C=C1)C(=0)N1CCC2=CC(=CC=C12)5(=0)(.0)N1CCCCC1 OU
C20HnFN2038 CC1=C(SC(=N1)C1=CC=CC=C1)C(=0)N1CCCC2=C1C=CC(=C2)5(=0)(=0)N1CCCC1 CO25113035,
65 -0 ____________________________________________________________________ S
283 N-0000841 COC1,-CC=0C=C1)C1,610--.C5HC(=0)N1CCCC2=C1C=CC(=C2)5(=0)(=0)N1CCCC1 C,41-125N304S2 CCN(CC)5(.0)(.0)C1=CC2=C(C=C1)N(CCC2)C(=0)C1=CC=CC=C1 CIC1=0562=CC=CC=C12)C1=NN=CINC2=CC=C(C=C2)5(=0)(=0)N2CCCC2)01 HN
/
0 Cry CC1=NN(C(NC2=CC=C(C=N2)5(.0)(=0)N2CCCCC2)=C1)C1=CC=CC=C1 / NH

COõN,02S
66 o_.=_s=o CCN(CC)S(.0)(.0)C1=CC=C(NC2=CC(=NC=N2)C2=CC=CC=C2)C.C1 NH
N
N
C201-12,1,4025 N

CC1=CCKC(C)=CNNIN=CC2=C(NC3=CC=C(C=C3)5(=0)(=0)N3CCOCC3)N=CN=C12 NH
N %
0 j 0 C231-124N,O,S
NH

COC1=CC=CC=C1NC1=CC=C(C=N1)5(=0)(=0)N1CCCC1 0=S=0 290 N-0000849 CC1=CC(C)=N
C(NC2=CC=C(C=C2)5(=0)(.0)N 2CCCCC2)=N 1 N
CoHz2N4O2S
67 S
291 h CC1=CC(C)=NC(NC2=CC=C(C=C2)5(.0)(=0)N2CCCCCC2)=N1 N
N H

,CC(NC2=CC=C(C=C2)5(.0)(.0)N2CCCCCC2)=NC=N1 0=S =0 C0122N40,5 N
HN
293 N-0000852 0=5(,-0)(N1CCCC1)C1=CC=C(NC2=CC=C(N=N2)C2=CC=CC=C2)C=C1 0=S=0 c 294 e ,N N-0000853 C=C1C(0C2=C1C=C(C=C2)5(=0)(.0)N1CCCCCCH=C1NC(=N01)C1=CC=CC=C1 C2,HN30,S
68 \O
N

C=C1C(0C2=CC=C(C=C12)5(=0)(=0)N1CCOCCI.)=C1NC(=N01)C1=CC=C2000C2=C1 296 N-0000855 .. C=C1C(0C2=CC=C(C=C12)5(=0)(=0)N
1CCOCC1)=C1NC(=N01)C1=CC=CC.C1 C2,1-1,9N,055 I /

C=C1C(0C2=CC=C(C=C12)5(=0)(=0)N1CCOCC1)=C1NO=N01)C1=CC=CS1 \ I
C1961793055, 0 ') %
298 * N 9-0000857 CCN(CC)5(.0)(=0)C1=CC=C2N=C(NC2=C1)C1=CC=CC=C1 \\O
CI7HI,N30,5 0 ') 299 = /

CCN(CC)5(=0)(.0)C1=CC=C2N(C)C(=NC2=C1)C1=CC=CC=C1 C.H2,N302S
( 0 CC(C)N1C=C(C=N1)C1=NC2=CC(=CC=C2NIC)5(.0)(=0)N1CCCC1 //
C,81-123N50,5
69 \
N N9 ( //0 301 ",..,,,s....7 N * N-0000860 CCN1N=CC(=C1C)C1=NC2=CC(=CC=C2N1C)8(=0)(.0)N1CCCC1 S

\
-===="-'...N., < N
IR
302 N "--........ \N 0 "0 CCN1C=C(C(C)=N1)C1=NC2=CC(=CC=C2N1C)S(=0)(=0)N1CCCC1 S
I NO
Cl8F123N,0,5 0.........1 CN1C2=CC=C(C=C2N=C1C1=CC=CC2=NON=C12)5(=0)(=0)N1CCCC1 N N
N
/
\ .....----NI
C181-10N,03S

2,10 S
N
304 N R < %
0 N-0000863 CN1N=CC(=C1C)C1=NC2=CC(=CC=C2N1C)5(=0)(=0)N1CCCC1 r!l /

i C171-12,N,02S
r.0 ,N1,.......) % N-0000864 0=5(=0)(N1CCOCC1)C1=CC=C2N=C(CC3=CC=CC=C3)NC2=C1 \
N
C.1-1,N,0,5 %s 0 /

306 N-0000865 CN1C(CC2-CC-CC-C2)-NC2-CC(-CC-C12)5(-0)(-0)N1CCCC1 N
/
C191-12,N3025
70 307 N-0000866 0=C(NC1CC1)C1-C2C-C(C-CC2-NC(=C1)C1=NC=CC=C1)5(.0)(=0)N1CCOCC1 C2,1-122N40.5 Br Sr..\\ N
NH_ 308 N-0000867 BrC1=-NC(=CS1)C(=0)NC1=CC=C(C=C1)S(.0)(.0)N1CCOCC1 C1011413rN30452 0=-S=0 309 N-0000869 0=C(NC1=CC=C(C=C1)5(=0)(=-0)N1CCOCC1)C1=CN=C(N1)C1=CC=CC=C1 NH
N(') NH

0=CiNC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1)C1,-NC2=CC=CC.C2N1CC1=CC=CC=C1 o/ N-S II ( NH
II
71 311 o/ = \ N-0000871 CN1C(=CC2=CC(=CC=C12)5(C)(=0)=0)C(=0)NC1=CC=C(C=C1)5(.=0)(--=0)N1CCOCC1 II

C2,1-123N30652 0=S=0 =

0=CiNC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1)C1=CC=C(S1)C1=CC=C51 SV) c.H.N204s3 ()=S=0 313 0 N-0000873 0=C(NC1=CC=C(C=C1)S(=-0)(=0)N1CCOCO1C1-C(SC-C1)C1-CC-CC-C1 CnI120N20aSz 314 / II 0 ( N-0000874 CCN(C(=0)C1=NC2=CC.,CC=C2N1CC)C1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 N-S
II

Cz2H26N40,5
72 o/ II
315 oNH
N-0000875 0=C( NC1=CO3C(C=CHS(=0)(=0)N1CCOCC
1)C1=CN(CC2=CC=CC=C2)C(=N1)C1=CC=CC=C1 N
=

C,H,A0,5 NH

CCN1C=C(N=C1C1=CC=CC=CHC(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 , CuHN,045 317 / II = \

COC1=CC=C2N(C)C(=CC2=CHC(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 II

C21H23N30,5 II
318 0 N¨S NH o7 N-0000878 COC1=CC=C2C=C(N(C)C2=CHC(r.0)NC1=CC=C(C=CHS(=0)(.0)N1CCOCC1 II

C,11-1N30,5 0 \\O
%s.1\1 319 * HN N-0000879 CCC1=C(C=NN1C1=CC=C(C)C=CHC(.0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 N
\N¨ 0 C,31-126N404S
73 * s\\

CC(C)C1=C(C=NN1C1=CC=C(C)C=C1)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 N
\N ____________ 0 C2,H.N,0,5 0 r\O
321 =0 CCC1=C(C=N N1C1=CC=C(C=C1)C(F)(F)OCKOC1=CC=C(C=C1)5(=0)(.0)N 1CCOCC 1 N
N-C2,H,3F,N4045 \µ) CCC1=C(C.NN1C1=CC=C(CI)C=C1)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 N

N-C221-1õCIN4043 :1=CC=C(C=C1)S(=0)(=0)N1CCOCC1)C1=CN(C=N1)C(C1-CC-CC-C1)(C1=CC=CC=C1)C1=CC.

NV) N
74 o 0=--S=0 0=CiNC1=CC=C(C=C1)5(=0)(.0)N1CCOCC1)C1=CN=CN1CC1-CC-CC-C1 ONH
C,,N22N404S

CC1=C(C=NN1C1=CC=CC=C1)C(70)NC1=CC=CC(=C1)5(=0)(=0)N1CCOCC1 N HN
\ 0 N-HN
326 = 0 N-0000888 CC
1=C(C=N N 1C1=CC=CC=C1)C(=0)NC1=CC=C(C=C1)C(=0)N 1CCOCC1 N N
\N- 0 CCN1C(=CC=C1C1=CC=C(C)C=C1)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 CN1C(=CC2=CC(CI)=CC=C12)C(=0)NC 1=CC=C(C-,C 1)S (=0)(=.0)N 1CCOCC1 0 N-S=
NH
II
75 \N

329 / II = \ 9-0000897 CN1C(=CC2=CC(OC(F)(F)F)=CC=C12)C(=0)NC1=CC=C(C=C1)S(=ON=0)N1CCOCC1 O N¨S=

NH
II

CH,0F381,0,S

330 o/ N-0000898 CN1C(=CC2=CC(NS(C)(-0)-0)-CC-C12)C(-0)NC1-CC-C(C-C1)5(-0)(-0)N1CCOCC1 N¨S=

NH N
____ /II 11 0 331 / II = \ N-0000899 CN1C(=CC2=CC(NC(C)=0)=CC=C12)C(=0)NC1=CC=C(C=C1)S(=08=0)N1CCOCC1 O N¨S=

NH
/ II

c22H.N40,s 0.7.--1 0 * Br N-0000900 CCN1C( BN=CC=C1C(-O)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 CoH20BrN,04S

333 0=S =-0 N-0000901 NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 = "N203S
Br j_ NH

= 9-0000903 BrC1=NC=C(S1)C(.0)NC1=CC=C(C=C1)S(=O)(=0)N1CCOCC1 os C¨) C,4H14BrN304S2
76 0=s=o 0=C(NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1)C1=C5C(=N1)C1=CC=CC=C1 oNH
N \V) S

0=C(NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1)C1=CC2=CC=CC=C251 II

C,,H.N2045o 0=C(NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1)C1=C(SC2=CC=CC=C12)C1=CC=CC=C1 NH

338 N N-0000907 0-C(N1C-C(C-N1)C1-CC-CC-C1)C1-CC-C(C-C1)5(-0)(-0)N1CCOCC1 NV
C2011,9N3045
77 0s=0 0=CiNC1=CC=C(C=C1)5(.0)(=0)N1CCOCC1)C1=CC(=NN1)C1=CC=CC=C1 HN
HN
\N ___ ¨

%scN
340 HN * 0 CCN1C(=CC=C1C1=CC=C(CC)C=C1)C(=0)NC1=CC=C(C=C1)5(=0)(=-0)N1CCOCC1 C251-1,03045 CCN1C2C=CC=CC2N=C1C(=0)NC1=CC=C(C=C1)5(=0)(.0)N1CCOCC1 0 N¨S NH
II

0=C(N1C=CC(=N1)C1,-CC=CC=C1)C1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 C20H,,N3043
78 0=s=0 0=C(NC1=CC=C(C=C1)5(.0)(=0)N1CCOCC1)N1C=C(C=N1)C1=CC=CC=C1 HN,0 (0-) 0,C(NC1=CC=C(C=C1)5(.0)(.0)N1CCOCC1)C1=CN(CC2=CC=CC=C2)C2=NC=CC=C12 /
C2,1124N404S

II.7 N-0000915 345 0 N¨S NH
0=C(NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1)C1=CN2C=CC=CC2=C1 II

C191-119N30,5 0 r\O

CCN1C(=CC=C1C1=CC=C(F)C(F)=C1)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 C23H23F,61,045
79 NN

CCOC1=CC=C(C=C1)C1=CC=C(N1CC)C(=0)NC1=CC=C(C=C1)5(=0)(.0)N1CCOCC1 NH
C 2!_ti3N9 N
4=j CC1=CC=CC(=C1)C1=NC=C(S1)C(.0)NC1=CC=C(C=C1)S(=0)(70)N1CCOCC1 I.
0, Nzz, CõHõN30,S2 Br NH

8rC1=CSC(=N1)C(=0)NCI,CC=C(C=C1)5(.0)(.0)N1CCOCC1 "0 C-) C141-I µ,,Br N30452
80 Lr s N
350 NH N-0000926 CC 1=CC-CC-C1C1-NC=C(S1)C(=0)NC1=CC=C(C=C1)5(=0)(=0) N 1CCOCC1 =
NõN, "0 CN) HN * 0 CCN1C(=CC=C1C1=CC=C(COC=C1)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 0=S=0 352 * N-0000928 0=Ci NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1)C1=C(C=CS1)C1=CC=CC=C1 S
C,1H20N,04S2 / o II
N¨S NH
353 \ / I I N-CN1C2=CC=C(CI)C=C2C(CN2CCOCC2)=C1C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 NV-) C25112,CIN40,5
81 o r\o *354 HN N-0000930 CCN1C(-CC=C1C1=CC=C(C=C1)C(F)(9F)C(=0)NC1=CC=C(C=C1)5(=0)(=0)NICCOCC1 C24H24F,N,045 CCN1C(=CC=C1C1=CC=C(C=C1)C(F)(F)F)C(=0)NC1=CC=C(C=C1)5(.0)(=0)N1CCOCC1 C24H,4F3N3043 0 r---\0 F
*\sJ 356 HN 0 N-0000933 CCN1C(=CC=C1C1=CC=C(C)C=C1F)C(=0)NC1=CC,C(C=C1)5(r0)(=0)N1CCOCC1 C241-12,FN3045 V.
\)=/

CC1=CC=C(C=C1)C1=NC=C(51)C(=0)NC1=CC=C(C=C1)5(=O)(=0)N1CCOCC1 NH
=
0, .",==
N,0 2
82 358 NH N-0000936 COC1=CC=C( C=C C(-70)NC2=CC=C(C=C2)5(.0)(=0)N2CCOCC2)C=C1 0=S=0 C20Hurb85.V...

359 HN * 0 CCN1C(=CC=C1C1=CC=C(C)C(C)=C1)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 C,5112,N3045 /\ / II

0=C1N(CC2=CC=CC=C12)C1=CC=C(C=C1)5(=0)(.0)N1CCOCC1 C,0118N,045 0 r"---\0 \\_.) CC1=C(C=NN1C1=CC=CC=C1)C(=0)0C1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 N N
\N- 0 C2,H2,N3055 0 \ 0 * 0 CCN1C(=CC=C1C1=CC=C(C=C1)C(C)C)C(.0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 \ 0 C2,H31N3045
83 o=s=o 0=ONC1=CC=C(C=C1)5(=0)(.0)N1CCOCC1)C1=CN=C(51)N1CCCCC1 oNH
SV) )¨N
C:0)õN4 2 0=S=0 0=CiNC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1)C1=CN=C(51)C1=CC=CN=C1 O.NR
¨N
0 (-No o HN

CCOC(=0)C1=C(CNC2=CC=C(C=C2)5(=0)(=0)N2CCOCC2)N(N=C1)C1=CC=CC=C1 N¨N
=
C22HõN40,5
84 \--A

CCI(C)C(C(=0)C2=CN(CCN3CCOCC3)C3=CC=CC=C23)C1ICIC

C22630N20.2 N

CC1=CI5N=NlICI=OINC1=CC=C(C=C1)N1N=C(C=C1C(F)(F)FICIFI(F)F
N N

N -S
C,5H9F,N,OS
CI
CI

COC1=CC=C2N(C(=0)C3=CC=CCICII=C3C1)C(C)=C(CCN3CCOCC3)C2=C1 (3"-j Cz31-1,4CI,N203
85 o=s=o 0=C(NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1)N1C=CC(=N1)C1=CC=CC=C1 oNH
õNN?
C, .0 =
0=S=0 0=C(NC1=CC=0C=C1)5(=0)(=0)N7CCOCC1)C1=CN=CN1 HN
NV) C14E1,6144045 =
\iN

0=C1N(CC2=CC=CC=C2)CC2=C1C=NN2C1=CC=CC=C1 CnH15N30 0 O r\

N\\..) 372 =N(1))1\N 0 CC1=C(C=NN1C1=CC=CC=C1)C(=o)NC1=CC=C(C=C1C(F)(9F)S(=0)(=0)N1CCOcCi N¨

C22H,1F3N4045 '0 N"H"D
HN
ID=J(N.(N))(23=3)D=D3=Z90D333JD30)J=JD=TD(N=)DN 8960000-,i4N NH
zS5OzN'J"Hzz3 S
....., \ 11 0 "...
I JDODDI N(0=)(0=)5(I3=3)J=JD=IDN(0.)DID=353=DHJ=J0=D7=00()(303 960000-N
1411111 o V........., LLE
A
0)c zS'O'N"H"D
S

N..
#
IJDODDIN(0=)(0=)5(0=D)D=3J=TDN(0=)Di3=DSJ=ID(tD=3)3-33=T303 9960000-N
0 0 \............./0 9LE
0,,, 'S1O'Nr'14"J
S

N., TODODDIN(0.)(0=)5(T7r0)7=DD=SDN(0.)DID=JSD=T D(TD=7)7=00=TDD 5960000-15 01N"H"3 0=33=33=1341SZD=3D=DD=2D0=T Dtf 3303DT N(0=)(0=)S(1J=J)J=33=IDN 0=0 4960000-N VLE

\ 0 S HN S-N

N VON"H"D

ID=DD=33=-D1NN-,D(ZDJ03DZ N(0=)(0=)5(ZD=J)J=DD=ZDOD0=TDD 6960000N % N
N = ELE

%s NH2 HN
379 N-0000969 CC1=C(C=NN
1C1=CC=CC=C1)C(=0)NC 1=CC=C(C=C1)5(N )(=0)=0 N
N-C,7H1044035 _________________________ N

N

% NH N-0000970 C(C-NN1C1-CC-CC-C1)C(-0)NC1=CC=0C=C1)S(=0)(=0)NC(=0)C1=C(C)N(N=C1)C1=CC=C

HN
N
\N _________ 0 C.H24N6045 N

NH

CCN1C=NC(=C1)6(.0)NC1=CC=C(C=C1)5(.0)(.0)N1CCOCC1 0, c16.20,04s o%
s%0 CCN1C(=CC=C1C1=CC=C(F)C=C1)C(=0)NC1=CC=C(C=C1)6(.0)(.0)N1CCOCC1 C,3H24FN3045 OH *

CCN1C(=CC=C1C1=CC=C(C7C1)C(CHOOK(=0)NC1=CC=C(C=C1)5(=OH=0)N1CCOCC1 C,6113,N305S

=
=
o=s=--o 384 N-0000974 0-C(NC1-CC-C(C-C1)5(-0)(-0)N1CCOCC1)C1=CN(CC2=CC.CC=C2)C=N1 HNO
C2,HN4 0 r CCCC1=C(NC(.0)C2=CC=C(C=C2)5(=0)(=0)N2CCOCC2)C=NN1C1=CC=CC=C1 o 0=C1N(CC2=CC=C(C=C2)5(=0)(=0)N2CCOCC2)CC2=C1C=NN2C1=CC=CC=C1 I \
C2,H,2N4045 HN

0=S(=0)(N1CCOCC1)C1=CC=C(NC2=C3C=CNC3=NC=N2)C=C1 OU
C,61-1050,5 V....-Nx) 388 /1\7(01 N-0000981 CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 N
=
N¨

S N

COC1=CC=C(C=C1)C1=NC=C(SNC(=0)NC1=CC=C(C=C1)8(=0)(.0)N1CCOCC1 NH
/so ____ N =

0=S=-0 390 411 9-0000984 0=C(Na.r-CC=C(C=C1)5(=0)(.0)NI.CCOCO.)C3.-C(SC-N1.)C1.-CC-CC-0.

N
_______ S

0=s=0 0=C(NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1)C1=C5C(=N1)N1CCCCC1 ONH
NV) )¨S
aN4ON2 0=S=0 392 N-0000986 0=C(NC1,CC-C(C-C1)5(-0)(=0)N1CCOCC1)C1=C(N=C51)C1CCCC1 S
\=N
c291.122N204s2 0=¨S =0 0=C(NC1=CC=C(C=C1)5(=0)(.0)N1CCOCC1)C1=CN=C(51)C1=CC=NC=C1 SV
co S'ON"H"D

,....N.,,,,,-I3=3(ZN=E3J=DJ=30=3N=Z3N)D=33=IJ(I)DODDIN)(0=)S=0 N

___________________________________________________________________ S'O'N"H"D
ID=D(ZD=D3--30=ZJCZN=bD=DN=Z7N1D=33=13(1MODDIN)(0=)5=0 0660000-N *

N NH
S'O'N'PH"3 _N _________________________________________________________________ _________________________________________________________ N
J

1D3D3DIN(ID=J)D=JD=ID(0=)(0-=)SN(0=)J(J(J)(AD(I3=3)3=DD=1DINN=3)3=13JJ 6860000-N \\ NH 06E
A A
___________________________________________________________________ S'IDN'PH¶D
01'zk N
A
IDDD3IN(0=)(0=)S(ID=7)3=JD=IJN(0=)J(Jii)(3)3(ID=D)J=33=ID1NN=3)J=IDD 8860000-N
* NH 0 A 06E

[6 =

N

NH

CCN1N=CC(C(.0)NC2=CC=C(C=C2)5(=0)(=0)N2CCOCC2)=C1C1=CC=CC=C1 \\NS
CON,N2028 0=8=-0 0=C(NC1=CC=C(C=C1)8(.0)(=0)N1CCOCC1)C1=C(N(CC2=CC=CC=C2)N=C1)C1=CC=CC=C1 NN.
N-N
,N

CCN1C=C(C=N1)0=0)NC1=CC=C(C=C1)8(=0)(.0)N1CCOCC1 \
=

=

NH

CCN1N=C(C=C1C(=0)NC1=CC=C(C=C1)5(70)(.0)N1CCOCC1)C1=CC=CC=C1 C22H,4N40,5 0=S=0 0=C(NC1,CC=C(C=C1)5(=0)(=0)N1CCOCC1)C1=CC(=NN1CC1=CC=CC=C1)C1=CC=CC=C1 N
\M-CC1=C(C=NN1C1=CC=CC=C1)C(=0)N1CCC2=C(NC3--CC=CC=C23)C1C1=CC=CC=C1F
/N
C.H23FN.0 \N

0.5(=0)(N1CCOCC1)C1=CC=C(NC2=C3C=CN(C3=NC=N2)C2=CC=CC=C2)C=C1 FIN
SN

(-.) \----N
\ ......--o ------s o------.

