Pesticidal compositions and processes related thereto

Description

THE FIELD OF DISCLOSURE

[0001] The invention disclosed herein relates to the field of methods for producing molecules which are useful as pesticides (e.g., acaricides, insecticides, molluscicides, and roundcicides), such molecules, and methods of using such molecules to control pests. BACKGROUND OF DISCLOSURE

[0002] Pests cause millions of human deaths in the world every year. In addition, there are over ten thousand species of pests that cause losses to agriculture. Every year agricultural losses around the world reach billions of US dollars.

[0003] Termites damage all kinds of private and public buildings. Each year, the damage caused by deadlines costs billions of dollars in losses.

[0004] Stored food pests eat up and spoil stored food. Stored food losses amount to billions of US dollars each year, but more importantly, they deprive people of needed food.

[0005] US 2002/068838 A1 describes aromatic amides and their use as pesticides.

[0006] There is an acute need for new pesticides. Some pests develop resistance to pesticides currently in use. Hundreds of pest species are resistant to one or more pesticides. Resistance to some of the older pesticides such as DDT, carbamates and organophosphates is known to develop. But resistance has also developed to some of the newer pesticides, for example imidacloprid.

[0007] Thus, for many reasons, including the above reasons, there is a need for new pesticides.

DEFINITIONS

[0008] The examples given in the definitions are generally not exhaustive and should not be construed as limiting the invention disclosed herein. It is understood that a substituent should conform to the rules of chemical bonding and steric compatibility limitations for the particular molecule to which it is attached.

[0009] Alkenyl is an acyclic, unsaturated (at least one carbon double bond), branched or unbranched, carbon and hydrogen substituent, for example, vinyl, allyl, butenyl, pentenyl, and hexenyl.

[0010] Alkenyloxy is alkenyl further composed of a single carbon-oxygen bond, for example, allyloxy, butenyloxy, pentenyloxy, hexenyloxy.

[0011] Alkoxy is an alkyl further composed of a single carbon-oxygen bond, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, and tert-butoxy.

[0012] Alkyl is an acyclic, saturated, branched or unbranched, carbon hydrogen substituent, for example, methyl, ethyl, (C3) alkyl which is n-propyl and isopropyl), (C4) alkyl which is n - butyl, sec-butyl, isobutyl, and tert-butyl.

[0013] Alkynyl means acyclic, unsaturated (at least one carbon-carbon triple bond), branched or unbranched, carbon hydrogen substituent, for example ethynyl, propargyl, butynyl, and pentynyl.

[0014] Alkynyloxy is alkynyl further composed of a single carbon-oxygen bond, for example, pentynyloxy, hexynyloxy, heptynyloxy, and octynyloxy.

EP-2934142B1PL

[0015] Aryl is a cyclic aromatic hydrogen and carbon substituent, e.g., phenyl, naphthyl, and biphenyl.

[0016] (C._x-C_y), where the subscripts x and y represent integers such as 1, 2, or 3 represent the range of carbon atoms for the substituent - for example, (C 1 -C 6 alkyl represents methyl, ethyl, n-propyl, isopropyl, n-butyl, sec- butyl, isobutyl, and tert-butyl each separately.

[0017] Cycloalkenyl is a monocyclic or polycyclic, unsaturated (at least one carbon-carbon double bond) substituent composed of carbon and hydrogen, for example, cyclobutenyl, cyclopentenyl, cyclohexenyl, norbornenyl, bicyclo [2.2.2] octenyl, tetrahydronaphthyl, hexahydronaphthyl, and octahydronaphthyl.

Cycloalkenyloxy is cycloalkenyl further composed of a single carbon-oxygen bond, for example, cyclobutenyloxy, cyclopentenyloxy, norbornenyloxy, and bicyclo [2.2.2] octenyloxy.

[0019] Cycloalkyl is a monocyclic or polycyclic saturated carbon and hydrogen substituent, for example, cyclopropyl, cyclobutyl, cyclopentyl, norbornyl, bicyclo [2.2.2] octyl, and decahydronaphthyl. Cycloalkoxy is cycloalkyl further composed of a single carbon-oxygen bond, for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, norbornyloxy, and bicyclo [2.2.2] octyloxy.

[0021] Halo means fluoro, chloro, bromo, and iodo.

Haloalkoxy is alkoxy further composed of from one to the maximum possible number of identical or different halogen atoms, for example, fluoromethoxy, trifluoromethoxy, 2,2-difluoropropoxy, chloromethoxy, trichloromethoxy, 1,1,2,2-tetrafluoroethoxy, and pentafluoroethoxy .

Haloalkyl is alkyl further composed of from one to the maximum possible number of identical or different halogen atoms, for example, fluoromethyl, trifluoromethyl, 2,2-difluoropropyl, chloromethyl, trichloromethyl, and 1,1,2,2-tetrafluoroethyl .

[0024] Heterocyclyl is a cyclic substituent which may be fully saturated, partially unsaturated, or fully unsaturated, wherein the cyclic structure comprises at least one carbon atom and at least one heteroatom, wherein said heteroatom is nitrogen, sulfur, or oxygen. In the case of sulfur, this atom may be in other oxidation states such as sulfoxide and sulfone. Examples of aromatic heterocycles include, but are not limited to, benzofuranyl, benzisothiazolyl, benzisoxazolyl, benzoxazolyl, benzothienyl, benzothiazolyl, cinnolinyl, furanyl, imidazolyl, indazolyl, indolyl, isoindolyl, isoquinolinal, isooxazinolyl, isoxazotiazolyl, isoxazinyl azolyl, isooxazinyl azolyl , pyrazolinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, thiazolinyl, thiazolyl, thienyl, triazinyl, and triazolyl. Examples of fully saturated heterocyclyls include, but are not limited to, piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, and tetrahydropyranyl. Examples of partially unsaturated heterocyclyls include, but are not limited to, 1,2,3,4-tetrahydroquinolinyl, 4,5-dihydro-oxazolyl, 4,5-dihydro-1H-pyrazolyl, 4,5-dihydro-isoxazolyl, and 2,3-dihydro- [1,3,4] oxadiazolyl.

[0025] Additional examples include the following

<img file="PL2934142T3_D0001.tif" />

Tietanyl Oxide Tiethanyl Dioxide

DETAILED DESCRIPTION OF DISCLOSURE

EP-2934142B1PL

[0026] The present document discloses molecules having the following formula (Formula One):

<img file="PL2934142T3_D0002.tif" />

Pattern One in which:

(a) R1 is selected from (1) H, F, Cl, Br, I, CN, NO₂, (C1-C8alkyl, halo (C1-C8) alkyl, (C1-C8) alkoxy, halo (C1-C8) alkoxy, S (C1-C8) alkyl, S (halo (C1-C8) alkyl), S ( O) (C 1 -C 6) alkyl, S (O) (halo (C 1 -C 8) alkyl), S (O)₂(Ci-Ce) alkyl, S (O)₂(halo (C1-C8) alkyl), N (R14) (R15), (2) substituted (C1-C8) alkyl, wherein said substituted (C1-C8) alkyl has one or more substituents selected from CN and NO₂, (3) substituted halo (C1-C8) alkyl, wherein said substituted halo (C1-C8) alkyl has one or more substituents selected from CN and NO₂, (4) substituted (C 1 -C 8) alkoxy, wherein said substituted (C 1 -C 8) alkoxy has one or more substituents selected from CN and NO₂, and (5) substituted halo (Ci-C8) alkoxy, wherein said substituted halo (Ci-C8) alkoxy has one or more substituents selected from CN and NO₂;

(b) R2 is selected from (1) H, F, Cl, Br, I, CN, NO₂ (C1-C8) alkyl, halo (C1-C8) alkyl, (C1-C8) alkoxy, halo (C1-C8) alkoxy, S (C1-C8) alkyl, S (halo (C1-C8) alkyl), S (O) (C1-C8) alkyl, S (O) (halo (C1-C8) alkyl), S (O)₂(Ci-C8) alkyl, S (O)₂(halo (C1-C8) alkyl), N (R14) (R15), (2) substituted (C1-C8) alkyl, wherein said substituted (C1-C8) alkyl has one or more substituents selected from CN and NO₂, (3) substituted halo (C 1 -C 8) alkyl, wherein said substituted halo (C 1 -C 8) alkyl has one or more substituents selected from CN and NO₂, (4) substituted (C 1 -C 8) alkoxy, wherein said substituted (C 1 -C 8) alkoxy has one or more substituents selected from CN and NO₂, and (5) substituted halo (C1-C8) alkoxy, wherein said substituted halo (C1-C8) alkoxy has one or more substituents selected from CN and NO₂;

(c) R3 is selected from (1) H, F, Cl, Br, I, CN, NO₂, (C 1 -C 8) alkyl, halo (C 1 -C 8) alkyl, (C 1 -C 8) alkoxy, halo (C 1 -C 8) alkoxy, S (C 1 -C 8) alkyl, S (halo (C 1 -C 8) alkyl), S (O) (C 1 -C 6) alkyl, S (O) (halo (C 1 -C 8) alkyl), S (O)₂(Ci-Csjalkyl, S (O)₂(halo (C1-C8) alkyl), N (R14) (R15), (2) substituted (C1-C8) alkyl, wherein said substituted (C1-C8) alkyl has one or more substituents selected from CN and NO₂, (3) substituted halo (C1-C8) alkyl, wherein said substituted halo (C1-C8) alkyl has one or more substituents selected from CN and NO₂, (4) substituted (C 1 -C 8) alkoxy, wherein said substituted (C 1 -C 8) alkoxy has one or more substituents selected from CN and NO₂, and

(5) substituted halo (Ci-C8) alkoxy, wherein said substituted halo (Ci-C8) alkoxy has one or more substituents selected from CN and NO2;

(d) R4 is selected from (1) H, F, Cl, Br, I, CN, NO2, (C1C4alkyl, halo (C1₁-C₈) alkyl, (C.₁-C₈) alkoxy, halo (C.₁-C₈) alkoxy, S (C₁-C₈) alkyl, S (halo (C.₁-C₈) alkyl), S (O) (C.₁-C₈) alkyl, S (O) (halo (C₁-C₈) alkyl), S (O)₂(C.₁-C₈) alkyl, S (O)₂(halo (C₁-C₈) alkyl), N (R14) (R15), (2) substituted (C1-C8) alkyl, wherein said substituted (C1-C8) alkyl has one or more substituents selected from CN and NO2, (3) substituted halo (C1 -C8) alkyl, wherein said substituted halo (C1-C8) alkyl has one or more substituents selected from CN and NO2, (4) substituted (C1-C8) alkoxy, wherein said substituted (C1-C8) alkoxy has one or more substituents selected from CN and NO2, and (5) substituted halo (C1-C8) alkoxy, wherein said substituted halo (C1-C8) alkoxy has one or more substituents selected from CN and NO2;

(e) R5 is selected from (1) H, F, Cl, Br, I, CN, NO2, (C₁-C₈) alkyl, halo (C.₁-C₈) alkyl, (C.₁-C₈) alkoxy, halo (C.₁-C₈) alkoxy, S (C₁-C₈) alkyl, S (halo (C.₁-C₈) alkyl), S (O) (C.₁-C₈) alkyl, S (O) (halo (C₁-C₈) alkyl), S (O)₂(C.₁-C₈) alkyl, S (O)₂(halo (C₁-C₈) alkyl), N (R14) (R15), (2) substituted (C1-C8) alkyl, wherein said substituted (C1-C8) alkyl has one or more substituents selected from CN and NO2, (3) substituted halo (C1 -C8) alkyl, wherein said substituted halo (C1-C8) alkyl has one or more substituents selected from CN and NO2, (4) substituted (C1-C8) alkoxy, wherein said substituted (C1-C8) alkoxy has one or more substituents selected from CN and NO2, and (5) substituted halo (C1-C8) alkoxy, wherein said substituted halo (C1-C8) alkoxy has one or more substituents selected from CN and NO2;

(f) R6 is (C1-C8) haloalkyl;

(g) R7 is selected from H, F, Cl, Br, I, OH, (C1-C8) alkoxy, and halo (C1-C8) alkoxy;

(h) R8 is selected from H, (C.₁-C₈) alkyl, halo (C.₁-C₈) alkyl, OR14, and N (R14) (R15);

(i) R9 is selected from H, F, Cl, Br, I, (C1-C8) alkyl, halo (C1-C8) alkyl, (C1-C8) alkoxy, halo (C1-C8)₈) alkoxy, OR14, and N (R14) (R15);

(j) R10 is selected from (1) H, F, Cl, Br, I, CN, NO2, (C₁-C₈) alkyl, halo (C.₁-C₈) alkyl, (C.₁-C₈) alkoxy, halo (C.₁-C₈) alkoxy, cyclo (C₃-C₆) alkyl, S (C.₁-C₈) alkyl, S (halo (C.₁-C₈) alkyl), S (O) (C.₁-C₈) alkyl, S (O) (halo (C₁-C₈) alkyl), S (O)₂(C.₁-C₈) alkyl, S (O)₂(halo (C₁-C₈) alkyl), NR14R15, C (= O) H, C (= O) N (R14) (R15),

CN (R14) (R15) (= NOH), (C = O) O (C1-C8) alkyl, (C = O) OH, heterocyclyl, (C2-C8) alkenyl, halo (C2-C8) alkenyl, ( C2-C8) alkynyl, (2) substituted (C1-C8) alkyl, wherein said substituted (C1-C8) alkyl has one or more substituents selected from OH, (C1-C8) alkoxy, S (C1-C8) alkyl, S (O) (C1-C8) alkyl, S (O) 2 (C1-C8) alkyl, NR14R15, and

(3) substituted halo (C1-C8) alkyl, wherein said substituted halo (C1-C8) alkyl has one or more substituents selected from (C1-C8) alkoxy, S (C1-C8) alkyl, S (O ) (C1-C8) alkyl,

S (O)₂(C.₁-C₈) alkyl, and N (R14) (R15);

(k) R11 is C (= X5) N (H) ((C₀-C₈) alkyl) N (R11a) (C (= X5) (R11b)) where each X5 is independently selected from O or S, and where each R11a is independently selected from H, (C1-C8) alkyl, substituted (C1-C8 ) alkyl, halo (C1-C8) alkyl, substituted halo (C1-C8) alkyl, cyclo (C3-C8) alkyl, and substituted cyclo (C3-C8) alkyl, each said substituted (C1-C8) alkyl having one or more substituents selected from F, Cl, Br, I, CN, NO2, OC (= O) H, OH, S (C₁-C₈) alkyl, S (O) (C.₁-C₈) alkyl, S (O)₂(C.₁-C₈) alkyl, OS (O) 2aryl, N ((C1-C8) alkyl) 2 (where each (C1-C8) alkyl is independently selected), aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, each of said substituted aryls having one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8) alkyl, halo (C1C₈) alkyl, (C.₁-C₈) alkoxy, halo (C.₁-C₈) alkoxy, S (C₁-C₈) alkyl, S (halo (C.₁-C₈) alkyl), N ((C₁C8) alkyl) 2 (where each (C1-C8) alkyl is independently selected), and oxo, wherein each of said substituted heterocycles has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1- C8) alkyl, halo (C1-C8) alkyl, (C1-C8) alkoxy, halo (C1-C8) alkoxy, S (C1-C8) alkyl, S (halo (C1-C8) alkyl), N ((C1-C8) ) alkyl) 2 (where each (C1-C8) alkyl is independently selected), C (= O) (C1-C8) alkyl, C (= O) (C3-C6) cycloalkyl, S (= O) 2 (C1 -C8) alkyl, NR14R15, and oxo, wherein each said substituted aryl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8) alkyl, halo (C1C₈) alkyl, (C.₁-C₈) alkoxy, halo (C.₁-C₈) alkoxy, S (C₁-C₈) alkyl, S (halo (C.₁-C₈) alkyl), N ((C₁C8) alkyl) 2 (where each (C1-C8) alkyl is independently selected), and oxo, wherein said substituted halo (C1-C8) alkyl has one or more substituents selected from CN and NO2, wherein said substituted cyclo (C3- C8) alkyl has one or more substituents selected from CN and NO2, where each R11b is independently selected from (C1-C8) alkyl, substituted (C1-C8) alkyl, halo (C1-C8) alkyl, substituted halo (C1-C8) ) alkyl, cyclo (C3-C8) alkyl, substituted cyclo (C3-C8) alkyl, wherein each said substituted (C1-C8) alkyl has one or more substituents selected from F, Cl, Br, I, CN, NO2, OC (= O) H, OH, S (C₁-C₈) alkyl, S (O) (C.₁-C₈) alkyl, S (O)₂(C.₁-C₈) alkyl, OS (O) 2aryl, N ((C1-C8) alkyl) 2 (where each (C1-C8) alkyl is independently selected), aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, each of said substituted aryls having one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8) alkyl, halo (C1-C8) alkyl, (C1-C8) alkoxy, halo (C1-C8) alkoxy, S (C1- C8) alkyl, S (halo (C1-C8) alkyl), N ((C1-C8) alkyl) 2 (where each (C1-C8) alkyl is independently selected), and oxo, wherein each of said substituted heterocycles has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C₁-C₈) alkyl, halo (C.₁-C₈) alkyl, (C.₁-C₈) alkoxy, halo (C.₁-C₈) alkoxy, S (C₁-C₈) alkyl, S (halo (C.₁C8) alkyl), N ((C1-C8) alkyl) 2 (where each (C1-C8) alkyl is independently selected), C (= O) (C1-C8) alkyl, C (= O) (C3-C6 ) cycloalkyl, S (= O) 2 (C1-C8) alkyl, NR14R15, and oxo, wherein each said substituted aryl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8) alkyl, halo (C1