0=C(NC1=CC=C(C=C1)5(.0)(.0)N1CCOCC1)C1=CN(C2=CC=CC=C12)C1=CC=CC=C1 NH

/
N
*
''..) F

N

N-0001001 CCN1C=C(C=N1)C(.0)N1CCC2,-C(C1C1=CC=CC=C1F)N(CC)C1=CC=CC=C21 N
L-..
C251-12sFN40 N
I
.. ./
HN N

0.5(.0)(N1CCOCC1)C1=CC=C(NC2=NC=C(C=N2)C2=CC=CC=C2)C=C1 0=1=0 .........A...,...

CC1=0C=NN1C1=CC=0C=C1)C(F)(OF)0=0)NC1=CC=0C=C1)5(=0)(=0)NC1CC1 0 /5) NH
A
Cz1HF,N4035 =

N

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)0=0)NC1=CC=C(C=C1)5(.0)(.0)N1CC0F)(F)CC1 N
\N 0 C2,H21FsN4035 =F NO

CCC1=0C=NN1C1=CC=C(C=C1)C(F)(F)F )C(.0)NC1=CC=0C=C1)S(=0)(=0)N1CCCCC1 N
\N¨ 0 C241-1,sF3N4035 N
\N ___________ CCC1=0C=NN1C1=CC=0C=C1)C(F)(F)F)0=0)NCC1=CC=0C=C1)5(=O)(=0)N1CCOCC1 h0 0 N"---) C241-125F,N4045 0 r\O

C0C)(C)C1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(=0)NC1=CC=0C=C1)5(.0)(.0)N1CCOCC1 N
\N¨

C2sH27F3N4045 N
HN

0.5(.0)(N1CCOCC1)C1=CC=C(NC2=C3NC=NC3=NC=N2)C=C1 OU

CIC1=CC,--C2N(C(=CC2=C 1)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N 1CCOCC1)C1=CC=CC=C1 o/ II
N¨S = NH
/ I I

C2,H22CIN30,5 N/

CN1C(=CC2=CC(C1)=CC=C12)C(.0)N1CCC2=CiNC3=CC=CC=C23)C1C1=CC=CC=C1F
CI
Cul-121C' FN,0 CN1C(=CC2=COOC(F)(F)F)=CC=C12)C(.0)N1CCC2-C(NC3-CC-CC-C23)C1C1-CC-CC-C1F

C.H21FPN30 2 OU

0.5(=0)(N1CCOCC1)C1=CC=C(NC2=C3NC=CC3=NC=N2)C=C1 C161-10N,O,S

418 o/ \ N¨ I I = \ N-0001017 0=C(N
C1=CC=C(C=C1)5(=0)(=0)N1CCOCC1)C1-CC2-CC-CC-C2N1 S NH

C191-11,N3045 0 r\O
*

CCC1=C(C=NN1C1=CC=C(F)C=C1)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 N N

N¨

420 NcH 9-0001019 CC1=C(C=NN1C1=CC=C(C=N1)C(F)(F)F)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 F N
N¨

C211-120F3N,04S
0 r----\0 CCC1=C(C=NN1CC1=CC=CC=C1)0=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 N Ns=
N¨ 0 CC(C)C1=C(C=NN1C1=CC=C(C=N1)C(F)(F)F)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 F N
N¨

C231-124F3N,04S

=
N

:C1=C(C=N N 1C1=CC=C(C=C1)C( OF)C(=0)N1CCC2=C(NC3=CC=CC=C23)C1C1=CC=CC=C11 C,1-1F=N=0 HN

0=5(=O)(N1CCOCC 1)C 1=CC=C( NC2=C3N=CN(C3=-NC=N2)C2=CC=CC=C2)C=C1 I
<N

0 \s( %sN

:C1=C(C=NN1C1=CC.C(C=C1)C(F)(F)F)C(.0)NC1=CC=C(C=C1)5(=0)(=0)N1CCS(=O)(=0)CC7 N
\N _____________ 0 C1262I1,N40552 CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(=0)NC1=CC=C(C=C1)5(=O)(=-0)NCC(F)(F)F
N
\N¨ 0 C0,6166140,5 \\ OH
HN

427 N-0001027 CC1=C(C=N N1C1=CC=C(C=C1)C( F)( F)F)C(=0)NC1=CC=C(C=C1)5(0)( =0)=0 N N's \N¨ 0 Cu,11,4F,N3045 428 NH N-0001028 0=0 NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1)C1-CN (CC2-CC-CC-C2)C2-CC-CC-C12 C2,HN,O,S
0=S =0 CN1CCN(CC1)5(.0)(.0)C1=CC=C(NC(=0)C2=C(C)N(N=C2)C2=CC=C(C=C2)C(F)(F)F)C=C1 N-N
C2,H,J3N,035 * 0 VAN) /y CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(=0)NC1=CC=C(C=C1)9(=0)(=0)N1C=CC=N1 N N
\ 0 N-C211-116F3N,03S

0=C(NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1)C1=CC2=CC=CC=C2N1C1=CC=CC=C1 0/ \NJ = NH
II

C2,H,,N3049 0 \ 0 432 Br = N-0001034 CCC1=C(C=NN1C1=CC=C(Br)C=C1)C(.0)NC1=CC=C(C=C1)5(.0)(=0)N1CCOCC1 N
\N- 0 C221-12,Br N4045 HN

CC1=C(C=NN1C1=CC=CC=C1)6(=0)NC1=CC=C(C=C1)5(6)(=0)=0 \ 0 N-C.NoN303S
F
N

CCN1C=C(C=N1)C(=0)N1CCC2,-C(NC3=CC=CC=C23)(C@@Elj1C1-CC-CC-C1F
Cõ1-12,FN20 IT II
J

CCN1C=C(C=N1)C(=0)N1CCC2=-C(NC3=CC=CC=C23)(C@H1161=CC--CC,-C1F

F

0 =-S=--0 0=CiNC1=CC=C(C=C1)5(=0)(.0)N1CCOCC1)C1=NC=C(S1)C1=CC=CC=C1 ONH
0:2 N¨N

CC1=C(C.NN1C1=CC=CC=C1)C(=0)N1CCN2C(C1)=NN=C2C(F)(F)F
N
C,71-1F3NO
= N

CC1=C(C=NN1C1=CC=CC=C1)C(.0)N1CCC2C=CC=CC2C1C1=CC=CC=C1 C2611,5N30 439 r') N-0001046 FC(F)(F)C1=CC=C(C=C1)N1N=CC(C(=0)NC2=CC=C(C=C2)5(=0)(=0)N2CCOCC2)=C1C1CC1 jo N, HN

0=5(=0)(N1CCOCC1)C1=CC=C(NC2=C3N(C=CC3=NC=N2)C2=CC=CC=C2)C=C1 C22H,IN,03S

C=CCN1C(=CC2=CC=CC=C12)Ci=0)NC1=CC=C(C=C1)5(=0)(.0)N1CCOCC1 o/ II
N¨S NH

CC1=C(C=NNIC1=CC=C(C=C1)C(F)(F)F)C(.0)NC1=CC=C(C=C1)C(N1CCOCC1)C(F)(F)F
HN
N
\N¨ 0 C2,H22F6N402 CC1=C(C=NN1C1=CC=C(C=C1)C(F)(9F)C(.0)NC1=CC=C(C=C1)5(=0)(=0)N1CCCC1C(0)=0 N
\N-C,3112,F3N4055 F F

,C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CC2(C0C2)C1 , ( N , C2,1-12,F3N4045 OH
HN

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(=0)NC1=CC=C(C=C1)C(0)C(F)(F)F
N N
\N- 0 C20HõF6N30, CCN1C=C(C=N1)0=0)N1CCC2=C(C1C1=CC=CC=C1F)N(CC1=CC=CC=C1)C1=CC=CC=C21 C30H,FN30 0=S=0 0.5(=0)(N1CCOCC1)C1=CC=C(NC2=NC=C3NC=CC3=N2)C=C1 NNH
C33H,7N3035 o/ * NH
448 \ __ II
N-0001057 CCCN 1C( -CC2-CC-CC-C12)C(-0)NC1-CC-C(C-C1)5(-0)(-0)N 1CCOCC1 449 r.N N-0001058 CCN1C(-CC=C1C1=CC=C(C)C=C1)C(=0)N1CCC2=C(NC3=CC=CC=C23)C1C1=CC=CC=C1F
C3,1-128FN30 0001059 CCN 1C=C(C=C1C(=0)N
1CCC2=C(NC3=CC=CC=C23)C1C1-CC-CC-C 1 FJC 1-CC-CC-C1 451 90001061 Cl-CC=CC=C1C1N(CCC2=C1NC1=CC=CC=C21)C(.0)C1=C2C=CC.CC2=N N1CC1=CC=CC=C1 HN

N
\ ......---0 ------.-S
0"....--"...

0=C(NC1=CC=C(C=C1)5(=0)(.0)N1CCOCC1)C1=NN(C2=CC=CC=C12)C1=CC=CC=C 1 NH

N /
N
C24HuNa' F
F
F
F

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(.0)NC1=CC=C(C=C1)C(N1CCCCC1)C(F)(F)F
F
N/\rc \ 0 N¨

N
-N \ i N

\
. N-0001064 CC1=C(C=NN1C1=CC=CC=C1)C(.0)N1CCC2=C(C1)C1-CC-CC-C1N2 N
H
Cz2H,,,N40 N
455 JN * N-0001065 COC1=CC2=C(CN(CC2)C(=0)C2=C(C)N(N=C2)C2=CC=CC=C2)C=C1OC
).......'' C: /\....
N

0=C(NC1=CC=C(C=C1)[ Sill=0)(=0)N1CCOCC1)C1=CC2=CC=CC=C2N1CC1=CC=CC=C1 o/ N-Si \ I I = \
NH
\ ____ / II

C2,H2,N304Si OP
457 0 / ¨Si N-0001066 0=C(NC1=CC=C(C=C1)1Sill=0)(=0)N1CCOCC1)C1=CC2=CC=CC=C2N1CC1=CC=CC=C1 o =
N NH
II

C261-12,N304Si 0=S =0 458 N-0001067 ..
0.5(.0)(N1CCOCC1)C1=CC=C(NC2=NC.C3N(C=CC3=N2)C2=CC=CC=C2)C=C1 NH
N
=
CuH,N5035 NH

CCN1C=C(C(=0)NC2=CC=C(C=C2)S(=0)(=0)N2CCOCC2P=C1)C1=CC=CC=C1 CHNOS
=

CC1=C(C=NN1C1=CC=CC=C1)0=0)N1CCC2C=CC=CC21C@@ Hi 1C1=CC=CC=C1 C261-12,N30 N.........
/ N O
461 H ./ N-0001076 CC1¨C(C¨NN1C1¨CC¨CC¨C1)C(-0)N1CCC2=C(C1)NC1=CC=CC=C21 N
/ N

...........,N ,,.....,0 CN(C(C1=CC=CC=C1)C1¨CC¨CC=C1)C(=0)C1=C(C)N(N=C1)C1=CC.CC=C1 0.---..
N¨N
C2sHz3N30 N
---CCC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(.0)N1CC2=CC=CC=C2C1 N
F
F
F
C211-1.F,N,0 11 )N
\..,N

0=5(=0)(N1CCOCC1)C1¨CC¨C(NC2¨C3C¨NN(C3¨NC¨N2)C2¨CC¨CC¨C2)C¨C1 HN O

i N

C211-120N,038 o o % ,N......õ.........õ, S
0' CN1C(=CC2=CiNC3=CC=C(C=C3)5(=0)(=0)N3CCOCC3)N=CN=C12)C1=CC=CC=C1 ..".7 N
N............ ) / N
CõF123N,O,S
F
F F
N
NN
\ /
466 N-0001085 : F)(F)C1=CC=C(C=C1)N 1N=CC(C(--0)NC2=CC=C(C=C2)5( =0)(=0)N2CCOCC2)=C1C1=CC=CC=

NH

N`NS
_____ /
C2 õF3 NN 45 ( I/

F
F
HN

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(90C(=0)NC1=CC=C(C=C1)5(.0)C1CCCCC1 F
N X
\N- 0 \\so F
468 F ,17.....1 0 N-0001087 CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(=0)NC1=CC=C(C=C1)5(=0)(.0)C1CCCCC1 F N X
\ 0 N-C,41-124F3N3035 F N \ %s----N \,) F 469 0 /1).....:(I ------ N-0001088 CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(=0)NC1=CC=C(C=N1)5(=0)(=0)N1CCOCC1 F
N X
\ 0 N-CH20F3Ns045 HN S

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(.0)NC1=CC=C(SC2CCCCC2)C=C1 N
\N¨ 0 CN1N=C(C2=CiNC3=CC=C(C=C3)S(=0)(=0)N3CCOCC3)N=CN=C12)C1=CC=CC=C1 N
\N
CH2,N6033 S

N \ I
o 472 N-0001091 CCC1=C(C=NN 1C1=CC=C(C=C1)C(F)( OF)C(.0)N 1CCC2=CC(OC)=C(OC)C=C2C 1C 1=CC=CS1 C,,,1-126F3N303S

0--=S=0 473 N-0001092 0=C( NC1=CC=C(C=C 1)S(=0)(=0)N
1CCOCC1)C1=CN (CC2=CC=CC=C2)C=C1C1=CC=CC=C1 C.11,113043 ZCC1=C(C=NN1C1=CC=C(C=C1)C(F)(99C(.0)N1CCC2=CC3=C(0CO3)C=C2C1C1=CC=CC=C1 FQ
475 6-0001094 CC1=CC(C)=NC(=N1)N1CCC2=C(NC3-,CC=CC=C23)C1C1=CC=CC=C1F
CH2,FN4 476 N-0001095 CCC1=C(C-NN1C1-CC-C(C-C1)C(F)(F)F)C(=0)N1CCCC2=CC=CC=C12 N

C221-120F,N30 S
HN =

477 0 6-0001096 CC1=C(C=NN1C1=CC=C(C=C1)C( F)(F)F)C(=0)NC1-,CC-,C(SC2CCOCC2)C=C1 N
\N 0 CuH22F3N3025 II
HN
*
478 N-0001097 ..
CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(=0)NC1=CC=C(0,C1)5(=0)C1CCOCC1 \OD
N
\N- 0 479 c 0- N N-0001098 CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(.0)NC1=CC=C(C=C1)5(.0)(=0)C1CCOCC1 \N-C231-1,F3N3045 0 ,µ
* \\ O

CC(C)C1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(=0)NCI=CC=C(C=C1)5(=0)(=0)N1CCOCC1 N
N-0 0 r---\
=
N\\õ...) HN

FC(F)(F)C1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(=0)NC1=CC=C(C7C1)5(=0)(.0)N1CCOCC1 N
N-C221-1,j6N4045 0 re- \\O

CCC1=C(C=NN1C1=CC=C(N=C1)C(F)(F)FJC(.0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 F N

N-C22F12,83N,045 0=C(NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1)C1=CN(C2=CC=CC=C12)C1=CC=CN=C1 NH

C,HNQJ

CN1C=C(C0=0)NC2=CC=C(C=C2)5(=0)(=0)N2CC0CC2)C2=CC=CC=C12 H
N

=

CC1=CC(=NN1C1=CC=CC=C1)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 \

0 s 0 486 HN * N-0001332 CCN1C(=CC=C1C1=CC=NC=C1)C(.0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 0 r-* \_j CCN1C(=CC=C1C1=CC=C(C=C1)N(C)C)C(.0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 C,51-130N4045 HO \VA

CCN1C(=CC=C1C1=CC=C(C=C1)C(0)=0)C(=0)NC1=CC=C(C=C1)S(=0)(=0)N1CCOCC1 CmHzsN3065 N \
489 iN

CN(C)5(.0)(=0)C1=CC=C2N(CCC2=C1)C(=0)C1=C(C)N(N=C1)C1=CC=C(C=C1)C(F)(F)F
0 =

s \iq CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(.0)NC1=CC=C(C5(=0)(=0)N2CCOCC2)C=C1 \ 0 N¨

õ601) 491 HO (10 C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1C[C@H]2CC[C@@HI
C2,H2,F,N403S

II
492 o N¨S NH Br N-0001338 CN1C(=CC2=CC=C(Br)C=C12)C(70)NC1=CC=C(C.C1)5(=0)(=0)N1CCOCC1 C20F12013rN,045 I
493 o/
N¨S NH rF N-0001339 CN1C(=CC2=CC(F)=CC=C12)C(=0)NC1=CC7C(C=C1)5(=0)(=0)N1CCOCC1 C,0H,0FN3045 \ 0 494 /N¨S 11 NH

CN1C(=CC2=CC=C(C=C12)C1=CC=CC=C1)0=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 N

495 \ N N-N(q=0)C1=C(CC)N(N=C1)C1=CC=C(N=C1)C(F)(F)F)C1=CC=C(C=C1)5(=0)(=0)N1CCOCC1)C1 C34H30F6N,0,S

\ I

1CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(=0)N1CCC2=CC(OC)=C(OC)C=C2C1C1=CC=CC=C:
C301-12j3N,O, Sx\k, CC1=CC=C(C=C1)C1,C(CC(=0)NC2=CC=C(C=C2)5(=0)(=0)N2CCOCC2)N2C=C(C)C=CC2=N1 498 / II = 9-0001344 CN1C(=CC2=CC(=CC=C12)[N.1([0-])=0)C(=ONC1=CC=C(C=C1)5(.0)(=0)N1CCOCC1 II

C301Iz0N0065 NH

C=CCN1C=C(C(.0)NC2=CC=C(C=C2)5(=0)(=0)N2CCOCC2)C2=CC=CC=C12 cot6c)N

500 = N-0001351 CN1C(=CC2=C(C0C=CC=C12)6(.0)NC1,-CC=C(C.C1)S(=0)(=0)N1CCOCC1 0 N¨S NH
II

C,0H,0CINOS
0 0, COC1=C(OC)C=C2N(C)C(=CC2=C1)C(=0)NC1=CC=C(C=C1)5(.0)(-.0)N1CCOCC1 II

%Sist/s.

0=C(CC1=CNC2=CC=CC=C14NC1=CC=C(C=C1)[54(=0)(=0)N1CCOCC1 C20H21N304Si 503 0/ \ II
N¨S NH N-0001355 CN1C(=CC2=CC(C)=CC=C12)C(=0)NC1=CC=C(C=C1)5(=0)(.0)N1CCOCC1 C,11-123N,0,5 504 / \ V # N-0001356 CN1C(=CC2=CC=C(C=C12)N1CCCC1)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 0/ N¨S H
II

CC1=NN2C(C=CC3=CC(=CC=C23)C(F)(F )F)=C1C(=0)NC1,-CC=C(C=C1)5(.0)(=-0)N 1660661 HN
FN

Nm2 506 o/ II N¨ N-0001359 CN1C(=CC2=CC(N)=CC=C12)C(=0)NC1=CC=C(C=C1)5(=0)(.0)N1CCOCC1 II

Cz0Hz2N40,15 0 0 r ( HN = 11-1µj CCN1C(=CC=C1C1=CC=C20C0C2=C1)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 Cz4H25N3065 0 r \ 0 Võ.-N

N-0001361 CCN1C(-CC-C1C1-CC(C)-CC(C)-C1)C(-0)NC1-CC-C(C-C1)5(=0)(=0)N1CCOCC1 C25112,N,O,S

HN =509 0 N-0001362 CCN1C(=CC=C1C1=CC=C2NC=CC2=C1)C(=O)NC1.CC=C(C=C1)5(=0)(=0)N1CCOCC1 C2s1-126N4045 0 1.--NO
Võ-N

510 s HN N-0001363 CCN1C(=CC=C1C1=CC=C(SC)C=C1)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 CHNOSZ
o=s=---0 COC1=CC(NC(.0)C2=C(C)N(N=C2)C2=CC=C(C=C2)C(F)(F)F)=CC=C15(=0)(.0)N1CCOCC1 Cr Cd-1,3F3N4055 F r * Nis) HN

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(.,0)NC1=CC=C(C=C1)N1CCC51(=0)=0 N N
\N¨ 0 0=1-0 CN(C(=0)C1=C(C)N(N=C1)C1=CC=C(C=C1)C(F)(99C1=CC=C(C=C1)5(=0)(=.0)N1CCOCC1 Cr Cz3H23F3N4045 _________________________________________________________ FF
0 r\O
N
F+= F

CCC1=C(C=NN1C1=CC=C(OC(F)(F )F)C=C1)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 N
\N¨ 0 C23H23F3N40,5 %sN

CCN1C(=CC=C1C1=CC=C(C=C1)5(C)(=0)=0)C(=0)NC1=CC=C(C=C1)5(.0)(=0)N1CCOCC1 CmH,N30652 0 r---\\\O

CCN1C(=CC=C1C1=CC=C(C=C1)5(C)=0)C(=0)NC1=CC=C(C=C1)5(=0)(.0)N1CCOCC1 C24577N305S, (OD
N
\ /....0 -0=ONC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1)C1=NN(C2=C1CCCC2)C1=CC=CC=C1 NH

N /
\ I
N
C,41-126N4 = O
F
/N
N

\

518 N-0001377 FC1=CC=C(C=C 1) N
1N=C(C(.0)NC2=CC=C(C=C2)9(=0)(=0)N2CCOCC2)C2=C 1CCC2 NH
0.....-----õs -----I
N
Cf_81),S

519 o/ \ II I 0 N-0001380 COC(=0)19C1=CC=C2N(C)C(=CC2=C1)C(=0)NC1=CC=C(C=C1)5(.0)(=-0)N1CCOCC1 N¨S H N
\ __________ / 11 /

C1-124N40,5 0 0 X,# h0 ___________ 0 / /Niz 520 / \ II N-0001381 CN(C)5(=OR=0)NC1=CC=C2N(C)C(=CC2=C1)C(gANC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 0 N¨S H N
\ __________ / 11 /

C0,6150652 521 0/ \ II
N¨S . NH N CI N-0001382 CN1C(=CC2=CC=C(CI)C=C12)C(=0)NC1=CC=C(C=C1)5(.0)(.0)N1CCOCC1 CmHzon N3045 .
=

522 __ o/ = N-0001383 CN
1C(=CC2=CC(OCC3-CC-CC-C3)-CC-C12)C(.0)NC1=CC=C(C=C1)5(=0)(.0)N 1CCOCC 1 N¨S NH N
II

C,H,N30,5 523 0 N¨S 411 NH 5-0001384 CN1C(=CC2=CC=C(C=C12)C(C)(C)0)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 ____ / II

CDH,N30,5 0 r \ 0 NN.
*

CC1=C(SC(=N1)C1=CC=CC=C1)C(.0)NC1=CC=C(C=C1)5(=O)(=0)N1CCOCC1 \ 0 S
C,,821N30452 *0 "INricsiN

CC1=C(N=C(51)C1=CC=CC=C1)C(=0)NC1=CC=C(C=C1)5(=O)(=0)N1CCOCC1 ¨N
OnFi2IN30452 0=CiNC1=CC=C(C=C1)5(=OH.0)N1CCOCC1)C1=NN(CC2=CC=CC=C2)C2=C1CCC2 N \ I
C,41-126N4045 \
o 0=C(NC1=CC=C(C=C1)5(.0)(=0)N1CCOCC1)C1=C2CCCC2=NN1CC1=CC=CC=C1 HN
ft C24Hz6No045 * NH

CC1=C(C=NN1C1=CC=C(C=CNC(F)(F)F)C(=0)NC1=CC=C(NS(C)(=0)=0)C=C1 N N
\N¨ 0 C1,1117F3N4035 0Sr H) \

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(.0)NCI=CC=C2N(CCC2=C1)S(C)(=0)=0 CHFNOS
\Si/
o /1\7A-IN

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(=0)NC1=CC,C(N5(=0)(=0)N2CCOCC2)C=C1 N
\ 0 N¨

C,2H,2F3Ns04S
CI

531 o/ II 9-0001392 CN1C2=CC=CC=C2C(CI)=C1C(=0)NC1=CC=C(C=C1)5(=0)(.0)N1CCOCC1 N¨S NH

532 o/
N¨S NH N-0001396 COC1=C2C=C(N(C)C2=CC=C1)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 ____ / I I

C2,1-1N3055 OH

533 o/ II = \
N¨S NH N-0001397 CC(0)C1=CC=C2C=C(N(C)C2=C1)C(.-0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 II

C221-12,N30,5 =
N¨S H N 0 II ./N N-0001398 CN1C(=CC2=CC=C(C=C12)C(=0)0C(C)(C)C)C(=0)NC1=CC=C(C=C1)5(=0)(.0)N1CCOCC1 II
535 0 N¨$ H N N-0001398 CN1C(=CC2=CC=C(C=C12)C(=0)0C(C)(C)C)C(=0)NC1=CC=0C=C1)5(=0)(=0)N1CCOCC1 \A' C2,H2,N3065 N¨S =

CN1C(=CC2=CC=C(C=C12)C(C)=0)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 II

I I

CN(C(=0)C1=C(C)N(N=C1)C1=CC-,C(C=C1)C(F)(F)F)C1=CC=C(C=C1)C4N
Cr C201-1,5F3N40 CC1=C(C=NN1C1=CC=C(C.C1)C(F)(F)F)C(=0)NC1=CC=C2NC=CC2=C1 C20HlsF,N40 HN

COC1=CC=C(NC(=0)C2=C(C)N(N=C2)C2=CC=C(C=C2)C(F)(F)F)C=C10C
N¨N

COC1=CC=C(N0=0)C2=C(C)N(N=C2)C2=CC=C(C=C2)C(F)(F)F)C=C1OC
N¨N
= F

541 / = \
0 N¨S=

NH

CN1C(=CC2=CC(=CC=C12)C(F)(F)F)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 II

OH

542 / II = \ N-0001404 C N
1C(=CC2=CC=C(CO)C=C12)C(=0)NC1=CC=C(C=C1)5(.0)(=0)N 1CCOCC 1 0 N-S=
NH
II

CO2,613055 0 'NF
543 / \ II 4-0001405 CN1CKC2=CC=C(OC(F)(F)F)C=C12)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 0 N-S=

NH

C2,F1,0F,N3055 544 N ____ HN N-0001407 CCN1C(=CC=C1C1=CNN=C1)0=0)NC1=CC=C(C=C1)5(.0)(.0)N1CCOCC1 H
C20HN,O,S

HN = S

CCN1C(=CC=C1C1=CC=C2C=CNC2=C1)0=0)NC1=CC=C(C.C1)6(=0)(=0)N1CCOCC1 N
NH

16(=CC=C1C1=C2C=CNC2=CC=C1)C(.0)NC1=CC=C(C=C1)5(=0)( =0) N1CCOCC1 \ C>
C,51-126N,045 110=CC=C1C1=CC2=CC=CC=C2N1C(.0)0C(C)(C)C)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCO
NH
0, 0/ %0 N, i/C3 Oil 0 0 548 N-0001411 LC(=CC=C1C1,-CN(C(=0)0C(C)(C)C)C2=CC=CC=C12)C(=0)NC1=CC=C(C=C1)5(.0)(=0)N1CC( cc 0\

0 \
\N 0 :CN1C(=CC=C1C1=CC=C(C=C1)5(=0)(=0)N(C)C)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC:

=
0 r 0 CCN1C(=CC=C1C1=CC=CN=C1)0=0)NC1=CC=C(C7C1)5(=0)(=0)N1CCOCC1 N

\ N
/

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(=0)NC1=CC=C2C=CNC2=C1 C20H,sF,N40 $

\N

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(70)NC1=CC=C20C0C2=C1 C194,413N303 ____ \ 0 553 0/ \NJ 11 NH OH

CN1C(=CC2=CC=C(C=C12)C(0)=0)C(.0)NC1=CC=C(C=C1)5(.0)(=0)N1CCOCC1 C,1HõN3065 0 r\O

554 Br HN N-0001417 CC(C)C1=C(C=NN1C1=CC=C(Br)C=C1)C(70)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 N
\N¨ 0 CHBrN404S

CCN1C(=CC=C1C1=CN=CN=C1)C(.0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 N
N
C211-1,3N,045 0\\O
HN W \\ 556 N N-0001424 CCN1C(=CC=C1C1=CN=C(C)N=C1)C(=0)NC1=CC=C(C=C1)5(=0)(70)N1CCOCC1 N /
C221-12,N,04S

o r\o 557 0 Hhl 0 N-0001425 CCN1C(=CC=C1C1=CC,-C(OC)N=C1)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 Nrko =
C231-126N40,5 N

NH

= N-0001426 CCN1C(=CC=C1C1=CN=C2C=CC=CC2=C1)C(=0)NC1=CC=C(C=C1)5(.0)(.0)N1CCOCC1 =

CmH26N,045 =====,, N

NH

= N-0001427 CCN1C(=CC=C1C1=CC=C2N=CC=CC2=C1)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 NH
NN

CC1=NN(C(C)=C1C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1)C1=CC=C(C=C180C(F)(F)F
Br C,31-122BrF3N4045 OH ____________________________________________________________________ 561 / __ II N-0001429 CN1C(=CC2=C(0)C=CC=C12)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 0 N¨S NH
II

C20H21N30,S

562 0/ \
N¨S H N N-0001430 CN1C(=CC2r.CC=C(C=C12)0=0)NC1CC1)C(=0)NC1=CC=C(C=C1)5(.0)(=0)N1CCOCC1 C241-12614,0,5 NH

CC1=C(C=C2C=CC=CC2=N1)C(=0)NC1=CC=C(C=C1)5(=0)(.0)N1CCOCC1 C21H2,N,04S

564 0/ \- II IN NS= H N-0001432 CN1C(=CC2=CC=C(C=C12)C(N)=0)C(=0)NC1=CC=C(C=C1)5(.0)(.0)N1CCOCC1 II

C21H2,N40s5 NH

CCCN1C=C(C(=0)NC2=CC=C(C=C2)5(=0)(=0)N2CC0CC2)C2=CC=CC=C12 O.
co: 0.4)N
Br ____________________________________________________________________ 566 / __ II N-0001434 CN1C(=CC2=CC=CC(Br)=C12)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 0 N¨S NH
II

C0H20BrN3045 567 0 HN 9-0001435 CC(C)C1=C(C=N
N1C1=CC=CC=C1)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 N N
\N 0 C231-126N,045 0 \ 0 _______________________________________ OH *568 HN N-0001436 C0C)C1=0C=NN1C1=CC=C(C=C1)C(C)(C)0)C(.0)NC1=CC=0C=C1)5(=0)(=0)N1CCOCC1 N
\N 0 C26113,N40s5 07--) NH

CC1=NN(0C)=C1C(=0)NC1=CC=C(C=C1)5(.0)(=0)N1CCOCC1)C1=CC=C(C=C1)C(F)(F)F
C2,H,3F3N40,5 /1),..01N N-0001438 ,C(C=NN1C1-,CC=C(C=COC( F)F)C(-0)NC1-CC(C2-CC-CC-C2)-C(C-C1C)5(-0)(-0)N1CC( N \
N¨

cj C2,H,F3N,O,S
HN =

S

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(=0)NC1=CC=C(SC2=CC=CC=C2)C=C1 Njskr( \ 0 N¨

C24H,,,F3N305 HN

CCI=C(C=NN1C1=CC=C(C=C1)C(F)(9F)0=0)NC1=CC=0C=C1)5(=0)C1=CC=CC=C1 N N
CHFNOS
\N¨ 0 F S\\

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)00=0)NC1=CC=C(C=C1)5(=0)(=0)C1=CC=CC=C1 N

/F

574 0 N¨S = NH 0 = N-0001442 CN1C(=CC2=CC3=C(00 003)C=C12)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 II

C211-1F2N,0,5 0 \ 0 HN
575 OHN __ 0 N-0001449 CC(C)C1=C(C=N N1C1=CC=CC=C1CO)C(-0) NC1-CC-C(C-C1)5(-0)(-0)N1CCOCC1 N
N
CzaH28N4055 HO
576 HN 0 N-0001450 CC(C)C1=C(C=N
N1C1=CC=C(CO)C=C1)C(=0)NC1=CC--C(C=C1)5(.0)(.0)N1CCOCC1 N N
\N¨ 0 CCN1C(=CC=C1C1=CC=C(N=C1)C(F)(F)00=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 F N
C23H23F3N40,S
(O.¨) 578 N-0001452 0=0 NC 1=CC=C(C=C1)5(=0 )(=0)N1CCOCC1)C1=C2CCCCC2=NN 1CC1-CC-CC-C1 HN
C2sH204045 0=C(NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1)C1=NN(CC2=CC=CC=C2)C2=C1CCCC2 /
\N
C20-1.1'4045 0=C(NC1=CC=C(C=C1)5(=0)(.0)N1CCOCC1)C1=NN(CC2=CC=CC=C2)C2=C1CCCC2 N I
C2sHz8N4045 NH

CCN1C(=CC=C1C1=CC2=CC=CC=C2N1)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 0, NV \

0, 0 CCNIC(CC=C1C1=CNC2=CC=CC=C12)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 N
CõHõN,04S
0 re \\O

CCN1C(=CC=C1C1=CC=C(C)N=C1)q=0)NC1=CC=C(C=C1)5(.0)(.0)N1CCOCC1 Nyc C,31-126N4045 0 \ 0 CCN1C(=CC=C1C1=CC=NC(C)=C1)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 NNir.õõko 0 \ 0 585 HN S%0 N-0001458 CCNIC(=CC=C1C1=CC=NC(OC)=C1)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 N.s.7r0 C231-I.N40,5 CCN1C=C(C=N1)C1=CC=C(N1CC)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 O
0 =--S =0 cuE,27N,04s =

p o ON/
iNN/N

7 o/¨\N-A = N N-0001461 N1C(=CC2=CC(NS(=0)(=0)N3CCOCC3)=CC.,C12)C(.0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC

Cz46z9950752 CC1=C(N=C2C=CC=CC2=C1)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 coo3045 ¨1 CN1C(=CC2=CC(C1)=CC=C12)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCC(F)(F)CC1 II

C2,H20CIF2N3035 590 Br HN S%() N-0001464 CC(C)C1=C(C=NN1C1=CC=C(Br)C=C1)C(=0)NC1=CC=C(C,C1)5(=0)(=0)N1CCC(F)(F)CC1 =
N

N¨

C,41-1,58rF,N403S
0 \ 0 NJ

* 0 N1C(=CC=C1C1=CC=C(C=C1)C#N)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 C24NõN40.5 o 592 9-0001470 CCC1-CC2-NC(C)-C(N2C-C1)C(-0)NC1-CC-C(C-C1)5(-0)(-0)N1CCOCC1 CmHzeN404S

o 1 593 / \ II . N-0001471 7.(=CC2=CC(N5(=ON=0)C3=CC=C(C)C=C3)=CC=C12)C(=0)NC1=CC=C(C=C1)5(.0)(=0)N1CCC
0 N¨s H N

C271-I zeN40652 0 kl ____ 0 \ / / N
594 / \ II # 9-0001472 CNC1=CC=C2N(C)C(=CC2=C1)C(,.0)NC1=CC=C(C=C1)5(.-0)(=0)N1CCOCC1 0 N¨S NH N
II /

CH24N,OaS
0 ) / / I
\ I I
595 0 N¨S NH N"----S\--.N."..' N-0001473 CN14,CC2=CC=CN=C12)C(.0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 /

C191-120N40.5 CI
) .....,,,, N

I / N

CN1C(=CC2=C(CON=CC=C12)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 596 \ II
----- '',....õ7.-", 0 N¨S NH

C,91-100 N4045 597 I \ II ' It, ,/
N¨S H N Nõ," 9-0001475 CC(C)NCC1=CC=C2C=C(N(C)C2=C1)C(=0)NC1=CC=C(C=C1)5(=0)(.0)N1CCOCC1 C241-130N40,5 \

NO
\
/
598 o/ \ II \ N-0001476 CN1C(=CC2=CC=C(CN3CCCC3)C=C12)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 N¨S H
\ __ II

\

599 o/ \ N,,N.
II . \ 9-0001477 CN1C(=CC2=CC=C(CN3CCN(C)CC3)C=C12)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 N¨S NH ,õõ,./

Cz6H33N,04S

(-D
\S"
OZ

CCN1C(=CC=C1C1=C2N=CC=CC2=CC=C1)C(=0)NC1=CC=C(C=C1)8(=0)(=0)N1CCOCC1 rN

0 r\O

CCN1C(=CC=C1C1=CSC=C1)C(=0)NC1r-CC=C(C=C1)5(.0)(.0)N1CCOCC1 S

0 \ 0 \\

CCN1C(=CC=C1C1=CC=C(COM)C=C1)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 =

C2sHz6N404S
=
0 r\O
= 0 :(C)C1=C(C=NN1C1=CC=C(C=C1)q=0)0C(C)(C)C)C(=0)NC1=CC=C(C=C1)5(--,0)(=.0)N1CCOC

N

CzaHuN40eS

04\
I \ N

604 N-0001482 ..
CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(.0)NC1=CC=C2C=C5(.0)(.0)C2=C1 C201-1,4F3N303S

NcHN 0 CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(.0)NC1=CC=C(0C2=CC=C(C)C=C2)C=C1 \N¨

C251-12.F3N302 HN \
04\ N) CC1=C(C=NN1C1=CC=C(C=C1)C( F)(F)F)C(=0)NC1=CC=C2C( =0)N S(=0)(=0)C2=C1 Col-113F3N4045 0 ../."\./OH

CN1C(=CC2=CC=C(CNCCO)C=C12)C(=0)NC1=CC=C(C=C1)5(.0)(.0)N10000C1 C,31-1,eN40,5 o/

HN
HNN

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(9F)C(=0)NC1=CC=C2C(=C1)C(=0)N52(=0)=0 CF1,3F3N40,5 \\N
HN

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)00=0)NC1=CC=C(C=C1)C1=CN=N51 N N
\N¨ 0 C20Hl4F3N,05 CN1C(=CC2=CC=CC(C(=0)N3CCCC3)=C12)C(=0)NC1=CC=C(C7C1)5(=0)(=0)N1CCOCC1 /
o II
N¨S NH

o \ NC N-0001496 CCN1C(C)=C(130C(C)=C1C(.0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 Br C,91-124BrN3045 612 HN N-0001497 CCN1C(-CC-C1C1-CC-C(C-C1)Cl-CC-CC-C1)C(-0)NC1-CC-C(C-C1)5(-0)(-0)N1CCOCC1 C29112,N,O,S

CCOC(.0)C1=CC=C(C=C1)C1=CC=C(N1CC)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 NH

C

N N-0001500 CCN1C( C-C C2-CC-CC-C2)-CC-C1C(-0)NC1-CC-0C-C1)5(-0)(-0)N1CCOCC1 C2sH2,N,04S

=
µ,.1,1\) 615 0 r HN

CCN1C(=CC=C1C1=CC(OC)=CC=ClOC)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 HN

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(=0)NC1=CC=C(CN2CCOCC2)C=C1 N
\N¨ 0 617 0/ \
N¨S
/ = NH N-0001504 CCN1C(=CC2=CC(C1)=CC=C12)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 I I

C20-122CIN,045 ,N N-0001505 CN1C(=CC2=C(N=CC=C12)N1CCOCC1)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 o/ II
N¨S NH

C231-12,N,055 0 Br / II
\619 o NH

BrC1=CC=C2N(CC3CC3)C(=CC2=C1)0=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 C1-1248rN3045 Br N
NH
620 N-0001507 BrC1=CN=C(NC2=CC=C(C=C2)5(=0)(,-0)N2CC0CC2)N=C1 cµ
N %
6,41-18rN4038 0 r NN/

C1=C(C=NN1C1=CC=C(C=C1)C(F)(F)9C(=0)NC1=CC=C2C=C(C=CC2=C1)5(=0)(=0)N1CCOCC
C26F123F3,1404S
HN

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(=0)NC1=CC=C(CC2CCOCC2)C=C1 N N

N¨

C241-1,4F3N302 N¨N
N
F
F H

CC1=C1C=NN1C1=CC=C(C=Cl)C(F)(F)FICI=OINC1=CC=C(C=C1)C1=NNN=N1 F
N N
\ 0 N¨

C,91114F3N,0 624 o/ N¨S \ II
. NH N"-----'\,7N N-0001513 CN1C(=CC2=CC(CI)=NC=C12)C(=O)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 i C,91-11,CIN4045 =
0 r\O
t....... N\,.......) * \\O
HN
, N..
625 \ 0 N-0001514 CC1=CINICC2-CC-CC-C2IN-ClICI-OINC1-CC-C(C-C1)5(-0)(-0)N1CCOCC1 N¨N , =
Cul-10404S
* Br t.........N.N... j %

HN
, N
626 \ 0 N-0001515 BrC1=C(NICC2=CC=CC=C2IN=C1)CI=OINC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 N¨N

C2,H2113rN4045 07--) 0 V.........../N-..,./ 0 N \ N-0001516 CC1=CN(CC2-,CC=CC=C2)N=C1C(=O)NC1=CC=C(C=C1)5(=O)(=OIN1CCOCC1 NN
=
C2,1-1,4N4045 I 0 \
tl \ N-0001517 BrC1=CN(CC2=CC=CC=C2)N=C1C(.0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 N¨N
CO2,BrN,045 \

629 / \ 11 = \N 1 N-0001518 CN1C(=CC2=CC=C(CNCC3=CC=CN=C3)C=C12)C(=0)NC1=CC=C(C=C1)5(=O)(=0)N1CCOCC1 NZ
0 N¨S H

H

630 o/ \ II = 0 N-0001519 CN1C(=CC2=CC(NC(=0)00CHC)C)=CC=C12)0=0)NC1=CC=C(C=C1)5(=OH=0)N1CCOCC1 N¨S NH N
\ ___ / II /

CõH3oN,06S

631 o/ \ II = 0 N-0001519 CN10=CC2=CC(NC(=0)0C(CHC)C)=CC=C12)C(=0)NC1=CC=C(C=C1)5(.0)(=0)N1CCOCC1 N¨S NH N
\ ___ / II /

C2,H30N40,S
111 =
\N

CN1C(=CC2=CC=CC(,1)=C12)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 o/ \ II \
N¨S NH

C2,H,0Nõ04S
I
) (.õ.... N

/ \ II
633 0 N¨S = NH N N-0001521 CN1C(=CC2=CN=CC=C12)C(.0)NC1=-CC--,C(Cr-.C1)5(=O)(=0)N1CCOCC1 CoH,0N4045 634 /\
\ II / N-0001522 C(CHC)0C(=0)C1=CC=C2N(CC3CC3)0=CC2=C1)C(=CHNC1=CC=C(C=C1)6(=OH=0)N1CCOCC
0 N¨S H N
\ II
V¨I