EP-2934142B1PL

C8) alkyl, (C1-C8) alkoxy, halo (C1-C8) alkoxy, S (C1-C8) alkyl, S (halo (C1-C8) alkyl), N ((C1-C8) alkyl) 2 (where each ( Ci-C₈) alkyl is independently selected), and oxo, wherein said substituted halo (C1-C8) alkyl has one or more substituents selected from

CN and NO₂wherein said substituted cyclo (C3-C8) alkyl has one or more substituents selected from CN and NO₂;

(l) R12 is selected from (v), H, F, Cl, Br, I, CN, (C1-C₈) alkyl, halo (C1-C₈) alkyl, (C1-C₈) alkoxy, halo (C1-C₈) alkoxy, and cyclo (C3-C6) alkyl;

(m) R13 is selected from (v), H, F, Cl, Br, I, CN, (C1-C₈) alkyl, halo (C1-C₈) alkyl, (C1-C₈) alkoxy, and halo (C1-C₈) alkoxy;

(n) each R14 is independently selected from H, (C1-C₈) alkyl, (C2-C8) alkenyl, substituted (C1-C8) alkyl, halo (C1-C8) alkyl, substituted halo (C1-C8) alkyl), (C1-C8) alkoxy, cyclo (C3-C6) alkyl, aryl , substituted aryl, (C1-C8) alkyl-aryl, (C1-C8) alkyl- (substituted aryl), O- (C1-C8) alkylaryl, O- (C1-C8) alkyl- (substituted aryl), heterocyclyl, substituted heterocyclyl, (C1-C8) alkylheterocyclyl, (C1-C8) alkyl- (substituted heterocyclyl), O- (C1-C8) alkyl heterocyclyl, O- (C1-C₈) alkyl (substituted heterocyclyl), N (R16) (R17), (C1-C₈) alkyl-C (= O) N (R16) (R17), C (= O) (C.₁-C₈) alkyl, C (= O) (halo (C₁-C₈) alkyl), C (= O) (C₃-C₆) cycloalkyl, (C₁-C₈) alkyl-C (= O) O (C.₁-C₈) alkyl, C (= O) H wherein each said substituted (C1-C8) alkyl has one or more substituents selected from CN, and NO2, wherein each said substituted halo (C1-C8) alkyl has one or more substituents selected from CN , and NO2, wherein each said substituted aryl has one or more substituents selected from F, Cl, Br, I, CN, NO₂, (C₁-C₈) alkyl, halo (C.₁-C₈) alkyl, (C1-C₈) alkoxy, halo (C1-C₈) alkoxy, S (C1-C8) alkyl, S (halo (C1-C8) alkyl), N ((C1-C8) alkyl) 2 (where each (C1-C8) alkyl is independently selected, and oxo, and where each said substituted heterocyclyl has one or more substituents selected from F, Cl, Br, I, CN, NO₂, (C₁-C₈) alkyl, halo (C.₁-C₈) alkyl, (C1-C₈) alkoxy, halo (C1-C₈) alkoxy, (C₃-C₆) cycloalkyl S (C₁-C₈) alkyl, S (halo (C.₁-C₈) alkyl), N ((C₁-C₈) alkyl)₂, (where each (C₁-C₈) alkyl is independently selected), heterocyclyl, C (= O) (C1-C8) alkyl, C (= O) O (C1-C8) alkyl, and oxo, (where said alkyl, alkoxy, and heterocyclyl may be further substituted by one or more of F, Cl, Br, I, CN, and NO2);

(o) each R15 is independently selected from H, (C1-C8) alkyl, (C2-C8) alkenyl, substituted (C1-C8) alkyl, halo (C1-C8) alkyl, substituted halo (C1-C8) alkyl), ( C1-C8) alkoxy, cyclo (C3-C6) alkyl, aryl, substituted aryl, (C1-C8) alkyl-aryl, (C1-C8) alkyl- (substituted aryl), O- (C1-C8) alkylaryl, O - (C1-C8) alkyl- (substituted aryl), heterocyclyl, substituted heterocyclyl, (C1-C8) alkylheterocyclyl, (C1-C8) alkyl- (substituted heterocyclyl), O- (C1-C8) alkyl heterocyclyl, O- (C1-C8) alkyl (substituted heterocyclyl), N (R16) (R17), (C1-C8) alkyl-C (= O) N (R16) (R17), C (= O) (C1-C8 ) alkyl, C (= O) (halo (C1-C8) alkyl), C (= O) (C3-C6) cycloalkyl, (C1-C8) alkyl-C (= O) O (C1-C8) alkyl, C (= O) H wherein each said substituted (C1-C8) alkyl has one or more substituents selected from CN, and NO2, wherein each said substituted halo (C1-C8) alkyl has one or more substituents selected from CN, and NO2 ,

EP-2934142B1PL wherein each said substituted aryl has one or more substituents selected from F, Cl,

Br, I, CN, NO2, (C1-C8) alkyl, halo (C1-C8) alkyl, (C1-C8) alkoxy, halo (C1-C8) alkoxy, S (C1-C8) alkyl, S (halo (C1- C8) alkyl), N ((C1-C8) alkyl) 2 (where each (C1-C8) alkyl is independently selected), and oxo, and wherein each said substituted heterocyclyl has one or more substituents selected from F, Cl, Br , I, CN, NO2, (C1-C₈) alkyl, halo (C1-C₈) alkyl, (C1-C₈) alkoxy, halo (C1-C₈) alkoxy, (C3-C6) cycloalkyl, S (C1-C8) alkyl, S (halo (C1-C8) alkyl), N ((C1-C8) alkyl) 2, (where each (C1-C8) alkyl is selected independently), heterocyclyl, C (= O) (C1-C8) alkyl, C (= O) O (C1-C8) alkyl, and oxo, (where said alkyl, alkoxy, and heterocyclyl may be further substituted with one or more among F, Cl, Br, I, CN, and NO2);

(p) each R16 is independently selected from H, (C1-C8) alkyl, substituted (C1-C8) alkyl, halo (C1-C8) alkyl, substituted halo (C1-C8) alkyl, cyclo (C3-C6) alkyl, aryl , substituted aryl, (C1-C8) alkyl-aryl, (C1-C8) alkyl- (substituted aryl), O- (C1-C8) alkyl-aryl, O- (C1-C8) alkyl (substituted aryl), heterocyclyl, substituted heterocyclyl, (C1-C8) alkyl-heterocyclyl, (C1-C8) alkyl- (substituted heterocyclyl), O- (C1-C8) alkyl-heterocyclyl, O- (C1-C8) alkyl- (substituted heterocyclyl), O- (C1-C8) alkyl wherein each said substituted (C1-C8) alkyl has one or more substituents selected from CN, and NO2, each said substituted halo ( C1-C8) alkyl has one or more substituents selected from CN, and NO2, wherein each said substituted aryl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8) alkyl, halo ( C1-C8) alkyl, (C1-C8) alkoxy, halo (C1-C8) alkoxy, S (C1-C8) alkyl, S (halo (C1-C8) alkyl), N ((C1-C8) alkyl) 2 (where each (C1-C8) alkyl is independently selected), and oxo, and wherein each said substituted heterocyclyl has one or more substituents selected among F, Cl, Br, I, CN, NO2, (C1-C8) alkyl, halo (C1-C8) alkyl, (C1-C8) alkoxy, halo (C1-C8) alkoxy, S (C1-C8) alkyl, S (halo (C1-C8) alkyl), N ((C1-C8) alkyl) 2 (where each (C1-C8) alkyl is independently selected), and oxo;

(q) each R17 is independently selected from H, (C1-C8) alkyl, substituted (C1-C8) alkyl, halo (C1-C8) alkyl, substituted halo (C1-C8) alkyl, cyclo (C3-C6) alkyl, aryl , substituted aryl, (C1-C8) alkyl-aryl, (C1-C8) alkyl- (substituted aryl), O- (C1-C8) alkyl-aryl, O- (C1-C8) alkyl (substituted aryl), heterocyclyl, substituted heterocyclyl, (C1-C8) alkyl-heterocyclyl, (C1-C8) alkyl- (substituted heterocyclyl), O- (C1-C8) alkyl-heterocyclyl, O- (C1-C8) alkyl- (substituted heterocyclyl), O- (C1-C8) alkyl wherein each said substituted (C1-C8) alkyl has one or more substituents selected from CN, and NO2, each said substituted halo ( C1-C8) alkyl has one or more substituents selected from CN, and NO2, wherein each said substituted aryl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8) alkyl, halo ( C1-C8) alkyl, (C1-C8) alkoxy, halo (C1-C8) alkoxy, S (C1-C8) alkyl, S (halo (C1-C8) alkyl), N ((C1-C8) alkyl) 2 (where each (C1-C8) alkyl is independently selected), and oxo, and

EP-2934142B1PL wherein each said substituted heterocyclyl has one or more substituents selected from

F, Cl, Br, I, CN, NO2, (C.₁-C8) alkyl, halo (C.₁-C8) alkyl, (C1-C8) alkoxy, halo (C1-C8) alkoxy, S (C1-C8) alkyl, S (halo (C1-C8) alkyl), N ((C1-C8) alkyl) 2 (where each (C1-C8) alkyl is independently selected), and oxo;

(r) X1 is selected from N and CR12;

(s) X2 is selected from N, CR9, and CR13;

(t) X3 is selected from N and CR9; and (v) R12 and R13 together form a linkage containing 3 to 4 atoms selected from C, N, O, and S, wherein said link is back-linked to the ring to form a 5 to 6 membered saturated or unsaturated cyclic ring, wherein said the connection has at least one X4, where X4 is selected from R14, N (R14) (R15), N (R14) (C (= O) R14), N (R14) (C (= S) R14), N (R14) (C (= O) N (R14) (R14)), N (R14) (C (= S) N (R14) (R14)), N (R14) (C (= O) N (R14 ) ((C₂C8) alkenyl)), N (R14) (C (= S) N (R14) ((C2-C8) alkenyl)), wherein each R14 is independently selected.

[0027] In another embodiment of the present invention, R1 may be selected from any combination of one or more of - H, F, Cl, Br, I, CN, NO2, methyl, ethyl, (C3) alkyl, (C6) alkyl, (C5) alkyl, (C6) alkyl, (C7) alkyl, (C8) alkyl, halomethyl, haloethyl, halo (C3) alkyl, halo (C4) alkyl, halo (C5) alkyl, halo (C6) alkyl, halo ( C7) alkyl, halo (C8) alkyl, methoxy, ethoxy, (C3) alkoxy, (C4) alkoxy, (C5) alkoxy, (C6) alkoxy, (C7) alkoxy, (C8) alkoxy, halomethoxy, haloethoxy, halo (C3) alkoxy, halo (C4) alkoxy, halo (C5) alkoxy, halo (C6) alkoxy, halo (C7) alkoxy, and halo (C8) alkoxy.

[0028] In another embodiment of the present invention, R2 may be selected from any combination of one or more of - H, F, Cl, Br, I, CN, NO2, methyl, ethyl, (C3) alkyl, (C4) alkyl, (C5) alkyl, (C6) alkyl, (C7) alkyl, (C8) alkyl, halomethyl, haloethyl, halo (C3) alkyl, halo (C4) alkyl, halo (C5) alkyl, halo (C6) alkyl, halo ( C7) alkyl, halo (C8) alkyl, methoxy, ethoxy, (C3) alkoxy, (C4) alkoxy, (C5) alkoxy, (C6) alkoxy, (C7) alkoxy, (C8) alkoxy, halomethoxy, haloethoxy, halo (C3) alkoxy, halo (C4) alkoxy, halo (C5) alkoxy, halo (C6) alkoxy, halo (C7) alkoxy, and halo (C8) alkoxy.

[0029] In another embodiment of the present invention, R3 may be selected from any combination of one or more of - H, F, Cl, Br, I, CN, NO2, methyl, ethyl, (C3) alkyl, (C4) alkyl, (C5) alkyl, (C6) alkyl, (C7) alkyl, (C8) alkyl, halomethyl, haloethyl, halo (C3) alkyl, halo (C4) alkyl, halo (C5) alkyl, halo (C6) alkyl, halo ( C7) alkyl, halo (C8) alkyl, methoxy, ethoxy, (C3) alkoxy, (C4) alkoxy, (C5) alkoxy, (C6) alkoxy, (C7) alkoxy, (C8) alkoxy, halomethoxy, haloethoxy, halo (C3) alkoxy, halo (C4) alkoxy, halo (C5) alkoxy, halo (C6) alkoxy, halo (C7) alkoxy, and halo (C8) alkoxy.

[0030] In another embodiment of the present invention, R4 may be selected from any combination of one or more of - H, F, Cl, Br, I, CN, NO2, methyl, ethyl, (C3) alkyl, (C4) alkyl, (C5) alkyl, (C6) alkyl, (C7) alkyl, (C8) alkyl, halomethyl, haloethyl, halo (C3) alkyl, halo (C4) alkyl, halo (C5) alkyl, halo (C6) alkyl, halo ( C7) alkyl, halo (C8) alkyl, methoxy, ethoxy, (C3) alkoxy, (C4) alkoxy, (C5) alkoxy, (C6) alkoxy, (C7) alkoxy, (C8) alkoxy, halomethoxy, haloethoxy, halo (C3) alkoxy, halo (C4) alkoxy, halo (C5) alkoxy, halo (C6) alkoxy, halo (C7) alkoxy, and halo (C8) alkoxy.

EP-2934142B1PL

[0031] In another embodiment of the present invention, R5 may be selected from any combination of one or more of - H, F, Cl, Br, I, CN, NO₂, methyl, ethyl, (C.₃) alkyl, (C4) alkyl, (C8) alkyl, (C6) alkyl, (C7) alkyl, (C8) alkyl, halomethyl, haloethyl, halo (C3) alkyl, halo (C4) alkyl, halo (C5) alkyl, halo (C6) alkyl, halo (C7) alkyl, halo (C8) alkyl, methoxy, ethoxy, (C3) alkoxy, (C4) alkoxy, (C5) alkoxy, (C6) alkoxy, (C7) alkoxy, (C8) alkoxy, halomethoxy, haloethoxy, halo (C3) alkoxy, halo (C4) alkoxy, halo (C5) alkoxy, halo (C6) alkoxy, halo (C7) alkoxy, and halo (C8) alkoxy.

[0032] In another embodiment of the present invention, R2 and R4 are selected from F, Cl, Br, I, CN, and NO₂ and R1, R3, and R5 are H.

[0033] In another embodiment of the present invention, R2, R3, and R4 are selected from F, Cl, Br, I, CN, and NO₂ and R1, and R5 are H.

[0034] In another embodiment of the present invention, R2, R3, and R4 are independently selected from F and Cl and R1 and R5 are H.

[0035] In another embodiment of the present invention, R1 is selected from Cl and H.

[0036] In another embodiment of the present invention, R2 is selected from CF3, CH3, Cl, F, and H.

[0037] In another embodiment of the present invention, R3 is selected from OCH3, CH3, F, Cl, or H.

[0038] In another embodiment of the present invention, R4 is selected from CF3, CH3, Cl, F, and H.

[0039] In another embodiment of the present invention, R5 is selected from F, Cl, and H.