C281-10,065 0 Br o/ N¨S \ II
NH N
635 \ / II N-0001523 FC(FHF)CN1C(=CC2=C0Br)=CC=C12)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 F F
C211-119BrF,N,045 F
.7 636 F )y-.. --...H
N N-0001526 CC1=C(C=NN1C1=CC=C(C=C1)C(F)( FMC(=0)NC1=CC=C2C=CC=NC2=C1 N
F
N
C2,HõF3N,0 N

CC1=C(C=NN1C1=CC=C(C=C1)C(F)IFIFIC(=0)NC1=CC=C2C=CN=CC2=C1 \N
C2111oF36140 HNO

COC1=CC=CINC(=0)C2=C(C)N(N=C2)C2=CC=C(C=C2)C(F)(F)FIC=N1 N¨N

F

"0 \ N
/

CC1=C(C=NN1C1=CC=C(C=Cl)C(F)(F)00=0)NC1=CC=C20C(F)(F)OC2=C1 CI,HuF561303 Fx CC1=C(C=NN1C1=CC=C(C=Cl)C(F)(F)FIC(.0)NC1=CC=C20C(F)(F)0C2=C1 C,gH,2F561303 FN
FA 0 =

/
, CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)9C(.0)NC1=CC=C20C(F)(F)0C2=C1 F F
C,9H11F5N303 0 "\\O

CC1=C(C=NN1C1=CC=NC=C1)C(=0)NC1=CC=C(C=C1)5(.0)(=0)N1CCOCC1 N N
\N- 0 C201-12,N504S
*

H
/N

CC1=C(C=NN1C1=CC=NC=C1)0=0)NC1=CC=C2000C2=C1 F,v0 0 F/Z\

CC1=C(C=NN1C1=CC=NC=C1)C(.,0)NC1=CC=C20C(F)(F)0C2=C1 645 Ar-N N-0001535 CC1=C(C=NN1C1=CC=NC=C1)C(=0)NC1=CC=C2N=CC=CC2=C1 \
C19111,N,0 HN

CN1C(=CC2=CC=C(130C=C12)C(.0)NC1=CC=C2N=CC=CC2=C1 Br HN

CN1C(=CC2=CC=C(Br)C=C12)0=0)NC1=CC=C2C=CC=NC2=C1 N \
Br C,91-1,4BrN,0 CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)00=0)NC1=CC=C2N=CC=CC2=C1 Cz,N,sF3(140 N, 649 F N, N-0001539 CC1=C(C=NN1C1=CC=C(C=C1)C(F)(99C(=0)NC1=CC=C2N=CC=NC2=C1 C,oHõF3N,0 650 o/ II
N¨S NH N N-0001540 CN1C =CC2=CC
=CC=C12 C1=NN=C C 01 C =0 NC1=CC=C C=C1 =0 =0 N1CCOCC1 ( ( ) ( ) ( ) ( I
( )( ) CõHõN,055 N

NH

CC1=C(C=NN1C1=CN=C2C=CC=CC2=C1)C(=0)NC1=CC=C(C=C1)5(=O)(=0)N1CCOCC1 C,H23N,045 0 Br II
652 0 N¨S 411 NH N-0001823 CC(C)N1C(=CC2=CC(130=CC=C12)C(--,0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 C2,HBrN,045 HOQ

CN1C(=CC2=CC=C(3r)C=C12)C(=0)NC1=CC=C2C=CN=CC2=C1 N
Br C191-1,48rN30 HN
654 0 N-0001825 CN1C(=CC2=CC=C(Br)C=C12)C(=-0)NC1=CC,-C2C=NC=CC2=C1 N
Br CI,HBrN30 HN

CN1C(=CC2=CC=C(Br)C=C12)C(=0)NC1=CC=C2N=CC=NC2=C1 N
Br C181-1,38rN40 656 / ______________________ N-0001827 CN1C(=CC2=CC=C(C=C12)C1=CN-,C(C)51)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 C,4H24N40452 CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(=0)NC1=CC=C2C=NC=CC2,-C1 C21111.F.N40 N

CC1=C(C=NN1C1=CC=NC=C1)C(=0)NC1=CC=C2N=CC=NC2=C1 C101,4N60 0 0 Br COC1=CC=CiNC(=0)C2=CC3=CC=C(Br)C=C3N2C)C=C10C
0 = NH
C,8111713rN203 CC1=C(C=NN1C1=CN=C2C=CC=CC2=C1)C(=0)NC1=CC=C20C0C2=C1 \N

)C/\

CC1=C(C=NN1C1=CN=C2C=CC=CC2=CHC(=0)NC1=CC=C20C(F)(00C2=C1 \

662 \ Nr.;-4. N-0001833 CC1=C(C=NN1C1=CN=C2C=CC=CC2=C1)C(=0)NC1=CC=C2N=CC=NC2=C1 663 \ N-0001834 CCI,C(C=NN1C1=CN=C2C=CC=CC2=C1)C(=0)NC1=CC=C2N=CC=CC2=C1 C2,H,N,0 N
N

NH

CC1=C(C=NN1C1=CC=C2N=CC=CC2=C HC(=0)NC1=CC=C(C=CHS(=0)(=0)N 1CCOCC 1 S

C241-123N,045 665 NI-CD__ N N-0001836 CC1=C(C=NN1C1=CC=CN=C1)C(=0)NC1=CC=C2N=CC=CC2=C1 N

N
666 N-0001837 CC1=C(C=NN1C1=CC=CN=C1)C(=0)NC1=CC=C2C=CN=CC2=C1 N
CoHnNs0 667 o/ fl N N-0001838 CC(C)N1C(=CC2=CCKC=C12)C(=0)0C(CHC)C)C(=0)NC1=CC=C(C=C1)5(=OH=0)N1CCOCC1 N¨S

c27.33N30es NH
X N
0 \668 Br N-0001839 CC1=NN(C=C1C(=0)NC1=CC=C(C=C1)5(=O)(=0)N1CCOCC1)C1=CC=C(C=C1B0C(F)(OF
C2,H20BrF,N,045 \
669 0 N¨SII = NH \ N-0001840 CN1C(=CC2=CC(=CC=C12)C1=NN=C(C)S1)C(=0)NC1=CC=C(C=C1)5(=OH=0)N1CCOCC1 II

II \
670 0 N¨S = NH \ N-0001840 CN1C(=CC2=CC(=CC=C12)C1=NN=C(C)51)0=0)NC1=CC=C(C=C1)5(=O)(=0)N1CCOCC1 C231-1,314,045, CC1=C(C=NN1C1=CC=C2N=CC=CC2=C1)C(=0)NC1=CC=C20C0C2=C1 N

F.v F /".

CC1=C(C=NN1C1=CC=C2N=CC=CC2=C1)C(=0)NC1=CC=C20C(F)(F)0C2=C1 \ N
CzIHNF2N403 673 N )0 ". N-0001845 CC1=C(C=NN1C1=CC=C2N=CC=CC2=C1)C(=0)NC1=CC=C2N=CC=NC2=C1 CC1=C(C=NN1C1=CC=C2N=CC=CC2=C1)C(=0)NC1=CC=C2N=CC=CC2=C1 CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(=0)NC1=CC=C(OC(F)F)C(OC(F)F)=C1 HN
N N

N-C20H,,F,N30, F

CC1=C(C=NN1C1=CC=NC=C1)C(=0)NC1=CC=C(OC(F)F)C(OC(F)F)=C1 N
\ 0 N-C.H14F4N403 N

CC1=C(C=NN1C1=CN=C2C=CC=CC2=C1)C(=0)NC1=CC=C(OC(F)F)C(OC(F)F)=C1 OF

II

N¨S NH

CN1C(=CC2=CC(F)=C(F)C=C12)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 C0H.F2N3045 07---) 0 NH
NN

CC1=NN(C=C1C(=0)NCI,CC=C(C=C1)5(.0)(=0)N1CCOCC1)C1=CC=C(C=C1)C(F)(F)F

(0-D

BrC1=CC=C2N(CCN3CCOCC3)C(=CC2=C1)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 o/
N¨S NH Br II

C2,Hz9BrN4055 HN
OO
681 Br N-0001853 BrC1=CC=C2N(CCN3CCOCC3) C(=CC2=C1)C(=0)NC1=CC=C2N=CC=CC2=C1 COBEir N402 COC1=CC=C(NC(=0)C2=CC3=CC(Br)=CC=C3N2CCN2CCOCC2)C=C10C
/ NH Br =
C2 3H ',Br N304 CC1=C(C=NN1C1=CC=C2N=CC=CC2=C1)C(=0)NC1=CC=C(OC(F )F )C(OC(F)F)r.C1 =
CõHI6F4N403 F-+

HN

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(=0)NC1=CC=C(OC(F)(F)F)C=C1 N

N-C19HuF6N302 F

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(=0)NC1=CC=CC(OC(F)F)=C1 HN
N N
\N¨ 0 C,,H14F,N304 HN
686 =N-0001858 CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(.0)NC1=CC=C(OC(F)F)C=C1 N N
\N¨ 0 C1914,4F1N302 Br ft CN1C(=CC2=CC=C(Br)C=C12)C(=0)NC1=C2C=CC=NC2=CC=C1 C01-1,4BrN30 HN

CN1C(=CC2=CC=C(Br)C=C12)0=0)NC1=CN=C2C=CC-CC2-C1 Ns\
Br CoH"BrN30 HN

CN1C(=CC2=CC=C(Br)C=C12)C(=0)NC1=CC2=CC=C(C)N=C2C=C1 N \
Br C20H,,Br 830 690 F NN N-0001865 CC1-,C(C=NN1C1-,CC=C(C=C1)C(F)(F)F)C(=0)NC1=CN=C2C=CC=CC2,C1 C21HõF3N,0 F
0 r\O
691 F \ N N-0001866 :(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(.0)N(CC1=CC=C(F)C=C1)C1=CC=C(C=C1)5(=0)(=0)N1C( F =

F Nkt'l \ 0 N-C29Hze.F4N4045 0 r\O
S
%

692 (...)..,.... HN 9-0001868 CC1=C(C=NN1C1=CC=CN=C1)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 \ / N N
\N- 0 1..õ....N.\\.) %

693 a HN N-0001868 CC1=C(C=NN1C1=CC=CN=C1)C(=0)NC1=CC=C(C=C1)5(.0)(=0)N1CCOCC1 \N- 0 <o 0 ______________________________________________________ 694 b N-0001869 CC1=C(C=NN1C1=CC=CN=C1)C(=0)NC1=CC=C20C0C2=C1 ..--._ C1,1-114N403 F\s/

F/\0 N)L`---"---N

695 Z--------N N-0001870 CC1=C(C=NN
1C1=CC=CN=C1)C(=0)NC1=CC=C20C(F)( F)0C2=C 1 b CoHN,03 N, N
N' 696 ....1,1 N-0001871 CC1=C(C=NN1C1=CC=CN=C1)C(=0)NC1=CC=C2N=CC=NC2=C1 11 \ / N
\ .....--N
ClaH.N,0 CC1=C(C=NN1C1=CC=CN=C1)C(=0)NC1=CC=C2C=CC=NC2.---C1 N
C,q1-115N,0 CC1=C(C=NN1C1=CC=CN=C1)C(=0)NC1=CC=C2C,NCnCC2,-C1 C,q1-1,5N50 COC1=CC(OC)=CC(NC(.0)C2=C(C)N(8=C2)C2=CC=C(C=C2)C(F)(F)F)=C1 N -N
oF
C2061eF3N303 ;cc N
700 \ F N-0001875 CN1N=CC2=CC(NC(=0)C3=C(C)N(N=C3)C3=CC=C(C=C3)C(F)(F)F)=CC=C12 C20hl.F3N50 H)N

CC1=C(C=NN1C1=CC7C(C=C1)C(F)(F)F)C(=0)NC1=CC=C2N=COC2=C1 =

COC1=CC=C(NO=0)C2=OC)N(N,C2)C2=CC=C(C=C2)C(F)(99C=C1C
N-N

OH
HN

COC1=CC=ONC(.0)C2=C(C)N(N=C2)C2=CC=C(C=C2)C(F)(F)F)C=C10 N-N
CI,H16F3N303 0, )r1 N-0001879 CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(.0)NC1=CC=C2OCCOC2=C1 152 =
SN
HN

CC1=NN=C(N0=0)C2=C(C)N (N=C2)C2=CC=C(C=C2)C(F )(9)6)51 FF
C1,11F,N,OS
F

COC1=CC=0N0=0)C2=0C)N(N=C2)C7=CC=C(C=C2)C(F)(F)F)C=C1F
N-N

/N\
Fx/

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(09)0=0)NC1=CC=CC(00F F)F)=C1 \ 0 N-C,91-113F6N302 CN(C)C1=CC=C(NC(=0)C2=C(C)N(N=C2)C2=CC=C(C=C2)C(F)(F)F)C=C1 N¨N
Cz0ll,9F3N40 CCC1=C(C=NN1C1=CC=C(C)C=C1)C(=0)NC1=CC=C(OC)C(OC)=C1 N N
\N 0 C2,H,3N303 CC1=C(C=NN1C1=CC=C(C=C1)C(F)(9F)C(=0)NC1=CC=C2C=CC=CC2=N1 C2111 õF3N40 0 Br o/ II
N¨S NH
II

711 cr.0 N-0001886 CC(C)(00C(,0)CN1C(=CC2=CC(130=CC=C12)C(.0)NC1=CC.-C(C=C1)5(=0)(=0)N1CCOCC1 0\z/
/\
C2,F12aBrN,065 = N¨S NH N-0001887 CN1C(=CC2=NC=CC=C12)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 CF1,0N4045 CN1C(=CC2=CC(=CC=C12)C#N)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 O N¨S

= H20N40aS

714 0/ \ II
N¨S NH N-0001889 CN1C(=CC2=CC(F)=CC(H=C12)C(=0)NC1=CC=C(C=CH5(=0)(=0)N1CCOCC1 C2oH,,F2N,045 F F

CN1C(=CC2=CC(=CC=C12)C(F)(6)00=0)NC1=CC=C2OC(F)(6)0C2=C1 Ev F

HN

CC1=C(C=NN1C1=CC=C(C=CHC(F)(F)HC(.0)NC1=CN=CN=C1 N
\ 0 N¨

N N

CC1=CIC=NN1C1=CC=C(C=C1)C(F)(F)F)C(.0)NC1=CN=CC-,N1 N N
\ 0 Cl6H12F3N,0 HNo COC1=CON0=0)C2=C(C)N(N=C2)C2=CC=C(C=C2)C1F)(9F)=CC=C1F
N¨N
F F

/N_ N
#719 N-0001894 CN1N=CC=C1NC(=0)C1=C(C)N(N=CHC1=CC=C(C=CHC(F)(F)F

C161-1,4F3N50 "INT
720 N-0001895 CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(=0)NC1=CSC=C1 N N
\ 0 =
N¨

C,614,2F,N3OS
721 N-0001896 CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(=0)NC1=CC=NC=C1 N N
\ 0 N _______________ ¨

C,71-113F31140 /I

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(90C(=0)NC1=CC=C(CCUN)C=C1 N
\N¨ 0 C201-11,F3N40 F.>(c) CCC1=C(C=NN1C1=CC=C(C)C=C1)C(=0)NC1=CC=C20C(F)(00C2=C1 \

CCC1=C(C=NN1C1=CC=C(C)C=C1)C(.0)NC1=CC=C20C(F)(00C2=C1 C,04,7F2N303 Th CCC1=C(C=NN1C1=CC=C(C)C=C1)C(=0)NC1=CC=C2C=NC=CC2=C1 C,2H20N40 CCC1=C(C=NN1C1=CC=C(C)C=C1)C(=0)NC1=CC=C2C=NC=CC2=C1 C,H,01,140 FE

N

4N1C1=CC=C(C=C1)C(F)(F)F)C(=0)NC1=CN(C(=0)C2=C(C)N(N=C2)C2=CC=C(C=C2)C(F)(F)F8 HN
N \

Cz9H20F,NHN
,03 COC1=CC=C(NC(=0)C2=C(C)N(N=C2)C2=CC=C(C=C2)C( F)( F)F)C(OC)=C 1 N -N
C2.H.F,N,03 N

CC1=C(C=NN1C1=CC=0C=C1)C(F)(990=0)NC1=CC2=N NN =C2C=C1 F F

COC1=CC=CC(N0=0)C2=C(C)N(N.C2)C2-,CC=C(C=C2)C(F)(F)F)=C1 N-N
C,0-116F3N307 I
N/N

HN

CN1C=C(NC(.0)C2=C(C)N(N=C2)C2=CC=C(C=C2)C(F)(FMC=N1 C,,H,4F3N30 HN

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(.0)NC1=CC=C(C=C1)CUN
N N
\N- 0 0,\\N
HN

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)9C(=0)NC1=CC=CN=C1 N
\ 0 N-C,,H13F3N40 CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(=0)NC1-CC-CC(=C1)C#N
HN
NV-NNyc \ 0 N-=

0 Br N¨S

o/ II
NH
735 \ ______________________ N-0001908 OC(=0)CN1C(=CC2=CC(80=CC=C12)C(.0)NC1=CC=C(C=C1)S(=0)(=0)N1CCOCC1 cr.0 HO
C,H20BrN,065 Br HN

COC1=CC=C(NC(=0)C2=C(C)N(N=C2)C2=CC=C(C=C2)C(F)(F)F)C=C1Br 7N
N¨N
C191-115BrF3N302 CI
No/N7.0 COCCOC1=CC=C(NC(70)C2=C(C)N(N=C2)C2=CC=C(C=C2)C(F)(F)F)C=C1C1 CH,9C1F3N30, ( 0 \ N
/

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(=0)NC1=CC=C20C=NC2=C1 FFF

N HN

CN1C(NC(=0)C2=C(C)N(N=C2)C2=CC=C(C=C2)C(F)(F)F)=CC2=CC=CC=C12 C2,H17F3N40 CC1=C(C=NN1C1=CC=C(C=Cl)C(F)(99C(=O)NC1=CCIFI=CCIFI=C1 N
\ 0 N¨

C,a1-11,F,N,0 741 / \ II = N-0001919 FC(F)(F)C1=CC=C2NICC3CC3/C(=CC2=CHC(=0)NC1=CC=CIC=C1I5I=OH=OIN1CCOCC1 0 N¨S NH
/ II
Vj0 C2,H24F3N30,5 \II
742 0 N¨S = NH 0-0001920 CN1C(=CC2=CC=CC(C)=C12ICI=OINC1=CC=CIC=C1I5I=OR=0/N1CCOCC1 II

C21H,3N3045 CI

CN1C(=CC2=C(CI)C=C(CI)C=C12)C(.0)NC1=CC=C(C=C1)5(.0)(=O)N1CCOCC1 0 N¨S NH
II

C.1-11,Cl2N3045 744 0 N¨S NH N-0001922 CCC1=CC=C2NICICI=CC2=C1)C(=0)NC1=CC=C(C=C1)6(=0)(=OIN1CCOCC1 II
____ / II

Cul-1N3045 NO

CC1=C(C=NN1C1=CC=C(C=Cl)C(F)(F)F)C(=O)NC1=CC=CC(CO)=C1 N
\ 0 N¨

CI,HIGF3N302 CCOC(=0)CC1=CC.C(NC(.0)C2=CICIN(N=C2)C2=CC=C(C=C2)C(F)(F)FIC=C1 C,A0F,N,03 HN

CC(C)0C1=CC=C(NC(=0)C2=C(C)N(N=C2)C2=CC=C(C=C2)C(F)(F)F)C=C1 N-N
CH20F,N302 FS
N HN

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)9C(=0)NC1CCC(=0)CC1 \ 0 N _______________ C101431,1302 F HN
/1\7.

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(9F)C(=0)NC1CCN(CC1)C1=CC=CC=C1 N
\ 0 N-NN
HN *

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(=0)NC1=CC=C(C=C1)N1C=CN=C1 N N

N-00,6F314,0 \
NN,N
HN

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(.0)NC1=CC=C(C=C1)N1C=CN=C1 N
\N- 0 C201,6F3N,0 HN

CC(C)NC(=0)C1=CC=0N0=0)C2=C(C)N(N=C2)C2=CC=C(C=C2)C(F)(F)F)C=C1 N¨N
C22112,F3N40, F F
* 0 /1\7AI

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(99C(=0)NC1=CC=00CC(F)(F)F)C=C1 N
\ 0 N¨

C201-1,516N302 I \ N-0001931 COC1=CC=C2C=C(NC(=0)C3=C(C)N(N=C3)C3=CC=0C=C3)C(F)(F)F)C=NC2=C1 NH
cnHoF3N40, 0 Br o/ =
N¨S NH
r 755 (0 N-0001932 BrC1=CC=C2N(CC(=0)NC3CC3)C(=CC2=C1)C(=0)NC1=CC=0C=C1)5(=0)(=0)N1CCOCC1 HN
Cm1-12,BrN40,S

HN

756 N-0001933 CN1Cfr-CC2=CO=CC=C12)C(F)(F)00=0)NC1=CC=C2N=CC=NC2=C1 COC1=CC.C(NC(.0)C2=CC3=C0=CC=C3N2C)C(F)(F)F)C=C10C
/0 NH ¨0 CIgH,F,N,03 758 0 N¨S = NH N-0001935 CN1C(=CC2=CC=C(C=C12)C(F)(99C(=0)NC1=CC=C(C=C1)5(.0)(.0)N1CCOCC1 C,11-120F3N30,5 *

CC1=C(C=NN1C1=CC=C(C.C1)C(F)(F)F)C(=O)NC1=CC=C(C=C1)N1C=CC=N1 N
\ 0 N¨

C2IFI.F3N,0 CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(=0)NC1=CC=C2CCC(.0)C2=C1 CnH.F3N302 o FIN

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(=0)NC1=CC=C(OCCN2CCOCC2)C=C1 C24625F,N403 =

N\
762 N-0001939 CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(-0)NC1-CC-C(C-COC1-N N
\ 0 N¨

C2,H,F3N40 CI

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(.0)NC1=CC=C(ClIN)C(C1)=C1 N N
\N¨ 0 CI,F1,2CIF3N40 CI
N

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(.0)NC1=CC=C(CUN)C(C1)=C1 N N
\N¨ 0 C,,H12CIF,N,0 CI

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)FJC(=0)NC1=CC=C(CttN)C(C1)=C1 N N
\N¨ 0 C,,F112CIF3Ny0 CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(=0)NC1=NC=C(CI)S1 \N¨ CI
CH,0CIF,N405 \ II 767 0 N¨S #

CN1C(=CC2=CC=C(C)C(C)=C12)C(.0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 C221,2,N304S

768 o/ II =
N¨S NH 5-0001944 CN1C(=CC2=C(F)C=CC=C12)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCCI
____ / I I

C,0F120FN3045 769 / II =

CC(C)C1=CC(Br)=C2NICIC(=CC2=C1)CI=OINC1=CC=C(C=C1)5(.0)(.0)N1CCOCC1 0 N¨S
I
I
0 Br C231-12eBrN,045 0 Br II
770 0 N¨S # NH N-0001946 CN1C(=CC2=CC(Br)=CC(CI)=C12)C(=0)NC1=CC=C(C=C1)S(=O)(=0)N1CCOCC1 II

C20H,913rCIN,045 OCI
NH

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(9F)C(=0)NC1=CC=C(C[C@HJ2C0C(=0)N2)C=C1 HN
\ 0 N¨

OH

CC1=CIC=NN1C1=CC=C(C=C1)CIFIIFIFIC(=0)NC1=CC=C(CC(0)=0)C=C1 N
\ 0 N¨

C20H,,F,N303 Oke HN

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(-0)NC1-CC-C(C-C1)C(-0)0C(C)(C)C
N N

N¨

C23H22F,N30, CI
Fv0 CC1=CIC=NN1C1=CC=C(C=Cl)C(F)IFIFIC(-.0)NC1=CC2=CIOC(F)(F)02)C=C1C1 C,91-1,,CIF,N303 =

CI
F.V) o =

\

CC1=C(C=NN1C1=CC=C(C=CHC(F)(F)F)C(.0)NC1=CC2=C(OC(F)(902)C=C1C1 HN
776 N-0001951 CC1=C(C=NN1C1=CC=C(C=C1)C(F)(99C(=0)NC1=CC=C(C=CHC#C
N N
\N¨ 0 C20Hl4F3N30 HN
777 N-0001951 CC1=C(C=NN1C1=CC=C(C.-CHC(F)(F)F)Cfr-O)NC1--,CC,C(C,C1)C4C
N N

C2oH.F3N30 ) HN *

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(=0)NC1=CC=C(C=C1)N1C=NC=N1 N X
\N¨ 0 N
779 \ F N-0001953 CN1C=CC2--,CC(NC(----0)C3,--C(C)N(N.C3)C3=CC=C(C=C3)C(F)(F)F)=CC=C12 CHFNO

j\N N-0001954 CN1N=CC2=CC=C(NC(=0)C3=C(C)N(N=C3)C3=CC=C(C=C3)C(F)(F)F)C=C12 NH
N \
C20H,6F3N50 II
781 0 N¨S
Br N-0001955 BrC1=CC=C2C=C(NC2=C1)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 , q,H2OrN3045 782 0 Br N-0001956 CN(C)CCN1C(=CC2=CC=C030C=C12)C(=0)NC1=CC=C(C=C1)9(=0)(=0)N1CCOCC1 o 410, N¨S NH
=
II

C23H27F3rN4045 CI

< I

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(=0)NC1=NC(C0=C2NC=NC2=N1 C,7HI,CIF3N70 II
784 0 N¨S NH N N-0001958 CN1C(=CC2=CC=NC=C12)CI=OINC1=CC=C(C=C1)5(=0)(.0)N1CCOCC1 II

C.H.N4045 o II
N¨S NH
\N-0001959 CN1C(=CC2=CC=CCI=C1201+1(10-B=0)Cfr-OINC1=CC=C(C=C1)5(=0)(=O)N1CCOCC1 C,0E1,,,N4065 II
786 0 N¨S NH 8-0001960 CN1C(=CC2=CC(C1)=CC(C1)=C12)C(.0)NC1=CC=C(C=C1)5(=0)(.0)N1CCOCC1 C20H,9C12N3045 o/
¨S=

NH N

CN1C(=CC2=CC=C(OCC3=CC=CC=C3)C=C12)C(=0)NC1=CC=C(C=C1)5(.0)(=0)N1CCOCC1 C2,H,N,O,S

0 ON, 788 / II = \
0 9-5=

CC(C)0C1=CC=C2C=C(N(C)C2=C1)C(N =OC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 C2,H,N,0,5 FIN

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(=0)NC1=CC=NC=C1C
CHFNO
NO
\ 0 COC1=CC=C(C=C1)N(C)C(=0)C1=C(C)N(N=C1)C1=CC=C(C=C1)C(F)(F)F
N-N

((N
õINiN

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)f)C(=0)NC1=CC(C)=NC(C)=C1 T:c N \µ=
\ 0 N

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)1)C(=0)NC1=CC=NC(F)=C1 N _______________ C÷HuF4N40 ,N
N \
HN Br CN1C=C(BOC(NC(=0)C2=C(C)N(N=C2)C2=CC=C(C=C2)C(F)(F)F)=N1 CH1,BrF,N50 ( ___ N) CN1C(=CC2=CC(=CC=C12)C(F)(F)F)C(=0)N1CCN(C)CC1 CI,HAF3N30 II
795 0 N¨S NH 9-0001969 CN1C(=CC2=CC=CC(N)=C12)C(=0)NC1.-CC=C(C=C1)S(=0)(=0)N1CCOCC1 C20FinN40,5 HN

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(1)1)C(=0)NC1=CC=C(C)N=C1 NVNNyk.
\ 0 N¨

C,eHBF3N40 CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(=0)NC1=CC=C(F)N=C1 N
\ 0 N¨

C"H"FaN40 N

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(=0)NC1=CC=NC(=C1)C(F)(F)F
N
\ 0 N¨

C.H12F6N40 N

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(9F)C(=0)NC1=CC=NC(=C1)CIFROF
HN
N N
\N 0 C.H,,FN40 N

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(=0)NC1=CC=NC(C)=C1 N
\ 0 N¨

C,HIsF3N40 COC1=CN=CC(NC(=0)C2=C(C)N(N=C2)C2=CC=C(Cr-C2)C(F)(F)F)=C1 N-N

COC1=CC(NC(=0)C2=C(C)N(N=C2)C2=CC=C(C=C2)C(F)(F)F)=C(C=C1OC)C8N
N¨N
C219l713N403 HN

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(.0)NC1CN2CCC1CC2 CO-1,1F3N40 N
\N-( 0 HN
804 N-0001977 C5C1=NC(NC(=0)C2=C(C)N
(N=C2)C2=CC=C(C=C2)C(F)(0F)=NN1C
FIF
Nc_805 \ N-0001978 CC1=C(C=NN1C1=CC=C(C=C1)C(F)(99C(=0)NC1=NN=C(51)C1CC1 HN
_r4\
SXN
C,71-114F,N,05 N_ N
HN NN

CN1N=C(C=C1NC(=0)C1=C(C)N(N=C1)C1=CC=C(C=C1)C(F)(F)F)C1=CC=CC=C1 C221-1,j3N,0 CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(.0)NC1=CC=CC=C1N1C=CC=C1 HN *
\ 0 N¨

CõH,F31,140 NH Br BrC1=C2N(CCC3CCNCC3)C(=CC2=CC=C1)C(=0)NC1=CC=C(C=C1)S(=0)(=0)N1CCOCC1 \¨S

o/ V
N
____ / II

C,,H,,BrN4045 \
809 _________________________ 0 HN 9-0001982 CC1=C(C=NN1C1=CC=C(C=C1)C(1)(F)F)C(=0)NC1=NC2=CC=C(C=C251)S(Q=0)=0 ,3o C,0HõF,N40352 CI
810 HN 9-0001983 CC1,-C(C=NN1C1=CC=C(C=CNC(F)(F)F)C(=0)NC1=CC=NC(C1)=C1 NrNirko N¨

C,711,2C1F3N40 oY
HN

C0C1=CC(C)=NC(NC(=0)C2=C(C)N(9=C2)C2=CC=C(C=C2)C(F)(F)F)=91 N¨N
C.1-11,F,N302 HN

CCC(=0)C1=CC=C(NC(J)C2=C(C)N(N=C2)C2=CC=C(C=C2)C(F)(F)F)C=C1 N¨N

813 HN __________ N-0001986 CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(=0)NC1=NC2=CC=C(F)C=C251 (s \N
N
\\O
CI9HuF4N,OS
814 N-0001987 CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(.0)NC1=CC=NN=C1 N N
\ 0 N¨

C,6H12F3N,0 CI

HN

COC1=CONC(=0)C2=C(C)N(N=C2)C2=CC=C(C=C2)C(F)(F)F)=C(OC)C=C1C1 N¨N
C20H,CIF3N303 HN <
816 ( N-0001989 COC1=C2N =C(NC(=0)C3=C(C)N( N=C3)C3=CC=C(C=C3)C(F)( F)F)5C2=CC=C1 rIzNO

CC1=NC2=CONC(=0)C3=C(C)N(N=C3)C3=CC=C(C=C3)C(F)(F)F)=CC=C251 C20Hl5F,N4OS

C) CCOC1=CC=C(OCC)C(NC(=0)C2=C(C)N(N=C2)C2=CC=C(C=C2)C(F)(F)F)=C1 N-N
CuHuF3N303 OH

lr.C(C=N N 1C1=CC=C(C=C1)0 F)( F)F)C(=0)NC1=CC=C(C=C1)C(0)(Ci F)F)C( FR OF
HN
Jr N
\N- 0 =

HN

COC1=CC=C(NC(=-0)C2.,C(C)N(N=C2)C2=CC=C(C=C2)C(F)(F)F)C=C1 N¨N
C19Hte.13N302 CC1=C(C=NN1C1=CC=C(C.,C1)C(F)(F)FIC(0)NC1=CC=C(F)CKlIC4N
riNsr N N
\ 0 N¨

CI9HuF4N40 CI
CI

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)FIC(=0)NC1=CC=C(C1)C(C1)=C1 N N
\N¨ 0 Cld-1CI,F3N30 N .'..71Nr11\

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(99C(=0)N1CCCC(F)C1 N _______________ Cul-117F4N,0 I NO

(C)C(=0)C1CCN(CC1)C(.0)C1=C(C)N( N =C1)C1=CC=C(C=C1)C( F)( F)F
N -N
C,01-12,F,N403 825 I j\N N-0001998 CC1CCC2=CC(F)=CC=C2N1C(=0)C1=C(C)N(N=C1)C1=CC=C(C=C1)C(F)(OF

C221-11,F4N30 Nrk0 ril\
\N-826 N-0001999 CC 1=C(C=N N 1C1=CC=C(C=C1)0 F)(90C(.0)N1CCN (CC 1)C(=0)0C(C)(C)C
ox \r0 N N
\N
827 N-0002000 CC1=C(C=NN1CI,CC=C(C=C1)C(F)(F)F
)C(.0)N1CCN(CC1)C1=CC=C(C)C=C1 =

828 N-0002001 CC 1=C(C=NN 1C1=CC=C(O.C1)C( F)(F)F)C(=0) N 1CCOCC1 \N ______________ C1,H15F3N302 829 N-0002002 .. COC1=CC2=C(CN(CC2)C(.0)C2=C(C)N
(N=C2)C2=CC=C(C=C2)C(F)(09C=C10C
C231-122F,N303 COC(=0)C1=CC=C(C=C1)N(C)C(.0)C1=C(C)N(N=C1)C1=CC=C(C=C1)C(F)(F)F
N-N

831 N-0002004 COC1=CC( NC
(=0)C2=C(C)N(N=C2)C2=CC=C(C=C2)C( F)( F)F)-CC-C1C1-CC-CC-C1 N-N

N
832 N-0002005 CCOC1,-CC=CC=C1N1CCN(CC1)0=0)C1=C(C)N(N=C1)C1=CC=C(C=C1)C(F)(F)F
N¨N

NrikNy( CC1=C(C=NN1C1=CC=C(C=C1)0 F)(F)F)C(.0)N1CCN(CC1)C(.0)C1=CC=CC=C 1 C33F13,F3N403 FC(F)(F)C1=CC=C2N(CC'C3CCNCC3)C(CC2=C1)C(.0)NC1.CC=C(C=C1)5(=0)(=0)N1CCOCC1 o/ NJ \ 0 = \
NH

N
N-CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(=0)N1CCC(0)(CC1)C1=CC=CC=C1 OH
Cu Hu F3N303 =

N
N)N

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(=0)NC1=CN2C=NN=C2C(C)=C1 C,91-1,5F3N60 837 9-0002013 CC1-C(C-NN1C1-CC-C(C-C1)C(F)(F)FM=0)N1CCCC(C1)C1=CC=C(F)C=C1 \ 0 N-C23112,F4N30 HN
1:1111 COC1CCC(CC1)NC(=0)C1=C(C)N(N=C1)C1=CC=C(C=C1)C(F)(F)F
N-N

r\O
N
HN *

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(D)NC1=CC-,C(C=C1)N1CCOCC1 N \N
\N- 0 C2,1-1,1F3N40, CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(=0)N1CCNCC1 \N NTh NH

o )¨N
HN

841 N-0002017 CC(.0)C1-C(C)N-C(NC(-0)C2-C(C)N(N=C2)C2=CC=C(C=C2)C(F)(1)051 CF11,F3N4025 \0 HO N

CC(C)(0)CN1C(=CC2=CC(Br)=CC=C12)0=0)NC1=CC,C(C=C1)5(=0)(=0)N1CCOCC1 o/ = \
N¨S NH Elf II

C2311268rN30,5 COC1=C2C=C(N(C)C2=C(C)C=C1)C(.0)NC1=CC=C(C=C1)5(.0)(.0)N1CCOCC1 0 N¨S NH

CN2sN3055 844 ( ______________________ N-0002025 CN1C(=CC2=CC(=CC=C12)C(F)(F)F)C(.0)N1CCN(CC1)C1=CC=CC=C1 C2,H20F3N30 N¨S NH N-0002026 CN1C(=CC2=CC=C(COC(C)=C12)C(=0)NC1=CC=C(C=C1)5(=0)(.0)N1CCOCC1 II

C2,1-1,2CIN30,5 F F

846 o/ \
N¨S NH N-0002027 FC(F)(F)C1=CC=C2N(C3CC3)C(=CC2=C1)C(=0)NC1=CC=C(C=C1)5(.0)(.0)N1CCOCC1 II

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(=0)N1CCC2=CC(Br)=CC=C12 N
Br C20H,5BrF3N30 COC1=CC=C(0C2=CC=CC=C2)C=C1NC(=0)C1=C(C)N(N=C1)C1=CC=C(C=C1)C(F)(F)F
N¨N
C2sH,0F3N303 N

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(=0)NC1=CC=C(C=C1)N1CCN(CC1)C(=0)0C(C)(C)C

N
N¨

C,71130F3N,03 OH
HN

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(=0)NC1=CC=C(CCO)C=C1 N N
\N¨ 0 COC1=CC(C)=CC=C1NC(=0)C1=C(C)N(N=C1)C1=CC=C(C=C1)C(F)(F)F
N¨N
C.H.F3N302 NNN
NH Ni 0fft (C(=0)C(NO=0)C2=CICIN(N=C2)C2=CC=C(C=C2)C(F)(F)1)=C1C)C1=CC=CC=C1 CI

853 / II N-0002034 CN1C(-CC2-C(CI)C-CC(CI)-C12)C(-0)NC1-CC-C(C-C 1)5(-0)(-0) N 1CCOCC1 0 N¨S 4. NH

C20H,9CI,N,04S
CI

854 / II = N-0002035 CN1C(=CC2=C(COC(C1)=CC=C12)C(=0)NC1.CC=C(C=C1)5(.0)(=0)N1CCOCC1 0/ N¨S NH
II

C2nHI,C12N304S

:C1=C(C=NN1C1=CC=C(C=C1)C(F)(99C(=0)NC1=CC=CISC2=CC=C(C=C2)tN+1([0-])=0)C=C:
N

N¨ 0 CCOC(=0)C1=C(C)C2=CC(NC(.0)C3=C(C)N(N=C3)C3=CC=C(C=C3)C(F)(F)F)=CC=C251 CC1=C(C=NN1C1=CC=C(C=C1)C(F)(99C(=0)NC1=NC(=CS1)C1=CC=C(C)C=C1 HN
\ 0 N-C,2H,F3N405 COC1=CC=C(NC(.0)C2=C(C)N(N=C2)C2=CC=C(C=C2)C(F)(F)F)C-C1C1-CC-CC-C1 N-N
F F

N-N
0' HN

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)Ci=0)NC1=CC=C(C=C1)C1=NN=C01 N
\N- 0 =
=

N
RN

860 Nir¨ N-0002041 CSC1=NSC(NC(=0)C2=C(C)N(N=C2)C2=CC=C(C=C2)C(F)(F)F)=N1 NN
CIsH12F3N,052 Fvo F/\0 C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C1=NC2=CC3=C(OC(F)(F)03)C=C201 COC1=CC(N0=0)C2=C(C)N(8=C2)C2=CC=C(C=C2)C(F)(F)F)=6C(SC)=61 N¨N
C.1-116F3N,025 HN

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(=0)NC1=CC=C(C=C1)[N+I([0-])=0 N
\N¨ 0 C,H,3F3N403 NO
)LN

CC(=0)N1CCN(CC1)C(=0)C17C(0N(N=C1)C1=CC=C(C=C1)C(F)(F)F
N-N
C.1-119F3N402 865 \N N-0002046 COC1=CC=C2N(CCC2=C1)C(=0)C1=C(C)N(N=C1)C1=CC=0C=C1)C(F)(1)F
cc COC1=CC=C2N=C(NC2=CNC1=C(C)N(N=CNC1=CC=C(C=C1)0F)(F)F
C.H15F3N40 Br RN

COC1=CC=0N0=0)C2=C(C)N(N=C2)C2=CC=C(C=C2)C(F)(F)008r)=C1 N-N
CI9H1,BrF3N302 o 0 Br HN

COC1=CC=C(Br)C(NC(=0)C2=C(C)N(N=C2)C2=CC=C(C=C2)C(F)(F)1fr-C1 N¨N
C191-115BrF3N302 HN

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)9C(=0)NC1=CC=C(CN2C=CN=C2)C=C1 N N
\N 0 CH.F3N50 N
OH
HN Br CN(C)CC(0)CN1C(=CC2=CC(Br)=CC=C12)C(=0)NC1=CC=C(C,C1)5(=0)(=0)N1CCOCC1 sOO

C241129BrN,O,S

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(=0)N1CCC[C@@H](0)C1 N _______________ HO
C,71-1.F,N30, =
O
N

COC1=CC.C(C=CI)N(CC1-CC-CC-C1)C(=0)C1=C(C)N(N=C1)C1=CC=C(C=C1)C(F)(F)F
N¨N

NH

CC1=C(C=NN1C1=CC=C(C=CNC(F)(F)F)C(=0)NC1-,CC=C2NC=NC(=0)C2=C1 Cm1-114F3N,02 CC1=C(C=NN1C1=CC.-C(C=C1)C(F)(F)F)C(=0)NC1=CC=C2N=C(C)C=CC2=C1 C2,H,F3 N40 HN

:C1=C(C=N N 1C1=CC=C(C=C1)C(F)( F)FJC(=0)NC1=CC=C(0C2-7CC=C(C=C2)[N+] ([0 ] )-0)C-C
N tr,0"
\N¨ 0II

C,41-1,7F3N404 FCQ

CC1=C(C=NN1C1,-CC=C(C=CNC(F)(NF)C(.0)N1CCOC(C1)C1=CC=CC=C1 N N
\N 0 C22 H,oF3N302 Br HNS

COC1=CC=C(NC(=5)C27C(C)N(N=C2)C2=CC=C(C=C2)C(F)(F)F)C(Br)=C1 N-N
FF
C191-1158rF3N305 NR

COC1=CC=C2N=C(0C2=C1)C1=C(C)N(N=C1)C1=CC=C(C=C1)C(F)(F)F
F F
CI,F1,4F3N302 r!I KN

COC1=CC=C20C(=NC2=C1)C1=C(C)N(N=C1)C1=CC,-C(C=C1)C(F)(F)F
C,91-11.F3N302 Br =
HN

COC1=CC=C(80C(NC(=5)C2=C(C)N(N=C2)C2=CC=C(C=C2)C(F)(F)f)=C1 N-N
CH15BrF3N3OS

N
/

COC1=CC=C2N=C(SC2=C1)C1=C(C)N(N=C1)C1=CC=C1C=C1)C(F)( C,9E114F3N303 882 / \ I I N-0002063 CN 1C(=CC2=C(C)C=CC(C)=C12)C(=0) NC 1=CC=C(C=C1)5(.0)(.0)N1CCOCC1 _____ / I I

883 o/ = \ N-0002064 CSC1=CC=C2C=C(N(C)C2=C1)0=0)NC1=CC=C(C=C1)3(=0)(=0)N1CCOCC1 N-5=

NH

Cm8,3N30.152 N

COC1=CC=CC=C1N1CCN(CC1)0=0)C1=C(C)N(N=C1)C1=CC=C(C=C1)C(F)(F)F
N¨N

NO

COC1=CC=CC(=C1)N1CCN(CC1)C(=0)C1=C(C)N(N=C1)C1=CC=C(C=C1)C(F)(F)F
N¨N

=

F
886 >< N-0002067 NC1=CC=C20C(F)(F)0C2=C1 C,H,F2NO2 '0 887 F F N-0002068 CC1=C(C=NIN1C1=CC=OC-,C1)OF)(F)FM=0)NC1=CC=00C(F)(F)F)C(=C10+1([0-1)=0 HN F
N