[0040] In another embodiment of the present invention, R6 may be selected from any combination of one or more of - halomethyl, haloethyl, halo (C3) alkyl, halo (C4) alkyl, halo (C5) alkyl, halo (C6) alkyl, halo (C7) alkyl, and halo (C8) alkyl.

[0041] In another embodiment of the present invention, R6 is trifluoromethyl.

[0042] In another embodiment of the present invention, R7 may be selected from any combination of one or more of - H, F, Cl, Br, and I.

[0043] In another embodiment of the present invention, R7 is selected from H, OCH3, and OH.

[0044] In another embodiment of the present invention, R8 may be selected from any combination of one or more of - H, methyl, ethyl, (C3) alkyl, (C4) alkyl, (C5) alkyl, (C6) alkyl, (C7 ) alkyl, (C8) alkyl, halomethyl, haloethyl, halo (C3) alkyl, halo (C4) alkyl, halo (C5) alkyl, halo (C6) alkyl, halo (C7) alkyl, and halo (C8) alkyl.

[0045] In another embodiment of the present invention, R8 is selected from CH3 and H.

[0046] In another embodiment of the present invention, R9 may be selected from any combination of one or more of - H, F, Cl, Br, I, methyl, ethyl, (C3) alkyl, (C4) alkyl, (C5) alkyl , (C6) alkyl, (C7) alkyl, (C8) alkyl, halomethyl, haloethyl, halo (C3) alkyl, halo (C4) alkyl, halo (C5) alkyl, halo (C6) alkyl, halo (C7) alkyl, halo (C8) alkyl, methoxy, ethoxy, (C3) alkoxy, (C4) alkoxy, (C5) alkoxy, (C6) alkoxy, (C7) alkoxy, (C8) alkoxy, halomethoxy, haloethoxy, halo (C3) alkoxy, halo (C4) alkoxy, halo (C5) alkoxy, halo (C6) alkoxy, halo (C7) alkoxy, and halo (C8) alkoxy.

[0047] In another embodiment of the present invention, R10 may be selected from any combination of one or more of - H, F, Cl, Br, I, CN, methyl, ethyl, (C3) alkyl, (C4) alkyl,

EP-2934142B1PL (C5) alkyl, (Cg) alkyl, (Cy) alkyl, (C₈) alkyl, halomethyl, haloethyl, halo (C3) alkyl, halo (C4) alkyl, halo (C5) alkyl, halo (C8) alkyl, halo (Cy) alkyl, halo (C₈) alkyl, methoxy, ethoxy, (C3) alkoxy, (C4) alkoxy, (Cg) alkoxy, (Cg) alkoxy, (Cy) alkoxy, (C₈) alkoxy, halomethoxy, haloethoxy, halo (C3) alkoxy, halo (C4) alkoxy, halo (C₃) alkoxy, halo (Cg) alkoxy, halo (Cy) alkoxy, halo (C₈) alkoxy, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0048] In another embodiment of the present invention, R10 may be selected from any combination of one or more of - H, Cl, Br, CH3, and CF3.

[0049] In another embodiment of the present invention, R10 is selected from Br, C (= NOH) NH₂, C (= O) H, C (= O) NH₂, C (= O) OCH₂CH₃, C (= O) OH, CF₃, CH₂CH₃, CH2OH, CH3, Cl, CN, F, H, NH₂, NHC (= O) H, NHCH3, NO₂Oh₃, OCHF2, and pyridyl.

[0050] In another embodiment of the present invention, R11 is selected from

C (= O) N (H) N (CH3) (C (= O) N (H) (CH2CH3)), C (= O) N (H) N (CH3) (C (= O) N (H ) (CH2CF3)), C (= O) N (H) N (CH₃) (C (= S) N (H) (CH2CH₃)), C (= O) N (H) N (CH₃) (C (= S) N (H) (CH2CF₃)), C (= O) N (H) CH2CH2N (CH₃) (C (= O) N (H) (CH2CH₃)), and C (= O) N (H) CH2CH2N (CH₃) (C (= S) N (H) (CH2CF₃)). [0051] In another embodiment of the present invention, R12 may be selected from any combination of one or more of - H, F, Cl, Br, I, methyl, ethyl, (C3) alkyl, (C4) alkyl, (C8) alkyl , (C8) alkyl, (Cy) alkyl, (C₈) alkyl, halomethyl, haloethyl, halo (C3) alkyl, halo (C4) alkyl, halo (C5) alkyl, halo (C8) alkyl, halo (Cy) alkyl, halo (C₈) alkyl, halomethoxy, haloethoxy, halo (C3) alkoxy, halo (C4) alkoxy, halo (C₃) alkoxy, halo (Cg) alkoxy, halo (Cy) alkoxy, and halo (C₈) alkoxy.

[0052] In another embodiment of the present invention, R12 is selected from CH3, and H.

[0053] In another embodiment of the present invention, R13 may be selected from any combination of one or more of - H, F, Cl, Br, I, methyl, ethyl, (C3) alkyl, (C4) alkyl, (C8) alkyl , (C8) alkyl, (Cy) alkyl, (C₈) alkyl, halomethyl, haloethyl, halo (C3) alkyl, halo (C4) alkyl, halo (C5) alkyl, halo (C8) alkyl, halo (Cy) alkyl, halo (C₈) alkyl, halomethoxy, haloethoxy, halo (C3) alkoxy, halo (C4) alkoxy, halo (C₃) alkoxy, halo (Cg) alkoxy, halo (Cy) alkoxy, and halo (C₈) alkoxy.

[0054] In another embodiment of the present invention, R13 is selected from CH3, Cl and H.

[0055] In another embodiment of the present invention, R12-R13 are a hydrocarbon linkage comprising CH = CHCH = CH.

In another embodiment of the present invention, R14 may be selected from any combination of one or more of - H, methyl, ethyl, (C3) alkyl, (C4) alkyl, (C8) alkyl, (C8) alkyl, (Cy ) alkyl, (C.₈) alkyl, halomethyl, haloethyl, halo (C3) alkyl, halo (C4) alkyl, halo (C₃) alkyl, halo (C6) alkyl, halo (Cy) alkyl, halo (C.₈) alkyl, methyl aryl, ethyl aryl, (C3) alkyl aryl, (C4) alkylaryl, (Cs) alkyl aryl, (Cg) alkyl aryl, (Cy) alkyl aryl, (C₈) alkyl-aryl, methyl (substituted aryl), ethyl (substituted aryl), (C3) alkyl- (substituted aryl), (C4) alkyl- (substituted aryl), (Cg) alkyl (substituted aryl), (Cg) alkyl- (substituted aryl), (Cy) alkyl- (substituted aryl), (C₈) alkyl (substituted aryl), O-methyl-aryl, O-ethyl-aryl, O- (C3) alkyl-aryl, O- (C4) alkyl-aryl, O- (C₃) alkylaryl, O- (Cg) alkyl-aryl, O- (Cy) alkyl-aryl, O- (C₈) alkyl-aryl, O-methyl- (substituted aryl), O-ethyl (substituted aryl), O- (C3) alkyl- (substituted aryl), O- (C4) alkyl- (substituted aryl), O (Cs) alkyl- (substituted aryl), O- (C8) alkyl- (substituted aryl), O- (Cy) alkyl- (substituted aryl), O- (C₈) alkyl- (substituted aryl), methyl-heterocyclyl, ethyl-heterocyclyl, (C3) alkyl

EP-2934142B1PL heterocyclyl, (C4) alkylheterocyclyl, (C5) alkylheterocyclyl, (C6) alkylheterocyclyl, (Cy) alkylheterocyclyl, (Cg) alkylheterocyclyl, methyl- (substituted heterocyclyl), ethyl- (substituted heterocyclyl) ), (C3) alkyl- (substituted heterocyclyl), (C4) alkyl- (substituted heterocyclyl), (Cs) alkyl- (substituted heterocyclyl), (C6) alkyl- (substituted heterocyclyl), (Cy) alkyl (substituted heterocyclyl) , (C8) alkyl- (substituted heterocyclyl), O-methyl-heterocyclyl, O-ethylheterocyclyl, O- (C3) alkylheterocyclyl, O- (C4) alkylheterocyclyl, O- (Cg) alkylheterocyclyl, O (Cg) alkylheterocyclyl, O- (Cy) alkyl-heterocyclyl, O- (C6) alkyl-heterocyclyl, O-methyl- (substituted heterocyclyl), O-ethyl- (substituted heterocyclyl), O- (C3) alkyl- (substituted heterocyclyl), O (C4) alkyl- ( substituted heterocyclyl), O- (C.₃) alkyl- (substituted heterocyclyl), O- (C6) alkyl (substituted heterocyclyl), O- (Cy) alkyl- (substituted heterocyclyl), O- (C8) alkyl- (substituted heterocyclyl), methyl-C (= O) N (R16) (Riy), ethyl-C (= O) N (R16) (Riy), (C₃) alkyl-C (= O) N (R16) (Riy), (C₄) alkyl-C (= O) N (R16) (Riy), (C₅) alkyl-C (= O) N (R16) (Riy), (C₆) alkyl-C (= O) N (R16) (Riy), (C_y) alkylC (= O) N (R16) (R and y), and (C8) alkyl-C (= O) N (R16) (R and y).

[0057] In another embodiment of the present invention, R14 may be selected from any combination of one or more of - H, CH3, CH2CF3, CH2-halopyridyl, oxo-pyrrolidinyl, halophenyl, thiethanyl, CH2-phenyl, CH2-pyridyl, thiethanyl dioxide , CH2-halothiazolyl, C ((CH3) 2) -pyridyl, N (H) (halophenyl), CH2-pyrimidinyl, CH2-tetrahydrofuranyl, CH2-furanyl, O-CH2-halopyridyl, and CH2C (= O) N (H ) (CH2CF3).

[0058] In another embodiment of the present invention, R15 may be selected from any combination of one or more of - H, methyl, ethyl, (C3) alkyl, (C4) alkyl, (C8) alkyl, (C6) alkyl, (Cy ) alkyl, (C8) alkyl, halomethyl, haloethyl, halo (C3) alkyl, halo (C4) alkyl, halo (C₃) alkyl, halo (C6) alkyl, halo (Cy) alkyl, halo (Cg) alkyl, methyl aryl, ethyl aryl, (C3) alkyl aryl, (C4) alkylaryl, (Cg) alkyl aryl, (C6 ) alkyl-aryl, (Cy) alkyl-aryl, (Cg) alkyl-aryl, methyl- (substituted aryl), ethyl (substituted aryl), (C3) alkyl- (substituted aryl), (C4) alkyl- (substituted aryl) ), (C8) alkyl (substituted aryl), (C6) alkyl- (substituted aryl), (Cy) alkyl- (substituted aryl), (C8) alkyl (substituted aryl), O-methyl-aryl, O-ethyl- aryl, O- (C3) alkyl-aryl, O- (C4) alkyl-aryl, O- (C.₃) alkylaryl, O- (C6) alkyl-aryl, O- (Cy) alkyl-aryl, O- (Cg) alkyl-aryl, O-methyl- (substituted aryl), O-ethyl (substituted aryl), O- ( C3) alkyl- (substituted aryl), O- (C4) alkyl- (substituted aryl), O (Cg) alkyl- (substituted aryl), O- (C6) alkyl- (substituted aryl), O- (Cy) alkyl - (substituted aryl), O- (C6) alkyl- (substituted aryl), methyl-heterocyclyl, ethyl-heterocyclyl, (C3) alkylheterocyclyl, (C4) alkyl-heterocyclyl, (C5) alkyl-heterocyclyl, (C6) alkyl- heterocyclyl, (Cy) alkylheterocyclyl, (Cg) alkylheterocyclyl, methyl- (substituted heterocyclyl), ethyl- (substituted heterocyclyl), (C3) alkyl- (substituted heterocyclyl), (C4) alkyl- (substituted heterocyclyl), (Cs) alkyl - (substituted heterocyclyl), (C6) alkyl- (substituted heterocyclyl), (Cy) alkyl (substituted heterocyclyl), (C8) alkyl- (substituted heterocyclyl), O-methyl heterocyclyl, O-ethylheterocyclyl, O- (C3) alkyl-heterocyclyl, O- (C4) alkyl-heterocyclyl, O- (C5) alkylheterocyclyl, O (C6) alkylheterocyclyl, O- (Cy) alkylheterocyclyl, O- (C8) alkylheterocyclyl, O-methyl- (substituted heterocyclyl), O-ethyl- (substituted heterocyclyl), O- (C3) alkyl- (substituted heterocyclyl), O (C4) alkyl- (substituted heterocyclyl), O- (C8) alkyl- (substituted heterocyclyl), O- (C6) alkyl (substituted heterocyclyl), O - (Cy) alkyl- (substituted heterocyclyl), O- (Cg) alkyl- (substituted heterocyclyl), methyl-C (= O) N (R16) (R17)_&gt; ethyl-C (= O) N (R16) (R17)_&gt; (C.₃) alkyl-C (= O) N (R16) (Riy),

EP-2934142B1PL (C4) alkyl-C (= O) N (R16) (R17), (C5) alkyl-C (= O) N (R16) (R17), (C₆) alkyl-C (= O) N (R16) (R17), (C₇) alkylC (= O) N (R16) (R17), and (Ce) alkyl-C (= O) N (R16) (R17).

[0059] In another embodiment of the present invention, R15 may be selected from any combination of one or more of - H, CH3, CH2CF3, CH2-halopyridyl, oxo-pyrrolidinyl, halophenyl, thiethanyl, CH2-phenyl, CH2-pyridyl, thiethanyl dioxide , CH2-halothiazolyl, C ((CH3) 2) -pyridyl, N (H) (halophenyl), CH2-pyrimidinyl, CH2-tetrahydrofuranyl, CH2-furanyl, O-CH2-halopyridyl, and CH2C (= O) N (H ) (CH2CF3).

[0060] In another embodiment of the present invention, R16 may be selected from any combination of one or more of - H, methyl, ethyl, (C3) alkyl, (C4) alkyl, (C5) alkyl, (C6) alkyl, (C7 ) alkyl, (C8) alkyl, halomethyl, haloethyl, halo (C3) alkyl, halo (C4) alkyl, halo (C5) alkyl, halo (C6) alkyl, halo (C7) alkyl, halo (C₃) alkyl, methyl aryl, ethyl aryl, (C3) alkyl aryl, (C4) alkylaryl, (C5) alkyl aryl, (C6) alkyl aryl, (C7) alkyl aryl, (Cg) alkyl aryl , methyl- (substituted aryl), ethyl (substituted aryl), (C3) alkyl- (substituted aryl), (C4) alkyl- (substituted aryl), (C5) alkyl (substituted aryl), (C6) alkyl- (substituted aryl) aryl), (C7) alkyl- (substituted aryl), (Cg) alkyl (substituted aryl), O-methyl-aryl, O-ethyl-aryl, O- (C3) alkyl-aryl, O- (C4) alkyl- aryl, O- (C5) alkylaryl, O- (C6) alkyl-aryl, O- (C7) alkyl-aryl, O- (C₃) alkyl-aryl, O-methyl- (substituted aryl), O-ethyl (substituted aryl), O- (C3) alkyl- (substituted aryl), O- (C4) alkyl- (substituted aryl), O (C5) alkyl- (substituted aryl), O- (C6) alkyl- (substituted aryl), O- (C7) alkyl- (substituted aryl), O- (C₃) alkyl- (substituted aryl), methyl-heterocyclyl, ethyl-heterocyclyl, (C3) alkylheterocyclyl, (C4) alkyl-heterocyclyl, (C5) alkyl-heterocyclyl, (C6) alkyl-heterocyclyl, (C7) alkylheterocyclyl, (C₃) alkyl-heterocyclyl, methyl- (substituted heterocyclyl), ethyl- (substituted heterocyclyl), (C3) alkyl- (substituted heterocyclyl), (C4) alkyl- (substituted heterocyclyl), (C5) alkyl- (substituted heterocyclyl), ( C6) alkyl- (substituted heterocyclyl), (C7) alkyl (substituted heterocyclyl), (Cg) alkyl- (substituted heterocyclyl), O-methyl-heterocyclyl, O-ethylheterocyclyl, O- (C3) alkyl-heterocyclyl, O- ( C4) alkyl-heterocyclyl, O- (C5) alkyl-heterocyclyl, O (C6) alkylheterocyclyl, O- (C7) alkylheterocyclyl, O- (C₃) alkyl-heterocyclyl, O-methyl- (substituted heterocyclyl), O-ethyl- (substituted heterocyclyl), O- (C3) alkyl- (substituted heterocyclyl), O- (C4) alkyl- (substituted heterocyclyl), O- ( C5) alkyl- (substituted heterocyclyl), O- (C6) alkyl- (substituted heterocyclyl), O- (C7) alkyl- (substituted heterocyclyl), and O- (C₃) alkyl- (substituted heterocyclyl).