N¨

CoH,2FN,O, CC1=C(C=NN1C1=CC=M=C1)C(F)(F)r)C(=0)N1CCCC2=CC(C)=CC=C12 N

* 0 0 ___ <
rL1N

CC1=C(C=NN1C1=CC=OC=C1)C(F)(F)F)C(=0)NC1-,CC=C2NC(.0)NC2=C1 / KN

COC1=CC=C2SC(=NC2=C1)C1=C(C)N(N=C1)C1=CC=C(C=C1)C(F)(F)F

o\ro .1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(=0)N1CCNUC@HHCC2=CC=CC=C2)C1)C(=0)0C(C)(C
NJNy \ 0 N¨

C281-131F,N,03 892 o/ II = N-0002073 CC N1C(=CC2=C0=CC=C12)C(F
)(F)F)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 N¨S NH
II

C2211,,F, N3045 \II
893 0 N¨S NH N-0002074 CN1C(=CC2=CC(C)-00Br)-C12)C(-0)NC1-CC-C(C-C1)5(-0)(-0)N1CCOCC1 0 Br C2,112213rN3045 o/ \ II 894 N¨S 11 NH N-0002075 CN10=CC2=CC(C1)=CC(C)=C12)C(=0)NC1=CC=CK=C1)5(.0)(=0)N1CCOCC1 _____ / II

C2,FInCIN,045 Br CN1C(=CC2=q80C=C3000C3=C12)C(=0)NC1=CC=C(C=C1)5(.0)(=0)N1CCOCC1 N

o C,1H208rN3065 Fq CC1=C(C=NN1C1=CC=C(C=C1)C(F)(6)9C(.0)N1CCOC2=CC=CC=C12 N

C20H16F3N30, N

CCCI=C(C=NN1C1=CC=C(C)C=C1)C(=0)N1CCC2=C(C1)NC1=CC=CC=C21 C241-1,,,N40 898 N-0002079 CCC1=C(C=N
N 1C1=CC-C(C)C-C1)0-0)C 1-NC2-CC=CC=C2S1 HN

COC1=CC=0N0C2=C(C)N(N-C2)62-CC-CC-C2)C(F)(F)F)C=C10C
N¨N
=
C,A0FaN,02 =
N¨N

CCC1=C(C=NN1C1=CC=C(C)C=C1)C(0)(C1-NC2-CC-CC-C251K1-NC2-CC-CC-C2S1 HO ________ N S
=
CnHuN,OS2 NC(=N)C1=CC=C(C=C1)C1=CC=C(01)C1=CC=C(C=C1)C(N)=N
RN

C18140,40 902 / N-0002083 CN1C(=CC2=C(C)C-C(C)C-C12)C(-0)NC1-CC-C(C-C1M-0)(=0)N1CCOCC1 0 N¨S NH
II

0, 9" o/ \ ¨S 0 = \ N-0002084 COC1=CC(C)=C2C=C(N(C)C2=C1C)C(=0)NC1=CC=C(C=C1)S(=0)(=0)N1CCOCC1 N NH

C2,H,N30,S

CN1C2=CC=CC=C2C=C1C1(C0C1)NC1=CC=C2N=CC=NC2=C1 C20H.N40 CCC1=C(C=NN1C1=CC=C(C)C=C1)C(.0)NCC1=CC=CC(OC)=C1 HN
N N

N
CnH,3N,02 OH
906 Fc N-0002088 CC1=C(C=N N 1C1=CC=C(C=C1)Ci OF)C(=0)N1CCOC(C1)6(0)=0 \ 0 N¨

C171-115F,N30, N
907 N¨N N-0002089 CN1CCN(CC1C1=CC=CC=C1)6(=0)C1=C(C)N(N=C1)C1=CC=C(C=C1)C(F)(F)F

908 I ,\N N-0002090 COC1=CC=C2N(CCCC2=C1)C(.0)C1=C(C)N(N=C1)C1=CC=C(C=C1)C(F)(F)F

Cz4Hz0F3N30, HN
909 N-0002091 CC1=C(C=N N1C1=CC=C(C=C1)6( F)( F)F)C(=0)NC1=CC=CC=N 1 \ 0 N¨

C,71113F3N40 o N
HN

CCOC(.0)C1=CC=NC(NC(=0)C2=C(C)N(N=C2)C2=CC=C(C=C2)C(F)(F)F)=C1 Cr C20H,F3N403 o 911 N-0002093 __ COC(.0)C1=CC=CON0=0)C2=C(C)N(N=C2)C2=CC=C(C=C2)C(F)(F)F)=N1 N¨N

EIXDj -912 N-0002094 CCC1=C(C=NNIC1=CC=C(C)C-t=C1)0=0)N1CCC2=CC=CC=C2CC1 C23H2sN30 HN

CN10=CC2=C0Br)=CC.,C12)C(=0)NC1=CC=C2N=CC=NC2=C1 Br C,aH1313rN40 ON
HN

CCN1C(=CC2=CC(F3r)=CC=C12)C(.0)NC1=CC=C2N=CC=NC2=C1 )Br N
C,,H158rN40 0 9" / N-0002097 CCN1C(=CC2=CC(Br)=CC=C12)C(.0)NC1=CC=C(C=C1)5(.0)(=0)N1CCOCC1 o II
N¨S NH Br II

CnE1BrN3048 N
HN

COC(.0)C1=CC=C(NC(=0)C2=C(C)N(N=C2)C2=CC=C(C=C2)C(F)(F)F)N=C1 Cr CI9HI,F3N403 N¨N

CCC1=C(C=NN1C1=CC=C(C)C=C1)C(=0)N1CCC2=CN=CC=C2C1 ON

HN

CCN1C(=CC2=CC(=CC=C12)C1=NN=C(C)51)C(=0)NC1=CC=C2N=CC=NC2=C1 /
C22H.NeOS

CCC1=C(C=NN1C1=CC=C(C)C=C1)C(=0)NCCC1=CC=NC=C1 N

CzoHuN40 F
920 NH N-0002103 FC1(00C2=CC=C( \ C=C3 C(=0)NC4=CC=CC=C34)C=C201 C1,1-19F2NO3 o/
F

COC1=CC=C(NC(C2=CC3=CC=CC=C3N2C)C(F)(9F)C=C1OC
NH

N NN
922 \N N-0002105 CCC1=C(C=NN1C1=CC=C(C)C=C1)C(=0)NCC1=CC=CC=C10C

CC1=C(C=NN1C1=CC=C(C=C1)CINFIF)C1=NC2=CC(C1)=C(COC=C2N1 CI
CleHlICI2F3N4 Br CC1=C(C=NN1C1=CC=C(C=C1)C(F)(90C(.0)NC1=CC2=C(OC(F)(F)02)C=ClEir CI1H11BrF5N303 925 < N-0002108 CCC1-0C¨NN1C1¨CC¨C(C)C¨C1)C1=NC2=CC=C(C=C2N1)C4N
N
C2oHl7N, N

CN1C2=CC=C(C=C2C=C1C1(COC1)NC1=CC=C2N=CC=NC2=C1)C(F)(F)F
F F
C2,1-117F,N40 CN1C2=CC=C(C=C2C=C1C1(COC1)NC1=CC=C(C=C1)C4N)C(F)(F)F
C20H,6F3N30 :x:\NH

CN1C2=CC=C(C=C2C=C1C1(COCBNC1=CC=C20C(F)(F)0C2,-C1)C(F)(F)F

F F =

NH /

CN1C2=CC=C(C=C2C=C1C1(C0C1)NC1=CC=C(C=C1)N1C=CN=C1K(F)(F)F
N
C221-11,F3N40 NH

CN1N=CC2=CC(NC3(COC3)C3=CC4=CC(=CC=C4N3C)C(F)(F)F)=CC=C12 CC1=C(C.NN1C1=CC=C(C=C1)C(F)(9F)C(=0)N1CCOC2=CC=NC=C12 N

N
o N

COC1=CC=CC(NC(=0)C2=C(C)N(N=C2)C2=CC=C(C=C2)C(F)(F)F)=N1 N¨N
CmH,sF,N402 N

\ I
933 N-0002116 COC1=CC=C2OCCN(C(,-0)C3=C(C)N(N=C3)C3=CC=C(C=C3)C(F)(OF)C2=C1 N I

CC1CN(C(.0)C2=C(C)N (N=C2)C2=CC=C(C=C2)C(F)(F)F)C2=CC=CC=C201 C2161,F3N302 CC1=C(C=NN1C1=CC=C(C=C1)C(1)(F)F)C1=NC(=N01)C1=CC=CNr-C1 N¨

C,,HuF3N50 =

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C1=NC(=N01)C1=CC=CC=C1 N

N¨

C,91-113F3N40 937 \N- N-0002120 CCC1=C(C=NN 1C1=CC=C(C)C=C1)C(=0)N1C=C(C=N 1)C1=CC=CC=C 1 \
N
cnH2oN40 COC1=CC=C(NC(=0)C2=CC3=CC(=CC=C3N2C)C(F)(F)F)C(N)=C1 C,ehl F39302 HN
939 N 'NO N-0002123 N(C1=NC2=CC=CC=C201)C1=CC=C2N=CC=NC2=C1 =
C,,F1,08140 CCC1=C(C=NN1C1=CC=C(C)C=C1)C(=0)N1CCC2=CC=C(F)C=C2C1 CUHUFNO
RN

N(C1=NC2=CC=CC=C2S1)C1=CC=C2N=CC=NC2=C1 =
HN ___________ ( CN1C(NC2=CC=C3N=CC=NC3=C2)=NC2=CC=CC=C12 N
C161-1,3N5 \

CCC1=C(C=NN1C1=CC=C(C)C=C1)C(=0)N1CCC2=CC=C(C=C2C1)C1=CC=CC=C1 CH,N30 N-NH
NZ/( )1,1 CCC1=C(C=NN1C1=CC=C(C)C=C1)C1=NNN=N1 \N ___________ CC1=C(C=NN1C1=CC=C(C=C1)C(F)(99C(=0)N1CCCCC1C1=CC=NC=C1 \N __ 0 N
C221-1,1F3N40 CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C1=NC(=N01)C1=CN=CC=N1 N\ N

N-C1,141,F,N,0 F F

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C1=NC(=N01)C1=CC=C(C=C1)C(F)(F)F
Zy( N ZN
\N¨ 0 so COC1=CC=C(C=C1)C1C5CCN1q=0)C1=C(C)N(N=C1)C1=CC=C(C=C1)C(F)(F)F
N¨N
F F
C231-122F3N30,S

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(=0)N1CCSCC1C1=CC=CN=C1 N
0 \
N¨

C,IHI9F3N4OS

COC1=CC=C(C=C1)C1CCCCN1C(=0)C1=C(C)N(N=C1)C1=CC=C(C=C1)C(F)(1)1 N¨N

951 N¨N N-0002135 COC1=CC=CC(=C1)C1CCCN(C1)C(=0)C1=C(C)N(N=C1)C1=CC=C(C=C1)C(F)(F)F
C2.1-124F3N302 <N N-0002136 CCC1=C(C=NN1C1=CC=C(C)C=C1)C1=NC2=CC=C(C=C2N1)C(F)(F)F
C20HõF3N, COC1=CC=C2N=C(NC2=C1)C1=CC2=CC(Br)=CC=C2N1C
Br CI,H14BrN30 954 <
5-0002139 CCC1=C C=NN1C1=CC=C C C=C1 C1=NC2=CC=C OC F F)F
( ( ) ) ( ( )(C=C2N1 ) N

C20HI,F3N40 \N-955 N-0002140 CCC1-C(C=NN1C1=CC-C(C)C-C1)C1-NOC(-N1)C1-CC=CC(=C1)C#N
\\
C2,HoN,0 956 \N¨ N-0002141 CCC1=C(C=NN1C1=CC-C(C)C-C1)C1-NOC(-N1)C1-CC=CC(OC)=C1 CnH2oN402 CCC1=C(C=NN1C1=CC=C(C)C=C1)C1(C0C1)NC1=CC7C(OC)C=C1 \
kl =
C,21-1259302 F77 \

,N

CCC1=C(C=NN1C1=CC=C(C)C=C1)C1(C0C1)NC1=CC=C20C(F)(F)0C2=C1 Cz ,F, N30 3 N
HN

CCC1=C(C=NN1C1=CC=C(C)C=C1)C(=0)NC1=CC=C(C=C1)CUN
1110 N\Z=Nyo N¨

C,oH"N.0 CCC1=C(C=NN1C1=CC=C(C)C=C1)C1=CC,C(C=C1)CUN
\N
C,9H,N3 NJ' I /
961 = N N-0002146 CN1C(=CC2=CC(80=CC=C12)C1=NC(4401)C1=CC=CC=C1 Br C,7H1213rN30 Br CN1C(=CC2=CC(BO=CC=C12)C1=NC2=CC=CC=C2N1 \N

963 N-0002148 CC N1 C(SC2=C1C=C(OC)C=C2)=C
C(C)=0 0 __ (_Ks C,3H,,N0,5 964 N-0002152 CN1C(=CC2=CC(8r)=CC=C12)C1=N
N=C(01)C1-CC-CC-C1 Br CI,H1,8rN30 NH

CCC1=CC=C(01)C1=CC=C2C(NC3=CC=C(C)03)=NC=NC2=C1 \ 0 C.1960N3.02 ON
<o CCC1=C(C=NN1C1=CC=C(C)C=C1)C1=NC2=CC3=C(0CO3)C=C2N1 C2oHl8N402 o CCC1=C(C=NN1C1=CC=C(C)C=C1)C1=NC2=CC=C(OC)C=C2N 1 N
C2.1120N40 CCC1=C(C=NN1C1=CC=C(C)C=C1)C1(C0C1)NC1=CC=C(OC)C(OC)=C1 \
o/

HN

CCC1=C(C=NN1C1=CC=C(C)C=C1)C(=0)NC1=CC=C(C=C1)C(=N)NO
\ 0 N-C2o1-12,Ns0, \ OH

CCC1=C(C=NN1C1=CC=C(C)C=C1)C1=CC,-C(C=C1)C(=N)NO
\N-C191-120N,0 NH
HN
971 N-0002162 CCC1=C(C=NN1C1=CC=C(C)C=C1)C(.0)NC1=CC=C(C=C1)C(N)=N
N7.irkb N¨

C,0HN50 972 / II = \ N-0002163 CN1C(=CC2=CC(Br)=CC=C12)C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 0 N¨S NH Br ____ / II

C20H,0BrN30,5 HO

CCC1=C(C=NN1C1=CC=C(C)C=C1)C1=NC2=CC=C(C=C2N1)C(=N)NO
N
CzoH2oN60 HN

CCC17C(C=NN1C1=CC=C(C)C=C1)C(=0)NC1=CC=C(C=C1)C(N)=0 N¨

C,0H,0N402 N
HN

CN1C(=CC2=CC(=CC=C12)C1=NN=C(C)S1)C(.0)NC1=CC=C2N=CC=NC2=C1 = 0 I /

HN

CN1C(=CC2=CC(=CC=C12)C1.NN=C(C)51)C(=0)NC1=CC=C2N=CC=CC2=C1 = 0 /
C221-117N,05 HN

CN1C(=CC2=CC(=CC=C12)C1=NN=C(C)51)C(=0)NC1=CC=C2N=CC=CC2=C1 = 0 I /

HN

CN1C(=CC2=CC(=CC=C12)C1=NN=C(C)S1)C(=0)NC1=CC=C2N=CC=CC2=C1 = 0 = /
C221-117N,OS
OOHN

CN1C(=CC2=CO=CC=C12)C1=NN=C(C)S1)C(=-0)NC1=CC=C2N=CC=CC2=0.

= /
CuHoNsOS
OOHN
980 N-0002172 ..
CN1C(=CC2=CC(=CC=C12)C1=NN=C(C)51)C(.0)NCI,CC=C2N=CC=CC2=C1 /
C22H,7N,OS
OOHN

CN1C(=CC2=CC(=CC=C12)C1=NN=C(C)51.)C(=0)NC1=CC=C2N=CC=CC2=C1 = 0 /
CnHoN,OS
Fvo 0 \
\N

CCC1=C(C=NN1C1=NN=C(C)51)C(=0)NC1=CC=C20C(F)(90C2=C1 CõHuF245035 HN

1111.](=0)C1=CC(=CC=C 1)C(=O)NC(NCI=SINC1=CC=CC2=CC=CC=C12)C(C1)(Cl)CI
HN
CI
CI

C2oHl5C13N4035 OH

CCCCCCC(=O)NCINC(=5)NC1=CC=CC=C1C(0)=0)C(C1)(CI)C1 CI S
0 Si cl,Hõo3N3o3s =

CC1=CC=C(C=C1)C1=C5C2=C1C(=O)N(CCI=CC=CC=C 1)C(SCC(N)=0)=N2 CCOC1=CC(CNC2CCCCC2)=CI8rIC=C10C1CCCC1 Br 0 C201-130BrNO2 HN

1101 9-0002180 NC(=5)N N=C C1=CC,-.CC(OCC2=CC=CC=C2)=C1 CHN
,OS
HO

0C1=C2C(SC3¨CC¨CC¨C3N¨C2C2¨CC¨CC¨C12)C1¨CC¨CC¨C1 .\\N
CuH15NOS

CCCN1C2=C(C=CC=C2)C2=C1N=C(SOCC)C(.0)NC1=CC=OC=C1)5(N)(=0)=0)N=N2 = NH

\

COC1=CC=OC=C1)C1C2CN(CC3=CC=CC=C3)CC=C2C(CItN)C(=N)C1(C8N)C#N
N¨

I I
C261-123Ns0 = 0 991 )S

CCOSC1=NC2=C(N=N1)C1=C(C=CC=C1)N2CC)O=0)NC1=CC=C(C=C1)5(N)(=0)-70 C2I822N6035, NH
N
N

CC1=CC=CC=C1 NC1=C2C=CC=CC2=C(N=N 1)C 1=CC=C(C)C(=C1)5(.0)(.0)NC(C)(C)C#C

I I
C,71-1261,14025 /

el N-0002186 CCC1=C(NC(.0)CN (C2=CC(C)=CC(C)=C2)5(.0)(=0)C2=CC(OC)=C(00C=C2)C=CC=C1 CõH01,1,0,5 994 N-0002187 COC(.0)C1=C(C)N (C(=0) C1=C/C1=CC=C(F )C=C1)C1=CC=C(F )C=C1 Cz0H15F,NO3 CI

HN

CC1=CC(C)=C(C2NC3=C(C=CC=C3)0=0)N2NC(.0)C2=CC=C(0)C=C2)C(C)=C1 c24HõciN,02 HN

0=C(NC1=CC=C2OCCOC2=C1)C(SC1=CC=CC=CNC1=CC=CC=C1 C221-11,N0,5 = N

0C1=CC=CC(=C1)N1C(=0)C2C(C(C=CC2C2=CC=CC=C2)C2=CC=CC=C2)C1,0 C261-1,1NO, HO
998 \ N-0002191 ZOC(=0)01=C(C)Nr.C25 \C(=C \C3=CC=C(0)C(OC)=C3)C(=0)N2C1C1=CC(OCC)=C(OCC=C)C=C

I
C2.,H0N2075 0 N Br l(C)CC(=0)C2=C(C1)N(C(=N)C(C2C1=CC=C20C0C2=C1)0=0)C1=CC=CC=C1)0,CC=CC(BH, C31H278rN204 Cr 0 0 CCOC(=0)C1C(CC2=C(C(C3=CC=C(F)C=C3)C(C(=0)0CC)=C(C)N2)C1=0)C1=CC=CC=ClOC

\N
N
1001 0 N-0002194 CN(C)N1C(=0) C(5 \ C1=N/C1=CC=CC=C1),-C C1=C
N(CC(=0)NCC2=CC=CO2)C2=CC=CC=C12 cr 0 HN
CõH25N,035 /NV N
S N

1002 N-0002195 CC1=CC(CSCC(-0)N \ N-C C2-CC-C(OCC(-0)0C(C)(C)C)C=C2)=CC(C)=C1 f) Cul-10204S
F

FC1=CC=C(NC(=0)C0C2=CC=C(C=C2)C2NC3=C(C=CC=C3)C(=0)N2C2=CC=C(F)C=C2)C=C1 NH
C2õHõF2N303 1004 N-0002197 CC1=C(C(C2=CC=C3000C3=C2)C(C(=-0)NC2=CC=CC=C2)=C(C)N1)C(=0)NC1=CC=CC=C1 * NH
C281-12,N304 FFF
0=S=0 1005 N-0002198 COC1=C(NC(=-0)CS(=0)(=0)C2=CC(=CC(7C2)C(F )(F )F )C(F)(F)F)C=CC=C1 o * NH
Cul-1,3661404S
HN
1006 6-0002199 COC(=0)C1CC2=C(NC3=CC=CC=C23)C2(CC
N(CC3=CC=CC=C3)CC2)N1 HN

C24E124,1301 N
OH
1007 N-0002200 CN1C2=C(N (CC(0)CN3CCN
(CC4=CC=CC=C4)CC3)C(NCC3=CC=CC=C3)=N2)4=0)N(C)C1=0 N
HN-\
N NO
C2.H35N703 "N,s HNNN
,NH2 1008 N =Nr- N-0002201 C C(,-N/NCINI=-9)C1=CC=CIOCCCOC2,---CC=C(C=C2)C( \ C)=N \ NC(N)=SIC-,C1 C211-1,6N602S, =