[0061] In another embodiment of the present invention, R16 may be selected from any combination of one or more of - H, CH2CF3, cyclopropyl, tietanyl, tietanyl dioxide, and halophenyl.

[0062] In another embodiment of the present invention, R17 may be selected from any combination of one or more of - H, methyl, ethyl, (C3) alkyl, (C4) alkyl, (C5) alkyl, (C6) alkyl, (C7 ) alkyl, (C8) alkyl, halomethyl, haloethyl, halo (C3) alkyl, halo (C4) alkyl, halo (C5) alkyl, halo (C6) alkyl, halo (C7) alkyl, halo (C₃) alkyl, methyl aryl, ethyl aryl, (C3) alkyl aryl, (C4) alkyl aryl, (C5) alkyl aryl, (C6) alkyl aryl, (C7) alkyl aryl, (Cg) alkyl -aryl, methyl- (substituted aryl), ethyl (substituted aryl), (C3) alkyl- (substituted aryl), (C4) alkyl- (substituted aryl), (C5) alkyl (substituted aryl), (C6) alkyl- (substituted aryl), (C7) alkyl- (substituted aryl), (C8) alkyl (substituted aryl), O-methyl-aryl, O-ethyl-aryl, O- (C3) alkyl-aryl, O- (C4) alkyl-aryl, O- (C5) alkylaryl, O- (C6) alkyl-aryl, O- (C7) alkyl-aryl, O- (C₃) alkyl-aryl, O-methyl- (substituted aryl), O-ethyl

EP-2934142B1PL (substituted aryl), O- (C3) alkyl- (substituted aryl), O- (C4) alkyl- (substituted aryl), O (C5) alkyl- (substituted aryl), O- (C6) alkyl- (substituted aryl), O- (C7) alkyl- (substituted aryl), O- (C8) alkyl- (substituted aryl), methyl-heterocyclyl, ethyl-heterocyclyl, (C3) alkylheterocyclyl, (C4) alkyl-heterocyclyl, ( C5) alkyl-heterocyclyl, (C6) alkyl-heterocyclyl, (C7) alkylheterocyclyl, (C8) alkyl-heterocyclyl, methyl- (substituted heterocyclyl), ethyl- (substituted heterocyclyl), (C3) alkyl- (substituted heterocyclyl), (C4) alkyl- (substituted heterocyclyl), (C5) alkyl- (substituted heterocyclyl), (C6) alkyl- (substituted heterocyclyl), (C7) alkyl (substituted heterocyclyl), (C8) alkyl- (substituted heterocyclyl), O-methyl-heterocyclyl, O-ethylheterocyclyl, O- (C3) alkyl-heterocyclyl, O- (C4) alkyl-heterocyclyl, O- (C5) alkyl -heterocyclyl, O (C6) alkyl-heterocyclyl, O- (C7) alkyl-heterocyclyl, O- (C8) alkyl-heterocyclyl, O-methyl- (substituted heterocyclyl), O-ethyl- (substituted heterocyclyl), O- (C3) alkyl- (substituted heterocyclyl), O- (C4) alkyl- (substituted heterocyclyl), O- (C5) alkyl- ( substituted heterocyclyl), O- (C6) alkyl- (substituted heterocyclyl), O- (C7) alkyl- (substituted heterocyclyl), and O- (C8) alkyl- (substituted heterocyclyl).

[0063] In another embodiment of the present invention, R17 may be selected from any combination of one or more of -H, CH2CF3, cyclopropyl, tietanyl, tietanyl dioxide, and halophenyl.

[0064] In another embodiment of the present invention, X1 is CR12, X2 is CR13, and X3 is CR9.

[0065] In another embodiment of the present invention, the heterocyclyl has preferably about 6 to 10 atoms in the ring structure, more preferably, 6 to 8 atoms.

[0066] The molecules of Formula One will generally have a molecular weight of about 100 Daltons to about 1200 Daltons. However, it is generally preferred that the molecular weight be from about 120 Daltons to about 900 Daltons, and even generally more preferably the molecular weight is from about 140 Daltons to about 600 Daltons.

[0067] Benzyl alcohol of formula IV, where R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, can be synthesized in two ways. One method, disclosed in step a of Scheme I, is to treat a ketone of formula II where R1, R2, R3, R4, R5, and R6 are as previously disclosed with a reducing agent such as sodium borohydride (NaBH4), in basic conditions such as aqueous sodium hydroxide (NaOH) in a polar protic solvent such as methyl alcohol (MeOH) at 0 ° C. Alternatively, an aldehyde of formula III, where R1, R2, R3, R4, R5, and R7 are as previously disclosed, is reacted with trifluoromethylsilane in the presence of a catalytic amount of tetrabutylammonium fluoride in a polar aprotic solvent such as tetrahydrofuran (THF) such as in step b of Scheme I. A compound of formula IV can be converted to a compound of formula V wherein Y is selected from Br, Cl or I, and R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed by reaction with a halogenating reagent such as N-bromosuccinimide, and triethyl phosphite, in a non-reactive solvent such as dichloromethane (CH2Cl2) at reflux to give Y = Br, or such as thionyl chloride and pyridine, in a hydrocarbon solvent such as toluene, at reflux to give Y = Cl, as in step c of Scheme I.

EP-2934142B1PL

Scheme I

<img file="PL2934142T3_D0003.tif" />

[0068] The formation of styrenic coupling partners can be accomplished as in Schemes II, III, IV and V.

[0069] In Scheme II, a vinyl benzoic acid of formula VI, where R11 is (C = O) OH and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, can be converted into two steps in the vinylbenzamide of formula VIIa, where R11 is (C = O) N (R14) (R15), and R8, R9, R10, R12, R13, R14, R15, and X are as previously disclosed. As in step d of Scheme II, a benzoic acid of formula VI is treated with oxalyl chloride in the presence of a catalytic amount of N, N-dimethylformamide (DMF) in a non-reactive solvent such as CH2Cl2 to form an acid chloride which is subsequently reacted with an amine ( HN (R14) (R15)) where R14 and R15 are as previously disclosed in the presence of a base such as triethylamine (TEA) in a polar aprotic solvent such as THF. to form a vinylbenzamide of formula VIIa, where R11 is (C = O) N (R14) (R15), and R8, R9, R10, R12, R13, R14, R15, X1, X2, and X3 are as previously disclosed, as in step e of Scheme II.

Scheme II

<img file="PL2934142T3_D0004.tif" />

In Schemes III and IV, the halobenzoic acid of formula VIII where R18 is Br or I, R11 is (C = O) OH and R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed may be converted to a vinylbenzoic acid ester of formula VIIb1 or formula VIIb2, where R18 is Br or I, R11 is (C = O) O (C1-C6 alkyl), and R8, R9, R10, R12, R13, X1, X2 and X3 are as previously disclosed. In step f of Scheme III, a halobenzoic acid of formula VIII, where R18 is Br, is treated with a base such as n-butyllithium (n-BuLi) and DMF in a polar aprotic solvent such as THF at a temperature of about -78 ° C. The resulting formylbenzoic acid is reacted with an acid such as sulfuric acid (H2SO4) in the presence of an alcohol such as ethyl alcohol (EtOH) as in step g to give the ethyl ester of formylbenzoic acid of formula IX, where R11 is (C = O) O (Ci-C6 alkyl), and R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed. The vinylbenzoic acid ester of formula VIIb1 is obtained by reacting compounds of formula IX with a base such as potassium carbonate (K2CO3) and bromide

Methyltriphenylphosphonium in a polar aprotic solvent such as 1,4-dioxane at ambient temperature as in step h of Scheme III.

Scheme III

<img file="PL2934142T3_D0005.tif" />

[0071] In step i of Scheme IV, the halobenzoic acid of formula VIII where R18 is Br, R11 is (C = O) OH, and R8, R9, R10, R12, R13, X1, X2, and X3 are as disclosed previously, treatment with di-tert-butyl dicarbonate in the presence of a base such as TEA and a catalytic amount of 4 (dimethylamino) pyridine (DMAP) in a polar aprotic solvent such as THF at ambient temperature. The resulting benzoic acid tert-butyl ester is reacted with a vinyl boronic anhydride-pyridine complex in the presence of a palladium catalyst such as tetrakis (triphenylphosphine) palladium (0) (Pd (PPh3) 4), and a base such as K2CO3 in a non-reactive solvent , such as toluene, at reflux as in step j, to give a vinylbenzoic acid ester of formula VIIb2, where R11 is (C = O) O (C1-C6 alkyl), and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed.

Scheme IV

<img file="PL2934142T3_D0006.tif" />

[0072] In step k of Scheme V, a vinyl benzoic acid ester of formula VIIb2, where R10 is Br, R11 is (C = O) O (C1-C6 alkyl), and R8, R9, R12, R13, X1, X2, and X3 are as previously defined, may be further converted to the corresponding vinylbenzoic acid ester of formula VIIb3 where R10 is CN, R11 is (C = O) O (C₁-C₆ alkyl), and R8, R9, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with copper (I) cyanide (CuCN), in a polar aprotic solvent such as DMF at 140 ° C .

Scheme V

<img file="PL2934142T3_D0007.tif" />

[0073] The coupling of compounds of formula V with compounds of formula VIIa, VIIb1, VIIb2 and VIIb3 can be performed as in Schemes VI, VII, and VIII. In step 1 of Scheme VI, a compound of formula V where Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and a vinyl benzamide of formula VIIa where R11 is (C = O) N (R14) (R15), and R8, R9, R10, R12, R13, R14, R15, X1, X2, and X3 are as previously disclosed, reacted in the presence of copper (I) chloride (CuCl) and 2, 2-bipyridyl in a solvent such as 1,2-dichlorobenzene at about 180 ° C to give a molecule of Formula One, where R11 is (C = O) N (R14) (R15) * not according to the invention, and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, X1 , X2, and X3 are as previously disclosed.

EP-2934142B1PL

<img file="PL2934142T3_D0008.tif" />

[0074] In step / of Scheme VII, a compound of formula V where Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and a vinylbenzoic acid ester of formula VIIb1 where R11 is ( C = O) O (Ci-C6alkyl), and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, reacted in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene at a temperature of about 180 ° C to give compounds of formula Xa where R11 is (C = O) O (C1-C6 alkyl), and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as it will reveal previously. Subsequently, compounds of formula Xa are converted to molecules of Formula One, where R11 is (C = O) N (R14) (R15) * not according to the invention, and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, X1, X2, and X3 are as previously disclosed, either in a two-step method as disclosed in steps min or in any step as disclosed in step o. In step m of Scheme VII, an ether of formula Xa is saponified to the corresponding acid under acidic conditions such as about 11-normal (N) hydrochloric acid (HCl) in a polar aprotic solvent such as 1,4-dioxane at a temperature of about 100 ° C. In turn, the acid can be coupled with an amine (HN (R14) (R15)), where R14 and R15 are as previously disclosed using peptide coupling reagents such as 1-hydroxybenzotriazole (HOBt), Λ / - (3dimethylaminopropyl) hydrochloride - / V-ethyl-carbodiimide (EDCHCI), benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), 2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate (CIP), 1-hydroxy-7-azabenzotria, or O-benzotrium ', N, N, N', N'tetramethyluronium hexafluorophosphate (HBTU), in the presence of a base such as N, N-diisopropylethylamine (DIPEA) or DMAP to form a molecule of Formula One, wherein R11 is (C = O) N (R14) (R15) * not according to the invention, and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, X1, X2 and X3 are as previously disclosed. Alternatively, an ester of formula Xa is reacted with an amine (HN (R14) (R15)) in the presence of a solution of trimethylaluminum in toluene in a non-reactive solvent such as CHpClp at ambient temperature as in step o of Scheme VII to give molecules of Formula One where R11 is (C = O) N (R14) (R15) * not according to the invention, and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, Χ1, X2, and X3 are as previously disclosed.

Scheme VII

<img file="PL2934142T3_D0009.tif" />

Pattern One

EP-2934142B1PL

[0075] In step / of Scheme VIII, a compound of formula V wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and a vinylbenzoic acid ester of formula VIIb2 or VIIb3, where R11 is (Ο = Ο) Ο (Οι-Οθ alkyl), and R8, R9, R10, R12, R13, X1, X2 and X3 are as previously disclosed, reacted in the presence of CuCl and 2,2-bipyridyl, in a solvent such as 1,2-dichlorobenzene at a temperature of about 180 ° C to provide compounds of formula Xb. where R11 is (C = O) OH, and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, X1, X2, and X3 are as previously disclosed . Compounds of formula Xb are then converted to molecules of formula One, where R11 is (C = O) N (R14) (R15), * not according to the invention, and R1, R2, R3, R4, R5, R6, R7, R8 , R9, R10, R12, R13, R14, R15, X1, X2, and X3 are as previously disclosed, in one step as disclosed in step n. In step n of Scheme VIII, an acid of formula Xb can be coupled to an amine (HN (R14) (R15)), where R14 and R15 are as previously disclosed, using peptide coupling reagents such as 1-hydroxybenzotriazole (HOBt ), N (3-dimethylaminopropyl) -N'-ethyl-carbodiimide hydrochloride (EDCHCI), benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), 2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate (CIP-7-azolidinium (CIP) azolidinium hexafluorophosphate HOAt), or O-benzotrium '\ azo \ oN, N, N', N'tetramethyluronium hexafluorophosphate (HBTU), in the presence of a base such as DIPEA or DMAP to give a molecule of Formula One where R11 is (C = O) N (R14 ) (R15) * not according to the invention, and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, X1, X2, and X3 are as previously disclosed.

Scheme VIII

<img file="PL2934142T3_D0010.tif" />

<img file="PL2934142T3_D0011.tif" />

R2

Pattern One

In step j of Scheme IX, a halobenzoketone of formula VIIbb where R18 is Br, R10 and R11 together form a connection having 3-4 carbon atoms and an oxo substituent, and with the ring carbon atoms form a 5- or 6-membered cyclic ring. and R8, R9, R12, R13, X1, X2, and X3 are as previously disclosed, reacted with a vinyl boronic anhydride-pyridine complex in the presence of a palladium catalyst such as Pd (PPh3) 4, and a base such as K2CO3 , in a non-reactive solvent such as toluene at reflux to form a vinyl benzoketone of formula VIIb4, where R10 and R11 together form a combination having 3-4 carbon atoms and an oxo substituent, and with the ring carbon atoms form a 5- or 6-membered ring, and R8, R9, R12, R13, Χ1, X2, and X3 are as previously disclosed.

EP-2934142B1PL

Scheme IX

<img file="PL2934142T3_D0012.tif" />

[0077] In step 1 of Scheme X, a compound of formula V where Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and a vinyl benzoketone of formula VIIb4 as previously disclosed, wherein R8, R9, R12, R13, X1, X2, and X3 are as previously disclosed, reacted in the presence of CuCl and 2,2-bipyridyl in a solvent such as 1,2-dichlorobenzene at a temperature of about 180 ° C with to form compounds of formula Xc, where R10 and R11 together form a link having 3-4 carbon atoms and an oxo substituent, and with ring carbon atoms form a 5- or 6-membered ring, and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12 , R13, X1, X2, and X3 are as previously disclosed. Subsequently, compounds of formula Xc are converted to molecules of formula Xd, where R10 and R11 together form a linkage having 3-4 carbon atoms and an oxime substituent [(C = N) (OH)], and form 5- or 6-6 with ring carbon atoms. a membered ring, and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X1, X2, and X3 are as previously disclosed in step p. In step p of Scheme X, a ketone of formula Xc is reacted with hydroxylamine hydrochloride in the presence of sodium acetate and in a polar protic solvent such as EtOH at about 78 ° C to provide molecules of formula Xd as previously disclosed.

Scheme X

<img file="PL2934142T3_D0013.tif" />

[0078] Compounds of formula Xc are also converted to molecules of formula Xe where R10 and R11 together form a link having 3-4 carbon atoms and an amino substituent, and with ring carbon atoms form a 5- or 6-membered ring, and R1, R2 , R3, R4, R5, R6, R7, R8, R9, R12, R13, X1, X2, and X3 are as previously disclosed as shown in step q of Scheme XI. The ketone of formula Xc is reacted with ammonium acetate in the presence of sodium cyanoborohydride and in a polar protic solvent such as MEOH at about 65 ° C to provide molecules of formula Xe.