=CN=[N] 1C1=CC=CC=ClIC(=0)N(CC1=CC=CS1)CC 1=CC=CC=C 1 NC.Nrko S
C2,Ha6N30S.
CI
HO

CN(C)C(=0)C(CCN1CCCIOHCC1K1=CC=CICIIC=C1I(C1=CC=CC=C1)C1=CC=CC=C1 -N

C,91-1330 N202 1011 N-0002204 CC IC@
HI1CN2CCC1C[C@@ H] 2[C@ @H](OIC1-,C2C=CIOCIC=CC2=NC=C1 CzoN26N202 CC1=CC=C(C=C1S(.0)(=0)N1CCCCCC1)C(-0)NC1-CC-CC-C1 Cz0HNIN203S

1013 \ HN N-0002206 COC1=C(OC)C=C(C=C1)C1(CCCC1)C(=0)NC1=CC=C(C=C1)C(C)=0 CCC(C(=0)NC1=CC=C(C=C1)C(C)=0)C1=CC=CC=C1 HIgNO, CC(=0)C1=CC=C(NC(=0)C2(CC0CC2)C2=CC=CC=C2)C=C1 C201-1,1NO3 IIN
N-S

0.5(=0)(N1CCCCCC1)C1=CC=C(C=C1)C1=CN2C=CC=CC2= N1 CC1=CC=C2N=C(SC2=C1)C1=CC=C(C=C1)N1C(=0)CC(C1=0)C1=CC=CC=C1 0=C(NC1=CC=C2OCCOC2=CHC1=CC=CC(=C1)5(=0)(=0)N1CCCCCC1 0=5=0 C,IHNN,05S

N

Br N-0002212 CC1=C(C=C2C=CC(80=CN12)C(.0)NC1=CC=C(C=C1)5(.0)(.0)N1CCOCC1 II

C301208rN3045 CCC1=C(C=NN1)C(=0)NC1=CC=C20C(1)(1)0C2=C1 NH
C13H11F2N30, HN
VQO
1021 N-0002215 ..
CN1C(=CC2=CC(Br),CC=C12)C(=0)NC1=CC=C2CN(CCC2=C1)C(=0)0C(C)(C)C

Br C241123BrN303 OOHN

CN1C(=CC2=CC(80=CC=C12)C(.0)NC1=CC=C2CN(CCC2=C1)C(C)=0 Br C33H238rN302 NH
HN

CN1C(=CC2=CC(130=CC=C12)C(=0)NC1=CC=C2CHCCC2=C1 Br C,,H18Br N30 \N Br 1024 __ 0 0 N-0002219 CN1C(=CC2=CC(13r)=CC=C12)C(=0)NC1=CC=C2CN(CC2=CHC(=0)0C(C8C)C
________ N

Cz3H,48rN,03 1025 N N-0002221 CCC1-C(C-NN1C1-CC-C(C)C-CHC1-NOC(-NHC1-CC-C(C-CHC4N
\IINN N
N¨

C2,HoNsO

1026 /Nil\NZ
N-0002222 CCC1=C(C=NN1C1=CC=C(C)C=CHC1=NOC(=NHC1=CC=C(OC)C=C1 o/
N¨

C21H2oNe02 ft 1027 NH N-0002224 BrC1=CC=C2NCe-CC2=CHC(=0)NCC1=CC=CC=C1 0 Br C161-1,38r N20 HN
1028 <0 Br N-0002225 BrC1=CC=C2NC(=CC2=CHC(.0)NCC1=CC=C20C0C2,-C1 C171-1,38rN203 NH Br COC1=CC(CNC(=0)C2=CC3=CC(Br)=CC=C3N 2)=66(06)=610C

\
C"H"BrN,04 COC1=CC(OC)=CC(CNC(=0)C2=CC3=CC(Br)=CC=C3N2)=C1 NH
0 Br C.HõBrN203 F\
\
N N
S
N

CCC1=C(C=NN1C1=CC=CC=C1C1=NN=C(C)S1)C(=0)NC1=CC=C20C(F)(90C2=C1 -C2,HõF2N5035 N
1032 N-0002229 CCC1=C(C=
N N 1C1=CC-C(C)C-C1)C 1- NOC(- N 1)C1 -CC=C20C(F)(90C2=C1 N

Fr/ \

FC(F)(F)C1=CC(=COCNC(.0)C2=CC3=CC(13r)=CC=C3N2).,C1)C(F)(F)F
NH
0 Br C.1-1,,BrF,N20 1034 N-0002231 [0-][Nii(r.0)C1=CC=C(CNC(=0)C2=CC3=CC(Br)=CC=C3N2)C=C1 NH
0 Br C.1-11,13r N303 1035 * N-0002232 FC(F)(00C1=CC=CC(CNC(.0)C2=CC3=CC(Br)=CC=C3N2)=C1 Br C171-1,2BrF3N202 _____ 0 1036 N-0002233 FC(F)(F)0C1=CC=C(CNC(=0)C2=CC3=CC(Br)=CC=C3N2)C=C1 NH
0 Br C171-112BrF3N201 1037 ___ NH

BrC1=CC=C2NC(=CC2=C1)C(=0)NCC1=CN=CC=C1 0 Br 1038 ___ NH N-0002235 BrC1=CC=C2NC(=CC2=C1)C(=0)NCC1=CC=NC=C1 0 Br CõH,213rN30 Br BrC1=CC=C2NC(=CC2=C1)C(.0)NC(C4N)C1=CC=CC=C1 CH1,13rN30 =
1040 N-0002237 FC1=CC=C(CNC(=0)C2=CC3=CC(8r)=CC=C3N2)C=C1 NH
C> Br C01213r FN,0 1041 0/ \ II
N-S NH *N., N-0002238 CC1=C(N=C2C=C(Br)C=CN12)C(=0)NC1=CC=C(C=C1)S(=0)(=0)N1CCOCC1 II

C191-1,03rN4045 -N

CN(C)C1=CC=C(CNC(=0)C2=CC3=CC(Eir)=CC=C3N2)C=C1 NH
0 Br C.H.BrN30 =

BrC1=CC=C2NC(=CC2=C1)C(=0)NCC1=CC7C(C=C1)CUN
NH
0 Br C"HuBrN30 N
=

rYN N-0002242 CC1=CIC=NN1C1=CC=C(C=C1)C(F)(990=0)NCC1=CC=CC=C1 N
C,91-116F3N30 N
N-1045 \ N-0002243 CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(=0)NCC1=CC=C(C=C1)[61.1([0-1)=0 C19HI,F,N403 F F
N-N
Si CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(=0)NCC1=CC=C2000C2=C1 111,10 ( C201-11,F3N303 F F

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(=0)NCC1,-CC(=CC(=C1)C(1)(F)F)C(F)(OF
HN
N N
\N- 0 C211-114F,N30 HN

COC1=CC(OC)=CC(CNC(=0)C2=C(C)N(N=C2)C2=CC=C(C=C2)C(F)(F)F)=C1 N-N

HN

CN(C)C1=CC=C(CNC(=0)C2=C(C)N(N=C2)C2=CC=C(C=C2)C(F)(F)F)C=C1 N-N
C2,1-121F36140 0 _____________________________________________________________________ 10,0 0 N-S ___ NH \ N-0002248 CC1=C(C=C2C=CC(80=NN12)Ci=0)NC1=CC=C(C=C1)5(.0)(.0)N1CCOCC1 C,91-1198rN4045 COC1=CC=CC=C1CNC(=0)C1=CC2=CC(Br)=CC=C2N1C
0 Br C181-117BrN202 COC1=CC=C(CNC(=0)C2=C(C)N(N=C2)C2=CC=C(C=C2)C(F)(F)9C(OC)=C10C
N¨N
C21411F3N,04 HN

COC1=CC=C(CNC(70)C2,-C(C)N(N=C2)C2=CC=C(C=C2)C(F)(F)F)C=C1 N¨N
'KT
F F
C20E11,,F3N30, CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(=0)NCC1=CC=CC=C15(C)(.0)=0 N __________________ 0 0 =
N'Y
\N-CC1=C(C=NN1C1=CC=C(C=C1)C(H(F)F)C(=0)NCC1=CC=C(C=C1)5(CH=0)=0 h0 si/
o C20HF3N,03S

N
1056 ,0 9-0002254 CC1=C(C=NN1C1=CC=C(C=C1)C(1)(F)F)C(.0)NCC1=CC=C01 N-1057 \N _________________ 9-0002255 CC17C(C=NN1C1=CC=C(C=C1)C(F)(6)9C(=0)NCC1=CC=NC=C1 N
CHF3N40 =

\\S

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(=0)NCC1=CC=CC(=C1)5(C)(=0)=0 HN
N

N¨

C,oH,.F3N,03S
0( 1059 N¨ 9-0002257 CC1=CIC=NN1C1=CC=C(C=C1)C(F)(F)F)C(=0)NCC1=CC=C(SC(F)(F)F)C=C1 c0Hl5F,N305 H N

N-0002258 COC1=CC=C(CNC(,-0)C2=C(C)N(N=C2)C2=CC=C(C=C2)C(F)(F)F)C=N1 N¨N
C19H,F3N401 =

F+

1061 FN-0002259 CC1=C(C=N
N 1C1=CC=C(C=C1)C(F)(F)F)C(=0)N CC1=CC=CC(OC(F )(F)F)=C1 HN
N
\N¨ 0 COnfeN30, COC1=CC=CC=C1CNC(=0)C1=C(C)N(N=C1)C1=CC=C(C=C1)C(F)(F)F
N¨N

HN

COC1=CC=CC(CNC(=0)C2=C(C)N(N=C2)C2=CC=C(C=C2)C(F)(F)F)=N1 N¨N

N N
1064 \N _________________ N-0002762 CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)FJC(=0)NCC1=CC=CN=C1 C.H,5F3N40 HN

COC1=CC=CC(CNC(.0)C2=C(C)N(N=C2)C2=CC=C(C=C2)C(F)(09-=C1 N¨N

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(.0)NCC1=CC=CC=C10C(H(F)F
HN
N N
\N 0 C5C1=CC=C(CNC(=0)C2=C(C)N(N=C2)C2=CC=C(C=C2)C(F)(F)F)C=C1 N¨N
620H.F3N3OS

1068 o/ fl = NN 7 7 N-0002266 COC1=NN2C=C(C(.0)NC3=CC=C(C=C3)5(.0)(=0)N3CCOCC3)C(C)=C2C=C1 N¨S NH
II

C20H,N4OsS
N
1069 \N __ vi N-0002267 CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(=0)NCC1CCCCC1 CI9H22F,N30 F
F

F

CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)9C(=0)NCC1=COC=C1 N-=-....., C"H,4F3N30, El o........õ..-NH
1071 ( \ NN N-0002269 N.7------CIC@HHNC(.0)C1=C(C)N(N=C1)C1=CC=C(C=C1)C(F)(F)F)C1=CC=CC=C1 N¨N
F
F
F
C2oH.F3N30 O IE) 1072 c \ NN N-0002270 C[C@@H](NC(.0)C1=C(C)N(N=C1)C1=CC=C(C=C1)C(F)(F)F)C1=CC=CC=C1 N¨N
F
F
F

\N Br 11 ---,, CN1C(=CC2=CC(Br)=CC=C12)C(=0)NC1=CC=C2CN(CC2=C1)C(C)=0 ____ N

CõF1188rN302 1074 -""'S 0 NH N N-0002272 CN1C(=CC2=CC(Br)=CC=C12)C(=0)NCC1=CC=CC=C1S(C)(=0)=0 /
\
Br C.HI,BrN403S

=

CN1C(=CC2=CC(8r)=CC=C12)C(=0)NCC1=CC=C01 0 Br C,,HI,BrN,O, 0Q_ CN1C(=CC2=CCOr)=CC=C12)6(=0)NCC1=COC=C1 0 Br C151113BrN102 CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(.0)NC1=CC=C(C=C1)5(6)(=0)=0 N
\N- 0 \

COC1=CC(OC)=CC(CNC(=0)C2=CC3=CC(Br)=CC=C3N2C)=C1 NH
0 Br C199,98rN,03 _il 091C(=CC2=CC(Br)=CC=C12)C(=0)NCC1=CC=CC(=C1)5(C)(=0)=0 NH
0 Br NH Br COC1=CC(CNC(.0)C2=CC3=CC(Br)=CC=C3N2C)=CC(06)=ClOC
C20H21BrN204 -o COC1=CC=C(CNC(.0)C2=CC3=CC(Br)=CC=C3N2C)C=C1 NH
O Br C,01,7BrN,02 COC1=CC=CC(CNC(=0)C2=CC3=CC(Br)=CC=C3N2C)=C1 NH
0 Br C181-1178rN201 0 Br 1083 < N-0002281 CN1C(=CC2,-CC(Br)=CC=C12)C(=0)NCC1=CC=C2000C2=C1 C.H15BrN203 C5C1=CC=C(CNC(=0)C2=CC3=CC(Br)=CC=C3N2C)C=C1 NH
O Br C.HI3BrN205 ft CN1C(=CC2=CC(Br)=CC=C12)C(=0)NCC1=CC=CC=C10C(F)(F)F
F)( 0 Br CI38õBrF3N202 _N

C0C1=CC=C(CNC(=0)C2=CC3=CC(Br)=CC=C3N2C)C=N1 NH
O Br CI76,6BrN302 NH Br CN1C(=CC2=CC(8r)=CC=C12)C(.0)NCC1=CC=CC(0C(F)(F)F)=C1 C.H,48rF3N10, _____ 0 1088 = N-0002286 CN1C(=CC2=CC(Br)=CC=C12)C(=0)NCC1=C0.C(0C(F)(F)F)C=C1 NH
0 Br C.H,48rF3N,02 1089 ___ NH 9-0002287 CN1C(=CC2=CC(8r)=CC=C12)C(=0)NCC1=CC=NC=C1 0 Br C36H,3BrN30 1090 = 9-0002288 CN1C(=CC2=CC(Br)=CC=C12)C(.0)NCC1=CC=C(C,C1)5(C)(=0)=0 NH
0 Br C.H,,Br N3 03S

NH
Br 9-0002289 CN1C(=CC2=CC(8r)=CC=C12)C(.0)NC1=CC=C(C=C1)5(C)(=0)=0 C,78138r92035 HN

CN(C)C(.0)C1=CC=C(CNC(.0)C2=C(C)N(N=C2)C2=CC=C(C=C2)C(F)(F)F)C=C1 N-N
F F

HN

CN1C(=CC2=CC(=CC=C12)C1=NN=C(C)51)C(=0)NC1=CC=C2C=CC=NC2=C1 I /
C22H,,N,OS
HN

CN1C(=CC2=CC(Br)=CC=C12)C(=0)NC1=CC=C2C=CC=NC2=C1 Br 1095 / = ry N-0002293 CC1=C2C=CC(Br)=CN2N=C1C(=0)NC1=CC=C(C=C1)5(=0)(=0)N1CCOCC1 0 N-S NHBr II

C1,1-11913rN4045 0) II
1096 0 \ N-S=

NH \N777N.Br 9-0002294 CC1=C(N=C2C=CC(Br)=NN12)C(=0)NC1=CC=C(C=C1)5(,-0)(.0)N1CCOCC1 CHBrNOS
II

\ N

COC1=CC=CC(CNC(.0)C2=CC3=CC(Br)=CC=C3N2C)=N1 ________ NH
0 Br C,7H1613r14302 1098 ___ NH N-0002296 CN1C(=CC2=CC(Br)=CC=C12)C(=0)NCC1=CC=CN=C1 0 Br C,e1-1"BrN30 CN(C)Ci=0)C1=CC=C(CNC(.0)C2=CC3=CC(Br)=CC=C3N2C)C=C1 NH
0 Br C1oH10BrN,02 HN

CN(C)C(.0)C1=CC=CC(CNC(.0)C2=C(C)N(N=C2)C2=CC=C(C=C2)C(F)(F)F)=C1 N¨N
C221-12,F3N402 Fv 0 F/
N

CCC1=C(C=NN1C1=CC,-CC(=C1)C1=NN=C(C)S1)C(=0)NC1=CC=C20C(F)(90C2=C1 Sjc C321-1,712N3035 \N Br CN1C(=CC2=CC(8r)=CC=C12)0=0)NC1=CC=C2CNCC2=C1 NH
HN
C.1-1168rN30 N/LiA
\N-1103 = N-0002301 CC1=C(C=NNIC1=CC=C(C=C1)C(F)(F)F)C(.0)NCC1=CC=C(C=C1)C(=0)N1CCCC1 \N-CC1=C(C=NN1C1=CC=C(C=C1)C(F)(F)F)C(=0)NCC1=CC=C(C=C1)C(.0)N1CCCCC1 N
1105 N-0002303 CC1=CC=C(C=C15(N
)(=0)=0)C1=C2C=CC=CC2=C(NC2=CC=CC=C2)N =N1 N
,NH
CnHIeN40,S
oI
HN
N

COC1=CC=C(NC2=C3C=CC=CC3=C(N=N2)C2=CC=C(C)C(=C2)5(N)(.0)=0)C=C1 N

H2N./
'0 H2N, //
=
N

CC1=CC=C(C=C15(N)(.0)=0)C1=C2C=CC=CC2=C(NC2=CC=CC(0)=C2)N=N1 N
* NH
OH

N

CNS(=0)(.0)C1=CC(=CC=C1C)C1=C2C=CC=CC2=C(NC2=CC=C(OC)C=C2)N=N 1 NH

CNS(=0)(=0)C1=C(C)C=CC(=C1)C1=C2C=CC=CC2.C(NC2=CC=CC=C2)N=N1 N
NH

N

C1NC1-C2C-CC-CC2-C(N-N1)C1-CC-C(C)C(-C1)5(N)(=0)=0 N
=NH
CuNzoN4025 //

N

CC1=CC=C(C=C1S(N)(=0)=0)C1=C2C=CC=CC2=C(NC2=CC=C(0)C=C2)N=N1 N
NH
HO
C,11.11014035 HN
N

CC1=CC=CiNC2=C3C=CC=CC3,C(N.N2)C2=CC=C(C)C(=C2)5(N)(=0)=0)C=C1 CO20N40,5 HN
N

CC1=CC=CC(NC2=C3C=CC=CC3=C(N=N2)C2=CC=C(C)C(=C2)S(N)(=0)=0).<1 N

C,21-1,0N,0,S

HN
N
N
1114 N-0002312 CC 1=CC=C(NC2=C3C=CC=CC3=C( N=N
2)C2=CC=C(C=C2)C(=0)NCCO)C=C1 OH
Cz4H22N402 OH

1115 N-0002313 OCCNO=0)C1=CC=C(C=C1)C 1=N
N=C(NC2=CC=CC=C2)C2=CC=CC.C12 N
N
HN

CC1=CC=C(C=C15(=0)(=0) N 1CCCCC1)C 1=C2C=CC=CC2=C( NC2=CC=C(0)C=C2) N=N 1 N
s NH
HO
C.H.N4035 NH
N
I!I

,CC=C(NC2=C3C-CC-CC3=C(N=N 2)C2=CC=C(C)C(=C2)5(.0)(=0)N 2CCCCC2)C.0 1 C,H28N402S
\) 1118 N N-0002316 CN(C)5(-0)(-0)61-C(C)C-CO-C1)C1-C2C-CC-CC2-C(NC2-CC-CC-C2)N-N1 NH

HN

CCOC(=0)CNS(.-0)(=0)C1=C(C)C=CC(=C1)C1=C2C=CC=CC2=C(NC2=CC=CC=C2)N= N 1 N
NII
HN
Cz51-124N404S

1-12ni 0 NC(.0)C1=CC=C(C=C1)C1=C2C=CC=CC2=C(NC2=CC=CC=C2)N=N 1 N
NH

NH
N

COC1=CC=C(NC2=C3C=CC=CC3=C(N.N2)C2=CC=C(C)C(=C2)S(=0)(.0)NC(C)(C)C)C=C1 oi c,6H,8N403s NH

CNS(.0)(=0)C1=CC(=CC=C1C)C1=C2C=CC=CC2=C(NC2=CC=CC(0)=C2)N=N1 N
HO = NH
Cul-1014403S

,N
N

CC1=CC=C(C=C 1S(=0)(=0)N 1CCOCC1)C1=C2C=CC=CC2=C( NC2=CC(0)=CC=C2)N=N 1 N
s NH
OH
C2sH24N4045 OH

NH

CC1=CC.C(C=C15(.0)(=0)NCCO)C1=C2C=CC=CC2=C(NC2=CC=C(0)C=C2)N=N1 N
N
* NH
HO

NH
N
N

CC1=CC=CC=C1NC1=C2C=CC=CC2=C(N=N1)C1=CC=C(C=C1)C(N)=0 HaN
C,H.N40 S=
N 1126 N-0002324 CN(C)5(-.0)(.0)C1=CC(=CC=C1C)C1=C2C=CC=CC2=C(NC2=CC=C(C)C=C2)N=N1 N
=NH
Cm1124N,0,5 ,NH

CC1=CC=C(C=C1S(=0)(=0)NC(C)(C)C)C1=C2C=CC=CC2=C(NC2=CC(0)=CC=C2)N=N1 NII
s NH
OH
C251126N40,5 NH
N
Nil C1NC1-C2C-CC-CC2-C(N-N1)C1-CC-C(C)C(-C1)5(-0)(-0)N1CCCCC1 o NH2 HN
N

COC1=CC=C(NC2=C3C=CC=CC3=C(N=N2)C2=CC=C(C)C(=C2)5(N)(=0)=0)C=C1C(N)=0 N

C231-121Ns048 HN
N
1,1 1130 t N-0002328 COC1=CC=C(NC2=C3C=CC=CC3=C(N=N2)C2=CC(=C(C)C=C2)8(=0)(=0)N(C)C)C=C1 NS%
I
C2,H2,N,035 N