Scheme XI

<img file="PL2934142T3_D0014.tif" />

EP-2934142B1PL

[0079] Compounds of formula Xe are converted to molecules of Formula One where R10 and R11 together form an association as previously disclosed in (u), and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12 , R13, X1, X2, and X3 are as before in one step as disclosed in steps r or s. In step r of Scheme XII, an amine of formula Xe is reacted with an isocyanate in a polar aprotic solvent such as diethyl ether at ambient temperature to provide a molecule of Formula One as previously disclosed. In step six of Scheme XII, an amine of formula Xe is coupled with an acid using HOBt HpO and EDC HCl in the presence of a base such as DIPEA in a non-reactive solvent such as CHpClp to give a molecule of Formula One as previously disclosed.

Scheme XII

<img file="PL2934142T3_D0015.tif" />

R2 R2

X_e Pattern One

[0080] In step t of Scheme XIII, a vinylbenzene chloride of formula Xla, where R11 is -CHpCl and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously defined, can be converted to the corresponding protected a benzylamine phthalimide of formula XIIa, where R11 is CH2N (phthalimide), and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed by reaction with the potassium salt of phthalimide in a polar aprotic solvent such as like DMF, at 70 ° C.

Scheme XIII

R8 R8

ΛΧ3 RIO "X" X3 "RIO

Π and i

XI RH XI RH

XIa XIIa

In step u of Scheme XIV, a 4-methylbenzonitrile of formula XIIla, where R11 is CH3 and R9, R10, R12, R13, X1, X2, and X3 are as previously defined, may be converted to the corresponding benzyl bromide of of formula XIVa, where R11 is CHpBr and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed by reaction with AZ-bromosuccinimide (NBS) and azobisisobutyronitrile (AIBN) in a non-reactive solvent , such as carbon tetrachloride, at 77 ° C. The nitrile (CN) group in formula XIVa can be reduced to the corresponding aldehyde of formula XVa, where R11 is CHpBr and R9, R10, R12, R13, X1, X2, and X3 are as previously defined by reaction with diisobutylaluminum hydride (DIBAL -H) in an aprotic solvent such as toluene at 0 ° C followed by quenching with 1.0 M hydrochloric acid (HCl) as in step v of Scheme XIV. The compound of formula XVa can be further converted to the corresponding phthalimide protected benzylamine of formula XVIa wherein R11 is CH2N (phthalimide) and R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed by reaction with a potassium salt phthalimide, in a polar aprotic solvent such as DMF at a temperature of 60 ° C, as in step t of Scheme XIV. In step w of Scheme XIV, an aldehyde of formula XVIa can be converted to an olefin of formula X11b, where R11 is CH2N (phthalimide) and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed. by reaction with bromide

Methyltriphenylphosphonium in a polar aprotic solvent such as 1,4-dioxane in the presence of a base such as K2CO3 at ambient temperature.

Scheme XIV

<img file="PL2934142T3_D0016.tif" />

An aldehyde of formula XVa where R11 is CH2Br and R9, R10, R12, R13, X1, X2, and X3 are as previously defined may be reacted with a nucleophile such as 2-aminopyridine in a polar aprotic solvent such as such as N, N-dimethylacetamide (DMA) in the presence of a base such as K2CO3 at ambient temperature to give a compound of formula XVII where R11 is CH2NH (2-pyridine) and R9, R10, R12, R13, X1, X2 , and X3 are as previously disclosed, as in step x of Scheme XV. In step w of Scheme XV, a compound of formula XVII can be converted to an olefin of formula XVIII where R11 is CH2NH (2-pyridine) and R8, R9, R10, R12, R13, X1, X2, and X3 are as disclosed previously.

Scheme XV

<img file="PL2934142T3_D0017.tif" />

[0083] In a one-pot two-step reaction as in steps y and z of Scheme XVI, a compound of formula XIX can be reacted with compounds of formula XX where R10 and R11 are Cl, X1 is N, and R9, R13, X2, and X3 are as previously disclosed in the presence of a base such as sodium hydride (NaH) and a polar aprotic solvent such as DMF at ambient temperature to give compounds of formula XXI where R10 is Cl, R11 is (CH) NH2CO2CH2CH3, X1 is N, and R9, R13, X2, and X3 are as previously defined. Hydrolysis and decarboxylation of compounds of formula XXI can be achieved by reaction under acidic conditions such as with 3N HCl at reflux to give compounds of formula XXII where R10 is Cl, R11 is CH2NH2^.HCl, X1 is N, and R9, R13, X2, and X3 are as previously disclosed, as in step aa in Scheme XVI. Compounds of formula XXII may be further converted to the corresponding phthalimide protected benzylamine of formula XXIIIa, where R10 is Cl, R11 is CH2N (phthalimide), X1 is N, and R9, R13, X1, X2, and X3 are as previously disclosed. by reaction with phthalic anhydride in the presence of a base such as TEA and an aprotic solvent such as toluene at reflux as in step ab of Scheme XVI. The bromide of formula XXIIIa can be converted to an olefin of formula XIIc where R10 is Cl, R11 is CH2N (phthalimide), X1 is N, and R8, R9, R13, X2 and X3 are as previously disclosed by reaction with an anhydride complex vinylboronic acid-pyridine in the presence of a palladium catalyst such as Pd (PPh3) 4, and a base such as K2CO3 in

A non-reactive solvent such as toluene at the reflux temperature of step ac of Scheme

XVI.

Scheme XVI

<img file="PL2934142T3_D0018.tif" />

[0084] In step u of Scheme XVII, 4-methylnaphthonitrile of formula XIIIb where X3 is CR9, R10 and X3 together form a linkage of 4 carbon atoms and with the ring carbon atoms form a 6 membered aromatic ring, R11 is CH3, and R12. R13, X1 and X2 are as previously defined, may be converted to the corresponding naphthyl bromide of formula XIVb, where X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring, R11 is CH2Br, and R12, R13, X1 and X2 are as previously disclosed by reaction with N-bromosuccinimide (NBS) and azobisisobutyronitrile (AIBN) in a non-reactive solvent such as carbon tetrachloride at 77 ° C. The nitrile (CN) group in formula XIVb can be reduced to the corresponding aldehyde of formula XVb, where X3 is CR9, R10 and X3 together form a linkage of 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring (or, if desired, non-aromatic ring), R11 is CH2Br, and R12, R13, X1 and X2 are as previously defined by reaction with diisobutylaluminum hydride (DIBAL-H) ​​in an aprotic solvent such as toluene at 0 ° C, followed by a stop with 1.0 M HCl, as in step ν of Scheme XVII. The compound of formula XVb can be further converted to the corresponding phthalimide protected benzylamine of formula XVIb, where X3 is CR9, R10 and X3 together form a linkage of 4 carbon atoms and with the ring carbon atoms form a 6 membered aromatic ring, R11 is CH2N (phthalimide). and R12, R13, X1 and X2 are as previously disclosed by reaction with the potassium salt of phthalimide in a polar aprotic solvent such as DMF at 60 ° C, as in step t of Scheme XVII. In step w of Scheme XVII, an aldehyde of formula XVIb can be converted to an olefin of formula XIId, where X3 is CR9, R10 and X3 together form a linkage of 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring, R11 is CH2N ( phthalimide), and R8, R12, R13, X1 and X2 are as previously disclosed by reaction with methyltriphenylphosphonium bromide in a polar aprotic solvent such as 1,4-dioxane in the presence of a base such as K2CO3. at ambient temperature.

EP-2934142B1PL

Scheme XVII

<img file="PL2934142T3_D0019.tif" />

[0085] A compound of formula XXIV, wherein R11 is NHNH₂HCl and R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, can be converted to the corresponding phthalimide protected hydrazine of formula XXV, where R11 is NHN (phthalimide) and R9, R10, R12, R13 , X1, X2, and X3 are as previously disclosed by reaction with phthalic anhydride in glacial acetic acid at reflux, as in step ad of Scheme XVIII. The bromide of formula XXV can be converted to an olefin of formula XIIe where R11 is NHN (phthalimide) and R8, R9, R10, R13, X1, X2 and X3 are as previously disclosed by reaction with a vinyl boronic anhydride-pyridine complex in the presence of a palladium catalyst such as Pd (PPh3) 4 and a base such as K2CO3 in a polar aprotic solvent such as 1,2-dimethoxyethane at 150 &amp; lt; 0 &amp; gt; C under microwave irradiation conditions as in step ae of Scheme XVIII.

Scheme XVIII

<img file="PL2934142T3_D0020.tif" />

[0086] In step af of Scheme XIX, the compound of formula XXVI, where R11 is B (OH) 2, and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, is reacted with 2-hydroxyisoindoline-1,3-dione in the presence of CuCl and pyridine in a solvent such as 1,2-dichlorobenzene at ambient temperature to give a compound of formula XIIf, where R11 is ON (phthalimide) and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed.

Scheme XIX

<img file="PL2934142T3_D0021.tif" />

[0087] In step 1 of Scheme XX, a compound of formula V where Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and compounds of formula XIIa where R11 is CH₂N (phthalimide) and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, reacted in the presence of CuCl and 2,2-bipyridyl in a solvent such as 1,2-dichlorobenzene at about 180 ° C to give the corresponding compounds of formula XXVIIa, where R11 is CH2N (phthalimide) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2 and X3 are as previously disclosed. The phthalimide protecting group in compounds of formula XXVIIa is removed as in step ag of Scheme XX by reaction with hydrazine hydrate in a polar protic solvent such as

EP-2934142B1PL

EtOH at 90 ° C to give compounds of formula XXVIIIa where R11 is CH2NH2 and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 have meanings as previously disclosed. Compounds of formula XXVIIIa can be converted to compounds of formula One where R11 is CH2N (C = O) (R14) * not according to the invention and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed by acylating with an anhydride such as acetic anhydride and a base such as TEA in a non-reactive solvent such as CH2Cl2 at 0 ° C as in step ahi from Scheme XX.

Scheme XX

<img file="PL2934142T3_D0022.tif" />

[0088] In step / of Scheme XXI, a compound of formula V where Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and compounds of formula XIIb where R11 is CH2N (phthalimide ) and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, reacted in the presence of CuCl and 2,2-bipyridyl in a solvent such as 1,2-dichlorobenzene at a temperature of about 180 ° C to give the corresponding compounds of formula XXVIIb where R11 is CH2N (phthalimide) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed. The phthalimide protecting group in compounds of formula XXVIIb is removed as in step ag of Scheme XXI by reaction with hydrazine hydrate in a polar protic solvent such as EtOH at 90 ° C to provide compounds of formula XXVIIIb where R11 is CH2NH2 and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed. Compounds of formula XXVIIIb can be converted to compounds of formula One where R11 is CH2N (C = O) (R14) * not according to the invention and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed by reaction with an acid in the presence of HOBt H2O, EDCHCl, and a base such as DIPEA, in a polar aprotic solvent such as DMF as in step ah2a of Scheme XXI.

[0089] In another embodiment, compounds of formula XXVIIIb can be converted to compounds of formula One, where R11 is CH2N (C = S) (R14) * not according to the invention and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed by reaction with a thio acid in the presence of HOBt H2O, EDC HCl, and a base such as DIPEA in a polar aprotic solvent such as DMF as in step ah2ze of Scheme XXI.

[0090] In another embodiment, compounds of formula XXVIIIb can be converted to compounds of Formula One, wherein R11 is CH2N (C = O) N (R14) (R15) * not according to the invention, and R1, R2, R3, R4 , R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed in two steps. The first stage (stage ahj_and of Scheme XXI) involves reaction with an aldehyde in a polar protic solvent such as MeOH followed by reaction with sodium borohydride. The second step (step ah3b of Scheme XXI) involves acylation with an acid chloride such as chloride

And a base such as TEA in a non-reactive solvent such as CH2Cl2 at ambient temperature from Scheme XXI.

[0091] In another embodiment, compounds of formula XXVIIIb can be converted to compounds of formula One, where R11 is CH2N (C = O) N (R14) (R15) * not according to the invention, and R1, R2, R3, R4 , R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed by reaction with an isocyanate (step aii of Scheme XXI) or carbamoyl chloride (step ai2 of Scheme XXI) in the presence of a base such as TEA and in a non-reactive solvent such as CH2Cl2, at 0 ° C.

[0092] In another embodiment, compounds of formula XXVIIIb can be converted to compounds of formula One, wherein R11 is CH2N (C = S) N (R14) (R15) * not according to the invention, and R1, R2, R3, R4 , R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with an isothiocyanate in the presence of a base such as TEA, and in a non-reactive solvent such as CH2Cl2 in at 0 ° C, as in steps Aj in Scheme XXI.

[0093] In another embodiment, compounds of formula XXVIIIb can be converted to compounds of formula One where R11 is CH2N (C = O) O (R14) * not according to the invention and R1, R2, R3, R4, R5, R6 , R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with a dicarbonate such as di-tert-butyl dicarbonate in the presence of a base such as TEA, and in a non-reactive solvent such as CH2Cl2 at ambient temperature, as in steps ake of Scheme XXI.

[0094] In yet another embodiment, compounds of formula XXVIIIb can be converted to compounds of Formula One, wherein R11 is CH2N (C = O) (C = O) O (R14) * not according to the invention and R1, R2, R3 , R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed by reaction with a chloro oxalic acid ester such as 2-chloro-2-oxoacetate in the presence of a base such as TEA, and in a non-reactive solvent such as CH2Cl2 at a temperature of Οΐ, as in steps al from Scheme XXI.

Scheme XXI

<img file="PL2934142T3_D0023.tif" />

XXVIIIb P^atrz Pattern One discussion

In step I of Scheme XXII, a compound of formula V where Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and compounds of formula X11c where R10 is Cl, R11 is CH2N (phthalimide), X1 is N, and R8, R9, R12, R13, X2, and X3 are as previously disclosed, reacted in the presence of CuCl and 2,2-bipyridyl in a solvent such as 1,2 -dichlorobenzene at a temperature of about 180 ° C to give the corresponding compounds of formula XXVIIc, where R10 is Cl, R11 is CH2N (phthalimide), X1 is N, and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X2, and X3 are as previously disclosed. The phthalimide protecting group in compounds of formula XXVIIc is removed as in step ag of Scheme XXII by reaction with hydrazine hydrate in a polar protic solvent such as EtOH at 90 ° C with

EP-2934142B1PL to give compounds of formula XXVIIIc, where R10 is Cl, R11 is CH2NH2, X1 is N, and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X2, and X3 are meanings as previously disclosed. Compounds of formula XXVIIIc can be converted to compounds of formula One where R10 is Cl, R11 is CH2N (C = O) (R14), X1 is N, and R1, R2, R3, R4, R5, R6, R7, R8 , R9, R12, R13, X2, and X3 are as previously disclosed by reaction with an acid in the presence of HOBtH2O, EDCHCI, and a base such as DIPEA in a polar aprotic solvent such as CH2Cl2 as in step ah2b of Scheme XXII.

Scheme XXII

<img file="PL2934142T3_D0024.tif" />

V xii_c XXVTIc

<img file="PL2934142T3_D0025.tif" />

R2 R2

XXVIII Pattern One

[0096] In step I of Scheme XXIII, a compound of formula V wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and compounds of formula Xlld where X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring (or a non-aromatic ring if desired), R11 is CH2N (phthalimide) and R8, R9, R12, R13, X1 and X2 are as previously disclosed, reacted in the presence of CuCl and 2,2-bipyridyl in a solvent such as 1,2-dichlorobenzene at a temperature of about 180 ° C to provide the corresponding compounds of formula XXVIId, where X3 is CR9, R10 and X3 together form a linkage having 4 atoms carbon and ring carbon atoms form a 6-membered aromatic ring, R11 is CH2N (phthalimide) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X1 and X2 are as previously disclosed. The phthalimide protecting group in compounds of formula XXVIId is removed as in step ag of Scheme XXIII by reaction with hydrazine hydrate in a polar protic solvent such as EtOH at 90 ° C to provide compounds of formula XXVIIId where X3 is CR9 , R10 and X3 together form a link having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring, R11 is CH2NH2 and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X1 and X2 are as previously disclosed. Compounds of formula XXVIIId can be converted to compounds of formula One, where X3 is CR9, R10 and X3 together form a linkage of 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring, R11 is CH2N (C = O) (R14) * not according to the invention and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X1 and X2 are as previously disclosed, by reaction with an acid in the presence of HOBt H2O, EDC HCl, and a base such as DIPEA, in a polar aprotic solvent, such as CH2Cl2, as in step ah2b of Scheme XXIII.

[0097] In another embodiment, compounds of Formula XXVIIId can be converted to compounds of Formula One, wherein X3 is CR9, R10 and X3 together form a linkage of 4 carbon atoms and form a 6 membered aromatic ring with the ring carbon atoms, R11 is CH2N (C = O) N (R14) (R15) * not according to the invention and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13,

EP-2934142B1PL

X1 and Χ2 are as previously disclosed by reaction with an isocyanate in the presence of a base such as TEA and in a non-reactive solvent such as CH2Cl2 at 0 ° C as in step aii of Scheme XXIII.

Scheme XXIII

<img file="PL2934142T3_D0026.tif" />

[0098] In step / of Scheme XXIV, a compound of formula V where Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and compounds of formula Xlle where R11 is NHN (phthalimide ) and R8, R9, R12, R13, X1, X2, and X3 are as previously disclosed, reacted in the presence of CuCl and 2,2-bipyridyl in a solvent such as 1,2-dichlorobenzene at a temperature of about 180 ° C, to give the corresponding compounds of formula XXVIIe, where R11 is NHN (phthalimide) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X1, X2, and X3 are as previously disclosed. The phthalimide protecting group in compounds of formula XXVIle is removed as in step ag of Scheme XXIV by reaction with hydrazine hydrate in a polar protic solvent such as EtOH at 90 ° C to provide compounds of formula XXVIIIe where R11 is NHNH2 and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X1, X2, and X3 are as previously disclosed. Compounds of formula XXVIIIe can be converted into compounds of formula One where R11 is NHN (C = O) (R14) * not according to the invention and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X1, X2, and X3 are as previously disclosed by reaction with an acid in the presence of HOBt H2O, EDC HCl, and a base such as DIPEA, in a polar aprotic solvent such as CH2Cl2 as in step ah2b of Scheme XXIV.

<img file="PL2934142T3_D0027.tif" />

[0099] In step / of Scheme XXV, a compound of formula V where Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and compounds of formula X11f where R11 is ON (phthalimide ) and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, reacted in the presence of CuCl and 2,2-bipyridyl in a solvent such as 1,2-dichlorobenzene at a temperature of about 180 ° C to give the corresponding compounds of formula XXVIIf where R11 is ON (phthalimide) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed. Group

The phthalimide protection in compounds of formula XXVIIf is removed as in step ag of Scheme XXV by reaction with hydrazine hydrate in a polar protic solvent such as EtOH at 90 ° C to give compounds of formula XXVIIIf, where R11 stands for ONH₂ and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed. Compounds of formula XXVIIIf can be converted to compounds of formula One where R11 is ON (C = O) (R14) * not according to the invention and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed by reaction with an acid in the presence of HOBt H₂O, EDC HCl, and a base such as DIPEA, in a polar aprotic solvent such as CH₂CI₂, as in step ah2b of Scheme XXV.

Scheme XXV

<img file="PL2934142T3_D0028.tif" />

<img file="PL2934142T3_D0029.tif" />

[0100] In step / of Scheme XXVI, a compound of formula V wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and compounds of formula XVIII where R11 is CH₂NH (2-pyridine) and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, reacted in the presence of CuCl and 2,2-bipyridyl in a solvent such as 1,2 -dichlorobenzene at about 180 ° C to give the corresponding compounds of Formula One where R11 is CH₂NH (2-pyridine) * not according to the invention, and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed.

[0101] The compounds of Formula One may be further processed by standard methods. For example, when R11 contains a thioether, the thioether can be oxidized to the sulfone by treatment with Oxone in the presence of an acetone: water mixture at ambient temperature. When R11 contains an oxalate ester, the compound of Formula One can be converted to the corresponding oxalamide by reaction with amine hydrochloride and a solution of trimethylaluminum in toluene in a non-reactive solvent such as CH₂CI₂.

Scheme XXVI

<img file="PL2934142T3_D0030.tif" />

<img file="PL2934142T3_D0031.tif" />

XVIII

<img file="PL2934142T3_D0032.tif" />

R2

Pattern One

[0102] In Scheme XXVII, a fluorobenzaldehyde of formula XXIX where R10, X1, X2, and X3 are as previously disclosed may be converted to (1,2,4-triazol-1-yl) benzaldehyde of formula XXX, where R11 is a substituted or unsubstituted 1,2,4-triazol-1-yl group, and R10, X1, X2, and X3 are as previously disclosed by reaction with a substituted or unsubstituted 1,2,4-triazole in the presence of a base. such as potassium carbonate in a solvent such as DMF as in step aj. In step ak, (1,2,4-triazol-1-yl) benzaldehyde of formula XXX is converted to (1,2,4-triazol-127

EP-2934142B1PL yl) vinylbenzene of formula XXXIa, where R11 is a substituted or unsubstituted 1,2,4-triazol-1-yl group, and R8, R10, X1, X2, and X3 are as previously disclosed by reaction with triphenylphosphonium bromide in the presence of a base such as potassium carbonate in an aprotic solvent such as 1,4-dioxane.

<img file="PL2934142T3_D0033.tif" />

<img file="PL2934142T3_D0034.tif" />

R8

<img file="PL2934142T3_D0035.tif" />

XXIX XXX XXXla

In Scheme XXVIII, a bromofluorobenzene of formula XXXII, where R10, X1, X2, and X3 are as previously disclosed, can be converted to (1,2,4-triazol-1-yl) vinylbenzene of formula XXXIb, where R11 is a substituted or unsubstituted 1,2,4-triazol-1-yl group, and R8, R10, X1, X2, and X3 are as previously disclosed in two steps. In step a1, bromofluorobenzene is reacted with a substituted or unsubstituted 1,2,4-triazole in the presence of a base such as potassium carbonate in a solvent such as DMF to give (1,2,4-triazol-1-yl) bromobenzene. In step c1, (1,2,4-triazol-1-yl) bromobenzene is reacted with a vinyl boronic anhydride-pyridine complex in the presence of a catalyst such as Pd (PPh₃) 4, and a base such as potassium carbonate in a solvent such as toluene.

Scheme XXVIII

R8

<img file="PL2934142T3_D0036.tif" />

^ΛΛΛ XXXIb

[0104] The coupling of compounds of formula V with compounds of formula XXXIa and XXXIb may be performed as in Schemes XXIX. In step I, a compound of formula V where Y is Br, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and vinylbenzene of formula XXXIa or XXXIb where R11 is a substituted or unsubstituted group 1 , 2,4-triazol-1-yl, and R8, R9, R10, X1, X2, and X3 are as previously disclosed, reacted in the presence of CuCl and 2,2-bipyridyl in a solvent such as 1, 2-dichlorobenzene at about 180 ° C to give a molecule of Formula One, where R11 is a substituted or unsubstituted 1,2,4-triazol-1-yl group, and R1, R2, R3, R4, R5, R6, R7, R8, R10, X1, X2, and X3 are as previously disclosed.

Scheme XXIX

<img file="PL2934142T3_D0037.tif" />

V XXXIa or XXXIb Pattern One

[0105] In Scheme XXX, compounds of formula XXXIII, where R11 is a 3-nitro-1,2,4-triazol-1yl group, and R1, R2, R3, R4, R5, R6, R7, R8, R10, X1 , X2, and X3 are as previously disclosed, can be converted to compounds of Formula One where R11 is a 3-amido-1,2,4-triazol-1-yl * group not according to the invention, and R1, R2, R3, R4 , R5, R6, R7, R8, R10, X1, X2, and X3 are as

EP-2934142B1PL has previously been disclosed in a two-step process. In step am, the 3-nitro-1,2,4-triazol-1-yl group is reduced to a 3-amino-1,2,4-triazol-1-yl group in the presence of zinc dust and ammonium chloride in a protic solvent such as MeOH. In step an, the 3-amino-1,2,4-triazol-1-yl group is acylated with an acid chloride such as cyclopropylcarbonyl chloride or acetyl chloride in the presence of a base such as TEA in a solvent such as CHpClp.

Scheme XXX

<img file="PL2934142T3_D0038.tif" />

ΧΧΧΤΙΙ Pattern One

[0106] In step ao of Scheme XXXI, a bromophenyl methyl ketone of formula XXXIV, where R10, X1, X2, and X3 are as previously disclosed, is converted to a phenyl methyl ketone of formula XXXV where R11 is a 1,2 group. 4-triazol-1-yl, and R10, X1, X2, and X3 are as previously disclosed by treatment with 1,2,4-triazole in the presence of a base such as cesium carbonate and a catalyst such as copper iodide in a solvent such as DMF. In step ap, the 1,2,4-triazolylacetophenone of formula XXXV is converted to the enol trimethylsilyl ether of formula XXXVI by treatment with trimethylsilyl triflate in the presence of a base such as TEA in an aprotic solvent such as CHpClp. In step aq, the enol silyl ether is reacted with a compound of formula V where Y is Br, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed in the presence of CuCl and 2,2-bipyridyl , in a solvent such as 1,2-dichlorobenzene at a temperature of about 180 ° C to give the ketone of formula XXXVII, where R11 is 1,2,4-triazol-1-yl, and R1, R2, R3, R4, R5 , R6, R7, R10, X1, X2, and X3 are as previously disclosed. In step ar, a ketone of formula XXXVII is treated with methylmagnesium bromide in an aprotic solvent such as THF to provide a tertiary alcohol. The tertiary alcohol then undergoes an elimination reaction when treated with a catalytic amount of p-toluenesulfonic acid in a solvent such as toluene while heated to a temperature that allows azeotropic removal of water to provide compounds of Formula One where R11 is a 1,2,4-triazole group. 1-clay * not according to the invention, R8 is methyl, and R1, R2, R3, R4, R5, R6, R7, R10, X1, X2, and X3 are as previously disclosed as in step as.

EP-2934142B1PL

<img file="PL2934142T3_D0039.tif" />

Scheme XXXI

<img file="PL2934142T3_D0040.tif" />

<img file="PL2934142T3_D0041.tif" />

XXXIV XXXV XXXVI

<img file="PL2934142T3_D0042.tif" />

χχχντ

<img file="PL2934142T3_D0043.tif" />

<img file="PL2934142T3_D0044.tif" />

R2

Pattern One

[0107] In Scheme XXXII, a compound of formula XXXVIII, wherein R10 and R11 together form a link having 3-4 carbon atoms and an oxo substituent, and with the ring carbon atoms form a 5- or 6-membered cyclic ring, and R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed, transformed into a molecule of Formula One, where R10 and R11 together form a combination *, not according to the invention, having 3-4 carbon atoms and an alkylamino substituent, with ring carbon atoms form a 5- or 6-membered cyclic ring and R1, R2, R3, R4, R5, R6, R7, R8, Χ1, X2, and X3 are as previously disclosed by treatment with an alkylamine such as 3, 3,3-trifluoropropylamine in the presence of a reducing agent such as sodium cyanoborohydride in a solvent such as DCE.

Scheme XXXII

<img file="PL2934142T3_D0045.tif" />

R2 R2

XXXVIII Pattern One

In Scheme XXXIII, a compound of formula XXXIX, where X1, X2, and X3 are as previously disclosed, is converted to a molecule of formula XL where X1, X2, and X3 are as previously disclosed by treatment with a reducing agent such as sodium cyanoborohydride in a solvent such as acetic acid as in step au. In step av, the nitrogen atom is protected with a tert-butyloxycarbonyl (BOC) group by reaction with di-tert-butyl dicarbonate in the presence of a catalyst such as DMAP in a solvent such as acetonitrile. The bromide of formula XL can be converted to an olefin of formula XLI, where R8, X1, X2 and X3 are as previously disclosed, by reaction with potassium vinyl trifluoroborate in the presence of a catalyst

Palladium EP-2934142B1PL such as PdCl2 (dppf), and a base such as K2CO3 in a polar aprotic solvent such as DMSO at a temperature of 100 ° C as in step aw.

Scheme XXXIII

<img file="PL2934142T3_D0046.tif" />

XXXIX XL _{XL [}

[0109] In Scheme XXXIV, a compound of formula XXXIX, where X1, X2, and X3 are as previously disclosed, is converted to a molecule of formula XLII where X1, X2, and X3 are as previously disclosed in two steps. In step ax, an olefin is formed by treating vinyl trifluoroborate with potassium bromide in the presence of a palladium catalyst such as PdCl2 and a ligand such as triphenylphosphine and a base such as CS2CO3 in a solvent mixture such as THF / H2O. In step ay, the nitrogen atom is protected with a tert-butyloxycarbonyl (BOC) group by reaction with di-tert-butyl dicarbonate in the presence of a catalyst such as DMAP in a solvent such as acetonitrile.

Scheme XXXIV

<img file="PL2934142T3_D0047.tif" />

XXXIX XLII

[0110] In step I of Scheme XXXV, a compound of formula V where Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and compounds of formula XLI or XLII where R8, X1 are , X2 and X3 are as previously disclosed, reacted in the presence of CuCl and 2,2-bipyridyl in a solvent such as 1,2-dichlorobenzene at about 150 ° C to give the corresponding compounds of formula XLIIIa or XLIIIb where R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed.

Scheme XXXV

<img file="PL2934142T3_D0048.tif" />

XLI or XLII XLIIIa or XLIIIb

[0111] In Scheme XXXVI, a compound of formula XLIIIa, where R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed, is converted to a molecule of formula XLIV, where R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed by treatment with trifluoroacetic acid in a solvent such as CH2Cl2 as in step az. Compounds of formula XLIV can then be converted to compounds of formula XLV where R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed in two steps. In step ba, the indoline is treated with sodium nitrite (NaNO2) in an acid such as concentrated HCl at about 5 około to give the nitrosoindole. In step bb, nitrosoindole is reacted with ammonium chloride v

The presence of zinc dust in a protic solvent such as MeOH. In step bc, compounds of formula XLV are converted to compounds of formula XLVI where X4 is N (R14) (C (= O) R14) and R1, R2,

R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed by treatment with an acid such as 3,3,3-trifluoropropanoic acid, PyBOP, and a base such as DIPEA in polar an aprotic solvent such as CH2Cl2.

Scheme XXXVI

<img file="PL2934142T3_D0049.tif" />

[0112] In Scheme XXXVII, a compound of formula XLIIIb where R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed, is converted to an indole of formula XLVII, where R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed by treatment with trifluoroacetic acid in a solvent such as CH2Cl2 as in step bd. Compounds of formula XLVII can be converted to compounds of formula XLVIII where R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed by reacting with 2 - ((tert -butoxycarbonyl) amino) with 4-nitrophenyl acetate in the presence of potassium fluoride and a crown ether such as 18-crown-6 ether in a solvent such as acetonitrile as in step be. Compounds of formula XLVIII can be converted to compounds of formula XLIX where R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed in two steps. In step bf, the Boc group is removed by treatment with trifluoroacetic acid in a solvent such as CH2Cl2. In step bg, the amine is treated with 3,3,3-trifluoropropanoic acid, PyBOP, and a base such as DIPEA in a polar aprotic solvent such as CH2Cl2.

Scheme XXXVII

<img file="PL2934142T3_D0050.tif" />

[0113] In Scheme XXXVIII, a compound of formula L where X1, X2, and X3 are as previously disclosed is converted to a compound of formula L1 where X1, X2, and X3 are as previously disclosed by treating with sulfate pentahydrate copper (II) and zinc dust in principle, such as sodium hydroxide, as in step bh. Compounds of formula LI can be transformed

Compounds of formula LII, where X1, X2, and X3 are as previously disclosed, by reaction with hydrazine in a solvent such as water at a temperature of about 95 ° C as in step bi. In step bj, an olefin of formula LIII where X1, X2, and X3 are as previously disclosed is formed by treating vinyl trifluoroborate with potassium bromide in the presence of a palladium catalyst such as PdCl2 (dppf) and a base such as K2CO3 in a mixture solvents such as DMSO. Compounds of formula LIV where X1, X2, and X3 are as previously disclosed may be formed from compounds of formula LIII by reaction with ethyl bromoacetate in the presence of a base such as Cs2CO3 in a solvent such as DMF.