1131 N-0002329 CC1=-CC=C(C=C1S( N)(.0)=0)C1=C2C=CC=CC2=0 NC2=CC=C(OCC( N )=0)C=C2)N=N 1 NH

o I o N

CNS(.0)(=0)C1=CO=CC=C1C)C1=C2C=CC=CC2=C(NC2=CC=C(OC)C(=C2)C(N)=0)N=N1 NH

C241-123N,04S

CC1=C(C=C(C=C1)C1=C2C=CC=CC2=C(NC2=CC=CC=C2)N=N1)5(=0)(=0)NC(C)(C)C
N
N
NH
C2sH26N402S
LO
o CCOC(=0)CNS(=0)(.0)C1=CC(=CC=C1C)C1=C2C=CC=CC2=C(NC2=CC=C(0)C=C2)N=N1 N
Nil HN
OH
C251-124N40,5 NN
N
NI

CC1=CiNC2=NN=C(C3=CC=C(C=C3)C(=0)NCCO)C3=CC=CC=C23)C=CC=C1 OH
C.24H22N40:
1:01 NH
N

CC1=CC=CC(NC2=C3C=CC=CC3=C(N=N2)C2=CC=C(C)C(=C2)5(=0)(=0)N C(C)(C)C)=C1 C.H.N402S
=

=

N N-0002335 CC1=CC=C(C=C15(=0)(=0) N 1CCCCC
1)C1=C2C=CC=CC2=0 NC2=CC(0)=CC=C2) N=N 1 Nil HO NH
C 112 N 0 ,S

HN, N

CNS(.0)(=0)C1=CC(=CC=C1C)C1=C2C=CC=CC2=0NC2.,-CC=C(OCC(N )=0)C=C2)N=N 1 HN

C241-123N,045 CNS(=0)(=0)C1=CC(=CC=C1C)C1=C2C=CC=CC2=C( NC2=CC=CC=C2C)N=N 1 N
NH
6d-1,19402S
OH

V, NH

CC1=CC=C(C=C1S(=0)(=0)NCCO)C1=C2C=CC=CC2=C(NC2=CC(0)=CC=C2)N=N1 N
NH
OH

%

N

CN(C)S(=0)(=0)C1=CC(=CC=C1C)C1=C2C=CC=CC2=C(NC2=CC=CC(0)=C2)N=N1 NH
OH

CCOC(=0)CNS(=0)(70)C1=CC(=CC=C1C)C1=C2C=CC=CC2=C(NC2=CC(0)=CC=C2)N=N1 N
N
NH
CõHõN405S OH

µN

CC1=CC=C(C=C1S(=0)(=0)N1CCOCC1)C1=C2C=CC=CC2=C(NC2=CC=CC=C2)N =N1 N
NH

HN
N

COC1=CC=C(NC2=C3C=CC=CC3=C(N=N2)C2=CC=C(C)O=C2)5(=0)(=0)N(C)C)C=C1C(N)=0 N
o/
C251-125N,04S
NH

CC1=CC=C(C=C15(=0)(=0)NC(C)(C)C)C1=C2C=CC=CC2=C(NC2=CC=C(0)C=C2)N=N1 N
Nil NH
HO =

OH
NH

CCI,C(C=C(C=C1)C1=C2C=CC=CC2=ONC2=CC=CC=C2IN=N1)5(---O)(=0)NCCO
N
N
NH

NH
N
Nil 1147 N-0002345 .. CC1=CC=C(NC2=C3C=CC=CC3=C(N.-N2)C2=CC=C(C)C(=C2)5(=0)(=0)N2CCOCC2)C=C1 C2,H26144035 \\O

CC1=C(C=C(C=C1)C1=C2C=CC=CC2=C(NC2=CC=CC=C2)N=N1)5(=0)(=0)N1CCCCC1 NII
=NH
C2,1-1.N 0 ,S
NH
N

CC1=CC=CC=C1NC1=C2C=CC=CC2=C(N=N1)C1=CC=C(C)C(=C1)5(=0)(=0)NC(C)(C)C

)(0 H

\) CN(C)S(.0)(.0)C1=CC(=CC=C1C)C1=C2C=CC=CC2=ONC2=CC=C(0)C=C2)N=N1 NH
HO
C23Hz2N40,5 HN
N

CC1=CC=CONC2=NN=C(C3=CC=C(C=C3)ON)=0)C3=CC=CC=C23)=C1 C,21-1N40 HN
N
N

CC1=CC=C(NC2=NN=C(C3=CC=C(C=C3)C(N)=0)C3=CC=CC=C23)C=C1 C22H181,140 HN

HN

CNC(=0)C0C1=CC=CiNC2=C3C=CC=CC3=C(N=N2)C2=CC=C(C)C(=C2)S(N)(=0)=0)C=C1 N

CzaH23N,04S
NH
N
N

CC1=CC=CC(NC2=C3C<C=CC3=C(N=N2)C2=CC=C(C)C(=C2)5(=0)(.0)N2CCOCC2)=C1 "SN

C261-126N¾03S

CNS(=0)(=0)C1=CC(=CC=C1C)C1=C2C=CC=CC2=C(NC2=CC=C(C)C=C2)N=N1 NI
NH
CaHuNOS

N

CN(C)5(.0)(=0)C1=CC(=CC.C1C)C1=C2C=CC=CC2=C(NC2=CC=C(OCC(N)=0)C=C2)N=N1 N
HN

CH2,N,045 NH
N

CNC(=0)C0C1=CC=C(NC2=C3C=CC=CC3=C(N=N2)C2=CC=C(C)C(=C2)5(=0)(=0)NC)C=C1 NH

C2,H2,N504s NH
N

1158 )1 N-0002356 CC1=CC=C(NC2=C3C=CC=CC3=C(N=N2)C2=CC(=C(C)C.C2)5(.0)(.0)NC(C)(C)C)C=C1 S' q c26HN402s =

CNS(=0)(.0)C1=CO=CC=C1C)C1=C2C=CC=CC2=C( NC2=CC(C)=CC=C2)N=N 1 NI
NH
Cul-10402s NH
N
N

CC1=CC=CC=C 1NC 1=C2C=CC=CC2=C(N=N 1)C1=CC=C(C)C(=C1)5(=0)(=0)N 1CCOCC1 1,0 / N

NH
N
NI I

COC1=CC=C(NC2=C3C=CC=CC3=C(N=N2)C2=CC(=C(C)C=C2)5(=0)(=0)N2CCOCC2)C=C1 C,61-1N4045 NH
N
N

CC1=CC=CC(NC2=C3C=CC=CC3=C(N=N2)C2=CC=0C)C(=C2)5(.0))=0)N2CCCCC2)=C1 Cz7H.N402S
NH
N
!II
1163 r N-0002361 CC1=CC=CC(NC2=C3C=CC=CC3=C(N=N2)C2=CC=C(C)C(=C2)Si=0)1=0)NCCO)=C1 C24H2,N,O,S
NH
N

1164 )1 N-0002362 CC1=CC=C(NC2=C3C=CC=CC3=C(N=N2)C2=C0=0C)C=C2)Si=0))=0)NCCO)C=C1 C2411,04035 NH
N

CC1=C(NC2=C3C=CC=CC3=C(N=N2)C2=CC(=C(C)C=C2)5(=0)(,-0)NCCO)C=CC=C1 0' HN
N

CC1=CC(NC2=C3C=CC=CC3=C(N=N2)C2=CC=C(C=C2)C(.0)NCCO)=CC=C1 raNHõNµ0, NH
=
N
N
1167 N-0002365 COC1,-CC.C(NC2=C3C=CC=CC3=C(N=N2)C2=CC----C(C)C(=C2)5(=0)(=0)N2CCCCC2)C=C1 C,HN4035 / =
NH
N
N

COC1=CC=C(NC2=C3C=CC=CC3=C(N=N2)C2=CC(=C(C)C=C2)9(=0)(=0)NCCO)C=C1 OH
C241-1,4N4045 CC1=CC=C(C=C1S(=0)(.0)N 1CCOCC 1)C1=C2C=CC=CC2=C( NC2=CC=C(0)C=C2)N=N 1 N
NH
HO =

y0 HN

CC(C)NS(=0)(=0)C1=CC(=CC=C1C)C1=C2C=CC=CC2=C( NC2=CC=C30C0C3=C2)N =N 1 N

<

C2s1-104045 CN1CCN(CC1)5(=0)(.0)C1=CC(=CC=C1C)C1=C2C=CC=CC2=C( NC2=CC=CC=C2)N=N 1 NII
NH
C2,H,N1 sO2S
NH
N
NII

CC1=CC=C(NC2=NN=C(C3=CC(=C(C)C=C3)5(.0)(=0)NCC3CCC03)C3=CC=CC=C23)C=C1 S, 0, N

CC1=CC=C(C=C1S(N)(.0)=0)C1=C2C=CC=CC2=C( NC2=CC=C30C0C3=C2) N=N 1 N
NH
<

CH NOS

hS

CN1CCN(CCHS(.0)(.0)C1=CC(=CC=C1C)C1=C2C=CC=CC2=C(NC2=CC=O0)C-C2)N=N1 N
NH
HO
C261127N50,5 %.NH

CC1=CC=OC=C1S(.0)(=0)NCC1CCC01)C1=C2C=CC=CC2=ONC2CCCCC2)N=N1 N
N
cr,NH

OH

NH

CC1=CC=C(C=C15(=0)(=0)NCCO)C1=C2C=CC=CC2=0NC2=CC=C3000C3=C2)N=N1 N
HN

C241-122N40,6 N

CN1CCN(CC1)5(=0)(.0)C1=CC(=CC=C1C)C1=C2C=CC=CC2=0NC2=CC=CC(C)=C2)N=N1 N
=NH
Cz7H29N502S
NH
N
NII
1178 N-0002376 CC1,-CC=CC=C1NC1=C2C-,-CC=CC2=C(N=N1)C1,-CC=0C)0=C1)5(=0)(=0)NCC1CCCO1 ThH

c27H20403s =
N

CN1CCN(CC1)S(=0)(=0)C1=CC(=CC=C1C)C1=C2C=CC=CC2=0NC2=CC(0)=CC=C2)N=N1 NH
OH
CH,714,03S

HN
N
N

CC(NC2=C3C=CC=CC3=C(N=N2)C2=CC=QC)C(=C2)8(=0)(=0)NC(C)(C)C0)=C1 S.
.C9H
C.H.N4038 NH
1181 N.'''.

CC1=CC=C(C=C1S(=0)(=0)NC(C)100C1=C2C=CC=CC2=C(NC2=CC3=C(00O3)C=C2)N=N 1 N
HN

CN5(=0)(=0)C1=CC(=CC=C1C)C1=C2C=CC=CC2=C(NC2=CC=C30C0C3=C2)N =N1 N
NH

OH
HN
N
N

CC1=CC=C(C=C1.5(=0)(=0)NCC1=CC=CN=C1)C1=C2C=CC=CC2=C(NC2=CC=C(0)C=C2)N=N1 HN-A

N
C,4-123N,035 ,.NH

CC1=CC=C(C=C15(=0)(.0)NCC1CCC01)C1=C2C=CC=CC2=C(NC2=CC=C(0)C=C2)N=N1 N
N

HO

Inc CN1CCN(CC1)5(.0)(=0)C1=CC(=CC=C1C)C1=C2C=CC=CC2,-C(NC2CCCCC2)N=N1 QNH
Cz6H33N5025 A
ON

IµJ' CC1=CC=C(C=C15(=0)(=O)NC(C)(C)C0)C1=C2C=CC=CC2=C(NC2=CC=C(0)C=C2)N=N1 HN
OH
C2sH26N404S

(CC1)5(=0)(=0)C1=CC(=CC=C1C)C1=C2C=CC=CC2=C(NC2=CC=CC=C2C)N=N 1 NI I
=NH
C,A1,0150,5 HN

CC1=CC=C(C=C1S(=0)(=0)NCC1=CC=CN=C1)C1=C2C=CC=CC2=C(NC2=CC=CC(0)=C2)61=N1 HN

C,7H23N,03S

NH

1=C(C=C(C=C1)C1= N N=C(NC2=CC=CC(0)=C2)C2=CC=CC=C12 )5(=0)(=0)N CC1CCCO1 N
NH
OH

HN
N
N

COC1=CC=C(NC2=C3C=CC=CC3=C(N=N2)C2=CC=C(C)C(=C2)S(=0)(=0)NC(C)(C)CO)C=C1 NH
OH
C261-12.N404S

HN

0002389 CNC(=0)C1=CC(NC2=C3C=CC=CC3=C(N=N2)C2=CC=C(C)C(=C2)S(N
)(=0)=0)=CC=C10C
N

o NH2 C241123N,0,5 =

HN
N
N

CC1=CC=CiNC2=C3C=CC=CC3=C(N=N2)C2=CC=C(C)C(=C2)5(=0)(=0)NC(C)(C)CO)C=C1 /NH
OH
Cz,H.N4035 NH
\µ0 CC1=CC=C(C=C1S(,-0)(=0)NCC1CCC01)C1=C2C=CC.CC2=C(NC2-,CC=CC=C2)N=N1 N
N
NH
CH NOS
HMO
N
N

1=CC.C(C=C1S(=0)(=0)NCC1=CC=CN=C1)C1=C2C=CC=CC2=C( NC2=CC=CC=C2)N =1,11 C24423N,025 N
Nil CC1=CC=CC(NC2-C3C-CC=CC3=C(N=N2)C2=CC=C(C)C(=C2)5(.0)(=-0)NCC2CCCO2)=C1 C271-1,N4035 0 S OH
N

CC1=CC=C(C=C15(=O)(=0)NC(C)(C)CO)C1=C2C=CC=CC2=C(NC2=CC(0)=CC=C2)N=N1 N
HN OH
Cõ1-126N,04S

Inc CN1CCN(CC1)5(=0)(.0)C1=CC(CC=C1C)C1=C2C=CC=CC2=C(NC2=CC=C(C)C=C2)N=N1 N
=NH
CuHõN50,S

HN

CNC(=0)C1=CC(NC2=C3C=CC=CC3=C(N=N2)C2=CC=C(C)C(=C2)5(.0)(.0)NC)=CC=ClOC

S

C25H2,N5045 CN(C)C(=0)C1=CC=C(C=C1)C1=C2C=CC=CC2=C(NC2=CC=CC(C)=C2)N=N1 N
NH
C,.1-122N,0 N
N

CN(C)S(=0)(=0)C1=CC(=CC=C1C)C1=C2C=CC=CC2=C(NC2=CC=CC(C)=C2)N=N1 N
NH
C,41424N40,5 H2N, *
N

CC1=CC=C(C=C15(N)(.0)=0)C1=NN=C(NC2=CC=CC=C2)C=C1 N
NH
C,71-116N402S

CN(C)C(=0)C1=CC=C(C=C1)C1=NN=C(NC2=CC=C(C)C=C2)C2=CC=CC=C12 N
N
NH

ON

FC(F)(CO0C1=CC=C(NC2=NN=C(C3=CC=C(C=C3)C(=0)N3CCOCC3)C3=CC=CC=C23)C=C1 N
N
HN
*CHCIFNO
02c CI

HN
N

0002402 CC 1=CC=C(NC2=C3C=CC=CC3=C(N=N
2)C2=CC=C(C)C(=C2)5(=0)(.0)NC(C)(C)C#C)C=C1 CnI126N4025 ,NH2 N
N

CC1=CC=C(C=C1S(N)(=0)=0)C1=NN=C(NC2=CC=C(OC(F)(F )0)C=C2)C2=CC=CC=C12 NH

______ CI

CC(C)(C) NC(=0)C1=CC=C(C=C1)C1=C2C=CC=CC2=C(NC2=CC=C(OC(F)( OCI)C=C2) N=N 1 NI
NH

F _____ CI
C26I-123 F21,1402

Claims (24)

1. A compound as described in Table A, or a pharmaceutically acceptable salt thereof.
2. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.
3. A method for treating a polynucleotide repeat disorder, said method comprising administering to a subject in need thereof an effective amount of the compound of claim 1 or the pharmaceutical composition of claim 2.
4. The method of claim 3, wherein said polynucleotide repeat disorder is myotonic dystrophy.
5. The method of claim 4, wherein said myotonic dystrophy is myotonic dystrophy type 1 (Steinert's disease).
6. Use of the compound defined in claim 1 or the pharmaceutical composition defined in claim 2 for treating a polynucleotide repeat disorder in a subject.
7. Use of the compound defined in claim 1 or the pharmaceutical composition defined in claim 2 for the manufacture of a medicament for treating a polynucleotide repeat disorder in a subject.
8. The use of claim 6 or 7, wherein said polynucleotide repeat disorder is myotonic dystrophy.
9. The use of claim 8, wherein said myotonic dystrophy is myotonic dystrophy type 1 (Steinert's disease).
10. The compound as defined in claim 1 or the pharmaceutical composition defined in claim 2 for treating a polynucleotide repeat disorder in a subject.
11. The compound as defined in claim 1 or the pharmaceutical composition defined in claim 2 for the manufacture of a medicament for treating a polynucleotide repeat disorder in a subject.
12. The compound as defined in claim 1 or the pharmaceutical composition defined in claim 2, wherein said polynucleotide repeat disorder is myotonic dystrophy.
13. The compound of claim 12, wherein said myotonic dystrophy is myotonic dystrophy type 1 (Steinert's disease).
14. A method for reducing the formation of RNA foci or aggregates in a cell, said method comprising contacting said cell with the compound as defined in claim 1 or the pharmaceutical composition defined in claim 2.
15. The method of claim 14, wherein said method is in vitro.
16. A method for determining whether a test compound may be useful for treating a polynucleotide repeat disorder, said method comprising (i) contacting said test compound with a cell expressing a reporter construct, said reporter construct comprising a first domain encoding a reporter transcript and a second domain comprising a plurality of polynucleotide repeats located downstream of said first domain; and (ii) determining the aggregation of said reporter transcript in said cell, wherein a decrease in the aggregation of said reporter transcript in said cell in the presence of said test compound, relative to the aggregation in the absence of said test compound, is indicative that said test compound may be useful for treating a polynucleotide repeat disorder.
17. The method of claim 16, wherein the decrease in the aggregation of said reporter transcript in said cell is determined by quantifying the number of reporter transcript foci in the nucleus of said cell.
18. The method of claim 16 or 17, wherein said reporter transcript is a luciferase or beta- galactosidase transcript.
19. The method of any one of claims 16 to 18, wherein said reporter construct is under inducible expression.
20. The method of claim 19, wherein said reporter construct is operably linked to a tetracycline- responsive element (TRE).
21. The method of claim 20, wherein said cell further expresses the tetracycline-responsive transcriptional activator (tTA) from the strong immediate early promoter of cytomegalovirus.
22. The method of claim 16, wherein said expression is induced by culturing said cell in the absence of tetracycline (Tc), or a derivative thereof.
23. The method of claim 22, wherein said tetracycline (Tc) derivative is doxycycline (Dox).
24. The method of any one of claims 16 to 23, wherein said method comprises:

(i) culturing said cell in the absence of tetracycline (Tc), or a derivative thereof to induce expression of the reporter transcript; and (ii) contacting said test compound with said cell in the presence of tetracycline (Tc), or a derivative thereof to inhibit expression of the reporter transcript.
CA2984073A 2017-10-27 2017-10-27 Inhibitors of polynucleotide repeat-associated rna foci and uses thereof Abandoned CA2984073A1 (en)

Priority Applications (1)

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Application Number Priority Date Filing Date Title
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Publications (1)

Publication Number Publication Date
CA2984073A1 true CA2984073A1 (en) 2019-04-27

Family

ID=66628964

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CN111991398A (en) * 2020-09-08 2020-11-27 中国医科大学附属盛京医院 Application of benzopyrazines compound in preparation of SOST protein inhibitor
WO2022243574A1 (en) * 2021-05-21 2022-11-24 Cemm - Forschungszentrum Für Molekulare Medizin Gmbh 3-(phthalazin-1-yl)benzenesulfonamide-based slc16a3 inhibitors and their therapeutic use
WO2022262855A1 (en) * 2021-06-18 2022-12-22 上海拓界生物医药科技有限公司 Malt1 inhibitor, and preparation method therefor and use thereof
WO2023050007A1 (en) * 2021-09-29 2023-04-06 Repare Therapeutics Inc. N-(5-substituted-[(1,3,4-thiadiazolyl) or (thiazolyl)])(substituted)carboxamide compounds and use thereof for inhibiting human polymerase theta

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020230134A1 (en) * 2019-05-14 2020-11-19 Metabomed Ltd Acss2 inhibitors and methods of use thereof
CN114127049A (en) * 2019-05-14 2022-03-01 美特波米德有限公司 ACSS2 inhibitors and methods of use thereof
CN109970654A (en) * 2019-05-21 2019-07-05 郑州大学 A series of substitution 2- phenylpyrazole derivatives and its preparation method and application
CN111991398A (en) * 2020-09-08 2020-11-27 中国医科大学附属盛京医院 Application of benzopyrazines compound in preparation of SOST protein inhibitor
WO2022243574A1 (en) * 2021-05-21 2022-11-24 Cemm - Forschungszentrum Für Molekulare Medizin Gmbh 3-(phthalazin-1-yl)benzenesulfonamide-based slc16a3 inhibitors and their therapeutic use
WO2022262855A1 (en) * 2021-06-18 2022-12-22 上海拓界生物医药科技有限公司 Malt1 inhibitor, and preparation method therefor and use thereof
WO2023050007A1 (en) * 2021-09-29 2023-04-06 Repare Therapeutics Inc. N-(5-substituted-[(1,3,4-thiadiazolyl) or (thiazolyl)])(substituted)carboxamide compounds and use thereof for inhibiting human polymerase theta

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