Scheme XXXVIII

<img file="PL2934142T3_D0051.tif" />

[0114] In step 1 of Scheme XXXIX, the compound of formula V where Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compound of formula LIV where R8, X1, X2 are and X3 are as previously disclosed, reacted in the presence of CuCl and 2,2-bipyridyl in a solvent such as 1,2-dichlorobenzene at about 180 ° C to provide the corresponding compound of formula LV, wherein R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed. The compound of formula LV can be further converted to a compound of formula LVI where R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed in two steps. In step b1, the ester is hydrolyzed to acid in the presence of HCl and acetic acid at a temperature of about 100 ° C. In step bm, the acid is treated with an amine such as 2,2,2-trifluoroethylamine, PyBOP, and a base such as DIPEA in a polar aprotic solvent such as CH2Cl2.

Scheme XXXIX

<img file="PL2934142T3_D0052.tif" />

EP-2934142B1PL

[0115] In step bn of Scheme XL, the carboxylic acids of formula LVII where R11 is C (= O) OH and R8, R10, X1, X2, and X3 are as previously disclosed, and compounds of formula V where Y is Br and R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, reacted in the presence of CuCl and 2,2-bipyridyl in a solvent such as N-methylpyrrolidine at a temperature of about 150 ° C, to give compounds of formula LVIII where R11 is (C = O) OH and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X1, X2, and X3 are as previously disclosed. Compounds of formula LVIII can be further converted to the corresponding benzamides of formula LIX, where R11 is (C = O) N (R14) (R15), and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 , X1, X2, and X3 are as previously disclosed by treatment with an amine such as 2-amino-N- (2,2,2-trifluoroethyl) acetamide, PyBOP, and a base such as DIPEA in a polar aprotic solvent. such as CH2Cl2 as in step bo.

Scheme XL

<img file="PL2934142T3_D0053.tif" />

EXAMPLES

[0116] The examples are for illustrative purposes only and should not be construed as limiting the invention disclosed in this document to only the embodiments disclosed in these examples.

[0117] The starting materials, reagents, and solvents obtained from commercial sources were used without further purification. Anhydrous solvents were purchased from Sure / Seal ™ from Aldrich and used as received. Melting points were obtained on a Thomas Hoover Unimelt capillary melting point apparatus or an OptiMelt Automated Melting Point System from Stanford Research Systems and are uncorrected. The molecules are given known names, named after the naming programs in ISIS Draw, ChemDraw, or ACD Name Pro packages. If such programs were unable to name the molecule, the molecule is named using conventional nomenclature rules. 1H NMR spectral data is reported in ppm (δ) and was recorded at 300, 400, or 600 MHz, and spectral data¹³C NMR are reported in ppm (δ) and were recorded at 75, 100, or 150 MHz, unless otherwise stated.

Example 1 * not according to the invention: dichlorobenzene (Al1) [0118]

Preparation of 1- (1-Bromo-2,2,2-trifluoroethyl) -3,5-

<img file="PL2934142T3_D0054.tif" />

EP-2934142B1PL

Step 1 Method A. 1- (3,5-Dichlorophenyl) -2,2,2-trifluoroethanol (Al2). To a mixed solution of 1- (3,5-dichlorophenyl) -2,2,2-trifluoroethanone (obtained from Rieke Metals, UK; 5.0 grams (g), 20.5 millimoles (mmol)) in MeOH (100 ml) at 0 ° C were added sodium borohydride (NaBH4; 3.33 g, 92.5 ml) and 1-normal (N) aqueous sodium hydroxide solution (NaOH; 10 ml). The reaction mixture was warmed to 25 ° C and stirred for 2 hours (h). After the reaction was judged complete by thin layer chromatography (TLC), a saturated (sat.) Aqueous (aq) ammonium chloride (NH4Cl) solution was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was diluted with diethyl ether (Et2O) and washed with water (H2O, 3 x 50 mL). The organic layer was dried over sodium sulfate (Na2SO4) and concentrated under reduced pressure to provide the title compound as a liquid (4.0 g, 79%):¹H NMR (400 MHz, CDCl 3) δ 7.41 (m, 3H), 5.00 (m, 2H), 2.74 (s, 1H); ESIMS m / z 242.97 ([MH] -).

Step 1 Method B. 1- (3,5-Dichlorophenyl) -2,2,2-trifluoroethanol (Al2). To a stirred solution of 3,5-dichlorobenzaldehyde (10 g, 57 mmol) in THF (250 ml) was added trifluoromethyltrimethylsilane (9.79 g, 69.2 mmol) and a catalytic amount of tetrabutylammonium fluoride (TBAF). The reaction mixture was stirred at 25 ° C for 8 h. After the reaction was judged complete by TLC, the reaction mixture was diluted with 3 N hydrochloric acid (HCl) and then stirred for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate (EtOAc; 3 x). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to provide the title compound as a liquid (8.41 g, 60%).

[0121] The following compounds * not according to the invention were prepared according to the procedures disclosed in

Step 1 of Method B of Example 1 above.

2,2,2-Trifluoro-1- (3,4,5-trichlorophenyl) ethanol (Al3) [0122]

<img file="PL2934142T3_D0055.tif" />

The product was isolated as a pale yellow liquid (500 mg, 65%): 1 H NMR (400 MHz, CDCl₃) δ 7.45 (s, 2H), 5.00 (m, 1H), 2.80 (s, 1H); ESIMS m / z 278 ([M + H] +); IR (thin layer) 3420, 1133, 718 cm^-1.

1- (3,5-Dichloro-4-fluorophenyl) -2,2,2-trifluoroethanol (Al4)

[0124]

<img file="PL2934142T3_D0056.tif" />

The product was isolated as a pale yellow liquid (500 mg, 65%): 1 H NMR (400 MHz, CDCl₃) δ 7.41 (s, 2H), 5.00 (m, 1H), 2.80 (s, 1H); ESIMS m / z 262 ([M + H]⁺); IR (thin layer) 3420, 1133, 718 cm^-1.

1- (3,4-Dichlorophenyl) -2,2,2-trifluoroethanol (Al5)

[0126]

<img file="PL2934142T3_D0057.tif" />

EP-2934142B1PL

[0127] The product was isolated as a pale yellow liquid (500 mg, 65%): ¹H NMR (400 MHz, CDCl₃) δ 7.60 (s,

1H), 7.51 (m, 1H), 7.35 (m, 1H), 5.01 (m, 1H), 2.60 (s, 1H); EIMS m / z 244 ([M] +).

1- (3,5-Dibromophenyl) -2,2,2-trifluoroethanol

[0128]

<img file="PL2934142T3_D0058.tif" />

[0129] The title molecule was isolated as a colorless liquid: 1H NMR (300 MHz, CDCl3) δ 7.67 (s, 1H), 7.58 (s, 2H), 5.08-5.02 (m, 1H), 4.42 (bs, 1H); EIMS m / z 333.7 ([M] +); IR (thin layer) 3417, 2966, 1128, 531 cm-1.

1- (4-Bromo-3,5-dichlorophenyl) -2,2,2-trifluoroethanol

[0130]

OH ^αγγΑ

Cl

The product was isolated as a colorless liquid: 1H NMR (300 MHz, DMSO-d₆) δ 7.75 (s, 2H), 7.24 (d, J = 6.0 Hz, 1H), 5.34 - 5.29 (m, 1H); EIMS m / z 321.88 ([M] +); IR (thin layer) 3420, 1706, 1267, 804, 679 cm-1.

1- (3,5-Dibromo-4-chlorophenyl) -2,2,2-trifluoroethanol

[0132]

<img file="PL2934142T3_D0059.tif" />

The product is isolated as a pale yellow gum: 1H NMR (300 MHz, DMSO-d₆) δ 7.89 (s, 2H), 7.20 (d, J = 6.0 Hz, 1H) 5.34 - 5.30 (m, 1H); EIMS m / z 366.0 ([M] +).

Step 2. 1- (1-Bromo-2,2,2-trifluoroethyl) -3,5-dichlorobenzene (Al 1). To a stirred solution of 1 (3,5-dichlorophenyl) -2,2,2-trifluoroethanol (4.0 g, 16.3 mmol) in CH2Cl2 (50 ml), N-bromosuccinimide (NBS; 2.9 g) was added , 16.3 mmol) and triphenyl phosphite (5.06 g, 16.3 mmol), and the resulting reaction mixture was heated at reflux for 18 h. After the reaction was judged complete by TLC, the reaction mixture was cooled to 25 ° C and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; eluting with 100% pentane) gave the title compound as a liquid (2.0 g, 40%): 1H NMR (400 MHz, CDCl3) δ 7.41 (s, 3H), 5.00 (m, 1H); EIMS m / z 306 ([M]⁺).

[0135] The following compounds * not according to the invention were prepared according to the procedures disclosed in

Step 2 of Example 1.

5- (1-Bromo-2,2,2-trifluoroethyl) -1,2,3-trichlorobenzene (Al6)

[0136]

EP-2934142B1PL

<img file="PL2934142T3_D0060.tif" />

The product is isolated as a colorless oil (300 mg, 60%): ¹H 2H), 5.00 (m, 1H); EIMS m / z 340.00 ([M] +).

5- (1-Bromo-2,2,2-trifluoroethyl) -1,3-dichloro-2-fluorobenzene (Al7) [0138]

NMR (400 MHz, CDCl₃) δ 7.59 (s,

<img file="PL2934142T3_D0061.tif" />

The product is isolated as a colorless oil (320 mg, 60%): ¹H 2H), 5.00 (m, 2H); EIMS m / z 324.00 ([M] +).

4- (1-Bromo-2,2,2-trifluoroethyl) -1,2-dichlorobenzene (Al8)

[0140]

NMR (400 MHz, CDCl3) δ 7.45 (s,

<img file="PL2934142T3_D0062.tif" />

The product is isolated as a colorless oil (300 mg, 60%): ¹H.

NMR (400 MHz, CDCl3) δ 7.63 (s,

1H), 7.51 (m, 1H), 7.35 (m, 1H), 5.01 (m, 1H); EIMS m / z 306.00 ([M]⁺).

1,3-Dibromo-5- (1-bromo-2,2,2-trifluoroethyl) benzene

[0142]

Br

<img file="PL2934142T3_D0063.tif" />

Br

[0143] The title molecule was isolated as a colorless liquid: 1H NMR (300 MHz, CDCl3) δ 7.71 (s,

1H), 7.59 (s, 2H), 5.04-4.97 (m, 1H); EIMS m / z 394.6 ([M]⁺); IR (thin layer) 1114.535 cm^-1.

2-Bromo-5- (1-bromo-2,2,2-trifluoroethyl) -1,3-dichlorobenzene

[0144]

<img file="PL2934142T3_D0064.tif" />

[0145] The title molecule was isolated as a colorless liquid: ¹H NMR (400 MHz, DMSO-d6) δ 7.79 (s, 2H), 6.27-6.21 (m, 1H); EIMS m / z 383.9 ([M]⁺); IR (thin layer) 2924, 1114, 749, 534 cm^-1.

1,3-Dibromo-5- (1-bromo-2,2,2-trifluoroethyl) -2-chlorobenzene

[0146]

EP-2934142B1PL

<img file="PL2934142T3_D0065.tif" />

[0147] The title molecule was isolated as a pale yellow liquid: 1H NMR (300 MHz, DMSO-d6) δ 7.97 (s,

2H), 6.27-6.19 (m, 1H); EIMS m / z 428.0 ([M] +).

Example 2 * not according to the invention: Preparation of N-Methyl-4-vinylbenzamide (Al9) [0148]

<img file="PL2934142T3_D0066.tif" />

Step 1. 4-Vinylbenzoyl chloride (Al10). A catalytic amount of DMF and oxalyl chloride (1.27 g, 10.12 mmol) was added dropwise over 15 minutes (min) to a stirred solution of 4-vinylbenzoic acid (1 g, 6.75 mmol) in CH2Cl2 (20 ml) at 0 ° C. . The reaction mixture was stirred at 25 ° C for 6 h. After the reaction was judged complete by TLC, the reaction mixture was concentrated under reduced pressure to provide the crude acid chloride.

Step 2. N-Methyl-4-vinylbenzamide (Al9). To 1 M N-methylamine in THF (13.5 mL, 13.5 mmol) at 0 ° C was added TEA (1.34 mL, 10.12 mmol) and the acid chloride from Step 1 above in THF (10 mL) and the reaction was stirred at 25 ° C for 3 h. After the reaction was judged complete by TLC, the reaction was quenched with water then extracted with EtOAc (3x). The combined EtOAc layers were washed with brine and dried over Na2SO4 and concentrated under reduced pressure to provide the title compound as an off-white solid (650mg, 60%): ¹H NMR (400 MHz, CDCl₃) δ 7.76 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 6.79 (m, 1H), 6.20 (br s, 1H), 5.82 (d, J = 17.6 Hz, 1H), 5.39 (d, J = 10.8 Hz, 1H); ESIMS m / z 161.95 ([M + H]⁺).

The following compounds * not according to the invention were prepared according to the procedures disclosed in accordance with Example 2.

N, N- Dimethyl-4-vinylbenzamide (Al11)

[0152]

<img file="PL2934142T3_D0067.tif" />

[0153] The product was isolated as an off-white solid (650 mg, 60%): ¹H NMR (400 MHz, CDCl 3) δ 7.42 (m, 4H), 6.71 (m, 1H), 5.80 (d, J = 17.6 Hz, 1H), 5.31 (d, J = 10.8 Hz, 1H), 3.05 (s, 3H), 3.00 (s, 3H); ESIMS m / z 176.01 ([M + H] +).

N- (2,2,3-Trifluoromethyl) -4-vinylbenzamide (Al12)

[0154]

<img file="PL2934142T3_D0068.tif" />

The product was isolated as an off-white solid (900 mg, 60%): 1 H NMR (400 MHz, CDCl 3) δ 7.76 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 6.79 (m, 1H), 6.20 (br s, 1H), 5.82 (d, J = 17.6 Hz, 1H), 5.39 (d, J = 10.8 Hz, 1H), 4.19 (m, 2H); ESIMS m / z 230.06 ([M + H] +).

Morpholino (4-vinylphenyl) methanone (Al13)

EP-2934142B1PL

[0156]

<img file="PL2934142T3_D0069.tif" />

The product was isolated as a white solid (850 mg, 60%): ESIMS m / z 218.12 ([M + H] +).

Example 3 * not according to the invention: Preparation of ethyl 2-methyl-4-vinylbenzoate (Al14) [0158]

<img file="PL2934142T3_D0070.tif" />

Step 1. 4-Formyl-2-methylbenzoic acid (Al15). To a stirred solution of 4-bromo-2-methylbenzoic acid (10 g, 46.4 mmol) in dry THF (360 mL) at -78 ° C was added n -BuLi (1.6 M solution in hexane; 58.17 mL, 93 , 0 mmol) and DMF (8 mL). The reaction mixture was stirred at -78 ° C for 1 h then warmed to 25 ° C and stirred for 1 h. The reaction mixture was quenched with 1 N HCl and extracted with EtOAc. The combined EtOAc extracts were washed with brine and dried over Na2SO4 and concentrated in vacuo. The residue was washed with n hexane to provide the title compound as a solid (3.0 g, 40%): mp 196-198 ° C; 1H NMR (400MHz, DMSO-d₆) δ 13.32 (br s, 1H), 10.05 (s, 1H), 7.98 (m, 1H), 7.84 (m, 2H), 2.61 (s, 3H); ESIMS m / z 163.00 ([MH] -).

Step 2. Ethyl 4-formyl-2-methylbenzoate (Al16). Sulfuric acid (H 2 SO 4, x M; 2 mL) was added to a stirred solution of 4-formyl-2-methylbenzoic acid (3 g, 18.2 mmol) in ethyl alcohol (EtOH; 30 mL), and the reaction mixture was heated at 80 ° C for 18 h. The reaction mixture was cooled to 25 ° C then concentrated under reduced pressure. The residue was diluted with EtOAc and washed with H2O. The combined EtOAc extracts were washed with brine, dried over Na2SO4 and concentrated in vacuo to provide the title compound as a solid (2.8 g, 80%): 1H NMR (400MHz, CDCl₃) δ 10.05 (s, 1H), 8.04 (m, 1H), 7.75 (m, 2H), 4.43 (m, 2H), 2.65 (s, 3H), 1.42 (m, 3H).

Step 3. Ethyl 2-methyl-4-vinylbenzoate (Al 14). To a stirred solution of ethyl 4-formyl-2-methylbenzoate (2.8 g, 4 mmol) in 1,4-dioxane (20 ml) was added potassium carbonate (K2CO3; 3.01 g, 21.87 mmol) and methyltriphenylphosphonium bromide (7. 8 g, 21.87 mmol) at 25 ° C. The reaction mixture was then heated at 100 ° C for 18 h. After the reaction was judged complete by TLC, the reaction mixture was cooled to 25 ° C and filtered, and the filtrate was concentrated under reduced pressure. The crude compound was purified by flash chromatography (SiO2, 100-200 mesh; eluted with 25-30% EtOAc in n-hexane) to provide the title compound as a solid (2.0 g, 72%): 1 H NMR (400 MHz, CDCl₃) δ 7.86 (m, 1H), 7.27 (m, 2H), 6.68 (dd, J = 17.6, 10.8 Hz, 1H), 5.84 (d, J = 17, 6 Hz, 1H), 5.39 (d, J = 10.8 Hz, 1H), 4.39 (m, 2H), 2.60 (s, 3H), 1.40 (m, 3H); ESIMS m / z 191.10 ([MH]^-); IR (thin layer) 2980, 1716, 1257 cm^-1.

Example 4 * not according to the invention: Preparation of tert-butyl 2-chloro-4-vinylbenzoate (Al17) [0162]

<img file="PL2934142T3_D0071.tif" />

EP-2934142B1PL

Step 1. tert-Butyl 4-Bromo-2-chlorobenzoate (Al18). To a stirred solution of 4-bromo-2-chlorobenzoic acid (5 g, 21.37 mmol) in THF (30 ml) was added di-tert-butyl dicarbonate (25.5 g, 25.58 mmol), TEA (3.2 g, 31.98 mmol) and DMAP (0.78 g, 6.398 mmol), and the reaction mixture was stirred at 25 ° C for 18 h. The reaction mixture was diluted with EtOAc and washed with H 2 O. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 100-200 mesh; eluted with 2-3% EtOAc in n-hexane) to provide the title compound as a liquid (3.2 g, 51%): 1 H NMR (400 MHz, CDCl₃) δ 7.62 (m, 2H), 7.44 (d, J = 8.4 Hz, 1H), 1.59 (s, 9H); ESIMS m / z 290.10 ([M + H] +); IR (thin layer) 1728 cm^-1.

The following compounds * not of the invention were prepared according to the procedures disclosed in Step 1 of Example 4.

Tert-Butyl 2-Bromo-4-iodobenzoate (Al19)

[0165]

<img file="PL2934142T3_D0072.tif" />

ABOUT

The product is isolated as a colorless oil (1.2 g, 50%): ¹H NMR (400 MHz, CDCl₃) δ 8.01 (s, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 1.59 (s, 9H ); ESIMS m / z 382.10 ([M + H] +); IR (thin layer) 1727 cm^-1.

Tert-Butyl 4-Bromo-2- (trifluoromethyl) benzoate (Al2O)

[0167]

<img file="PL2934142T3_D0073.tif" />

ABOUT

The product was isolated as a colorless oil (1 g, 52%): 1 H NMR (400 MHz, CDCl₃) δ 7.85 (s, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 1.57 (s, 9H ); ESIMS m / z 324.10 ([M + H] +); IR (thin layer) 1725 cm^-1.

Step 2. tert-butyl 2-chloro-4-vinylbenzoate (Al17). To a stirred solution of tert-butyl 4-bromo-2-chlorobenzoate (1.6 g, 5.50 mmol) in toluene (20 mL) was added tetrakis (triphenylphosphine) palladium (0) (Pd (PPh3) 4; (0.31 mg, 0.27 mmol), K2CO3 (2.27 g, 16.5 mmol) and vinylboronic acid anhydride-pyridine complex (2.0 g, 8.3 mmol) and the reaction mixture was heated at reflux for 16 h. The reaction mixture was filtered and the filtrate was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. Purification by flash column chromatography (SiO2, 100-200 mesh; eluted with 5-6% EtOAc in n-hexane) provided the title compound as a liquid (0.6 g, 46%):¹H NMR (400 MHz, CDCl 3) δ 7.72 (d, J = 8.1 Hz, 1H), 7.44 (m, 1H), 7.31 (d, J = 8.0 Hz, 1H), 6.69 (dd, J = 17.6, 10.8 Hz, 1H), 5.85 (d, J = 17.6 Hz, 1H), 5.40 (d, J = 10.8 Hz, 1H ), 1.60 (s, 9H); ESIMS m / z 238.95 ([M + H]⁺); IR (thin layer) 2931, 1725, 1134 cm^-1.

[0170] The following compounds * not according to the invention were prepared according to the procedures disclosed in Step 2 of Example 4.

Tert-Butyl 2-bromo-4-vinylbenzoate (Al21)

[0171]

EP-2934142B1PL

<img file="PL2934142T3_D0074.tif" />

The product was isolated as a colorless oil (1 g, 52%): 1 H NMR (400 MHz, CDCl₃) δ 7.68 (m, 2H), 7.36 (d, J = 8.0 Hz, 1H), 6.68 (dd, J = 17.6, 10.8 Hz, 1H), 5.84 (d, J = 17.6 Hz, 1H), 5.39 (d, J = 10.8 Hz, 1H), 1.60 (s, 9H); ESIMS m / z 282.10 ([M + H] +); IR (thin layer) 2978, 1724, 1130 cm^-1.

Tert-Butyl 2- (trifluoromethyl) -4-vinylbenzoate (Al22)

[0173] χχ / Τ ΧΤγΟχΑ O

The product is isolated as a colorless oil (1.2 g, 50%): ¹H NMR (400 MHz, CDCl₃) δ 7.71 (d, J =

6.4 Hz, 2H), 7.59 (d, J = 7.6 Hz, 1H), 6.77 (dd, J = 17.6, 10.8 Hz, 1H), 5.89 (d, J = 17.6 Hz, 1H), 5.44 (d, J10 = 10.8 Hz, 1H), 1.58 (s, 9H); ESIMS m / z 272.20 ([M + H] +); IR (thin layer) 2982, 1727, 1159 cm-1.

Example 5: Preparation of tert-butyl 2-cyano-4-vinylbenzoate (Al23)

[0175]

ΧίγΑ / 'o

[0176] To a stirred solution of tert-butyl 2-bromo-4-vinylbenzoate (0.5 g, 1.77 mmol) in DMF (20 mL) was added copper (I) cyanide (CuCN; 0.23 g, 2. 65 mmol), and the reaction mixture was heated at 140 ° C for 3 h. The reaction mixture was cooled to 25 ° C, diluted with H 2 O, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 100-200 mesh; eluted with 15% EtOAc in n-hexane) to provide the title compound as a white solid (0.3 g, 72%): mp 51-53 ° C ; 1 H NMR (400 MHz, CDCl₃) δ 8.03 (s, 1H), 7.77 (s, 1H), 7.64 (d, J = 8.4 Hz, 1H), 6.75 (dd, J = 17.6, 10, 8 Hz, 1H), 5.93 (d, J = 17.6 Hz, 1H), 5.51 (d, J = 10.8 Hz, 1H), 1.65 (s, 9H); ESIMS m / z 229.84 ([M + H] +); IR (thin layer) 2370, 1709, 1142 cm^-1.

Example 6 * not according to the invention: Preparation of ethyl 2-Bromo-4-iodobenzoate (Al46) [0177]

ABOUT

[0178] To a stirred solution of 4-iodo-2-bromobenzoic acid (5 g, 15.29 mmol) in ethyl alcohol (EtOH; 100 mL) was added sulfuric acid (H2SO4; 5 mL), and the reaction mixture was heated to 80 ° C. C for 18 h. The reaction mixture was cooled to 25 ° C and concentrated under reduced pressure. The residue was diluted with EtOAc (2 x 100 mL) and washed with water (100 mL). The combined 30 extracts in EtOAc were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the compound as a pale yellow solid (5 g, 92%): 1H NMR (400 MHz, DMSO-d6) δ 8.04 (d, J = 1.2 Hz, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 4.41 (q, J = 7 , 2 Hz, 2H), 1.41 (t, J = 7.2 Hz, 3H).

[0179] The following compounds * not of the invention were prepared according to the procedures disclosed in Example 6.

EP-2934142B1PL

Ethyl 4-bromo-2-chlorobenzoate (Al47) [0180]

<img file="PL2934142T3_D0075.tif" />

[0181] The title compound was isolated as an off-white solid (2.0 g, 80%): ¹1 H NMR (400 MHz, DMSO-d₆) δ 8.25 (d, J = 1.2 Hz, 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 4.65 (q, J = 7.2 Hz, 2H), 1.56 (t, J = 7.2 Hz, 3H).

Ethyl 4-bromo-2-methylbenzoate (Al48)

[0182]

<img file="PL2934142T3_D0076.tif" />

The title compound is isolated as a pale yellow liquid (3.0 g, 83%): 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 8.4 Hz, 1H), 7.41 (s, 1H), 7.39 (d, J = 8.4 Hz, 1H), 4.42 (q, J = 7.2 Hz, 2H), 2.60 (s, 3H), 1.40 (t, J = 7.2 Hz, 3H) ESIMS m / z 229.11 ([M + H] +); IR (thin layer) 1725 cm-1.

Ethyl 4-bromo-2-fluorobenzoate (Al49)

[0184]

<img file="PL2934142T3_D0077.tif" />

The title compound was isolated as a colorless liquid (9.0 g, 79%): 1H NMR (400 MHz, DMSO-d6) δ 7.84 (t, J = 8.4 Hz, 1H), 7.76 ( d, J = 2.0 Hz, 1H), 7.58 (d, J = 1.6 Hz, 1H), 4.34 (q, J = 7.2 Hz, 2H), 1.32 (t, J = 7.2 Hz, 3H); ESIMS m / z 246.99 ([M + H] +), IR (thin layer) 1734 cm-1.

Example 7 * not according to the invention: Preparation of ethyl 4-bromo-2-ethylbenzoate (Al50)

[0186]

<img file="PL2934142T3_D0078.tif" />

[0187] To a stirred solution of 4-bromo-2-fluorobenzoic acid (2.0 g, 9.17 mmol) in THF (16 mL), 1.0 M ethylmagnesium bromide in THF (32 mL, 32.0 mmol) was added dropwise. ) at 0 ° C and the resulting reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was quenched with 2N HCl and extracted with ethyl acetate. The combined ethyl acetate layers were dried over anhydrous Na2SO4 and concentrated in vacuo to give crude 4-bromo-2-ethylbenzoic acid as a colorless liquid which was used in the next step without purification (0.4 g): 1H NMR (400MHz, CDCl₃) δ 7.64 (d, J = 8.4 Hz, 1H), 7.47 (m, 1H), 7.43 (m, 1H), 2.95 (q, J = 4.0 Hz, 2H ), 1.32 (t, J = 4.0 Hz, 3H); ESIMS m / z 228.97 ([M + H]⁺).

[0188] The title compound was synthesized from 4-bromo-2-ethylbenzoic acid according to the procedure in Example 6, isolated as a colorless liquid (0.15 g, 68%): ¹H NMR (400 MHz, DMSO-d6) δ 7.90 (d, J = 8.4 Hz, 1H), 7.47 (m, 2H), 4.40 (q, J = 7.2 Hz, 2H ), 3.06 (q, J = 7.6 Hz, 2H), 1.42 (t, J = 7.2 Hz, 3H), 1.26 (t, J = 7.6 Hz, 3H); ESIMS m / z 226.96 ([MH] -); IR (thin layer) 3443, 1686, 568 cm-1.

Example 8 * not according to the invention: Preparation of ethyl 2-bromo-4-vinylbenzoate (Al51)

EP-2934142B1PL

[0189]

<img file="PL2934142T3_D0079.tif" />

To a stirred solution of ethyl 2-bromo-4-iodobenzoate (5 g, 14.3 mmol) in THF / water (100 mL, 9: 1) was added potassium vinyl trifluoroborate (1.89 g, 14.3 mmol) , CspCO3 (18.27 g, 56.07 mmol) and triphenylphosphine (0.22 g, 0.85 mmol) and the reaction mixture was degassed with argon for 20 min, then PdCl2 (0.05 g, 0.28 mmol) was added. The reaction mixture was heated to reflux for 16 h. The reaction mixture was cooled to ambient temperature and filtered through a celite pad and washed with ethyl acetate. The filtrate was back extracted with ethyl acetate and the combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure to provide the crude compound. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; eluted with 2% ethyl acetate / petroleum ether) to afford the title compound as light brown gummy material (2 g, 56%): ¹H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 1.2 Hz, 1H), 7.51 (d, J = 8 , 4 Hz, 1H), 6.69 (dd, J = 17.6, 10.8 Hz, 1H), 5.86 (d, J = 17.6 Hz, 1H), 5.42 (d, J = 11.2 Hz, 1H), 4.42 (q, J = 7.2 Hz, 2H), 1.43 (t, J = 3.6 Hz, 3H); ESIMS m / z 255.18 ([M + H] +); IR (thin layer) 1729 cm-1.

[0191] The following compounds * not of the invention were prepared according to the procedures disclosed in Example 8.

Ethyl 2-methyl-4-vinylbenzoate (Al52)

[0192]

<img file="PL2934142T3_D0080.tif" />

The title compound was isolated as a colorless liquid (0.8 g, 80%): 1 H NMR (400 MHz, CDCl 3) δ 7.89 (d, J = 8.4 Hz, 1H), 7.27 (m, 2H), 6.79 (dd, J = 17.6, 10.8 Hz, 1H), 5.86 (d, J = 17.6 Hz, 1H), 5.42 (d, J = 11.2 Hz, 1H), 4.42 (q, J = 7.2 Hz, 2H), 2.60 (s, 3H), 1.43 (t, J = 7.2 Hz, 3H); ESIMS m / z 191.10 ([M + H]⁺); IR (thin layer) 1717, 1257 cm^-1.

Ethyl 2-fluoro-4-vinylbenzoate (Al53)

[0194]

<img file="PL2934142T3_D0081.tif" />

The title compound is isolated as a pale yellow liquid (2.0 g, 50%): 1H NMR (400 MHz, DMSO-d6) δ 7.87 (t, J = 8.0 Hz, 1H), 7.51 ( d, J = 16.0 Hz, 1H), 7.48 (d, J = 16.0 Hz, 1H), 6.82 (dd, J = 17.6, 10.8 Hz, 1H), 6, 09 (d, J = 17.6 Hz, 1H), 5.50 (d, J = 10.8 Hz, 1H), 4.35 (q, J = 7.2 Hz, 2H), 1.35 ( t, J = 7.2 Hz, 3H); ESIMS m / z 195.19 ([M + H] +); IR (thin layer) 1728 cm^-1.

Example 9: Preparation of ethyl 2-chloro-4-vinylbenzoate (Al54)

[0196]

<img file="PL2934142T3_D0082.tif" />

EP-2934142B1PL

To a stirred solution of ethyl 2-chloro-4-bromobenzoate (2 g, 7.63 mmol) in dimethyl sulfoxide (20 mL) was added potassium vinyl trifluoroborate (3.06 g, 22.9 mmol) and potassium carbonate (3.16 g, 22.9 mmol). The reaction mixture was degassed with argon for 30 min. Bistriphenylphosphine (diphenylphosphinoferrocene) palladium dichloride (0.27 g, 0.38 mmol) was added and the reaction mixture was heated to 80 ° C for 1 h. The reaction mixture was diluted with water (100 ml), extracted with ethyl acetate (2 x 50 ml), washed with brine, dried over Na2SO4 and concentrated in vacuo to give the compound as a brown gummy material (1.1 g, 69%): ¹H NMR (400 MHz, CDCl 3) δ 7.81 (d, J = 8.4 Hz, 1H), 7.46 (s, 1H), 7.33 (d, J = 8.4 Hz, 1H), 6.70 (dd, J = 17.6, 11.2 Hz, 1H), 5.87 (d, J = 17.6 Hz, 1H), 5.42 (d, J = 10.8 Hz, 1H ), 4.41 (q, J = 7.2 Hz, 2H), 1.43 (t, J = 7.2 Hz, 3H); ESIMS m / z 211.22 ([M + H]⁺); IR (thin layer) 1729,886 cm^-1.

[0198] The following compounds * not of the invention were prepared according to the procedures disclosed in Example 9.

Ethyl 2-ethyl-4-vinylbenzoate (Al55)

[0199]

<img file="PL2934142T3_D0083.tif" />

[0200] The title compound was isolated as a colorless liquid (1.0 g, 66%): 1H NMR (300 MHz, CDCl3) δ 7.85 (m, 1H), 7.29 (m, 2H), 6.76 ( d, J = 10.8 Hz, 1H), 5.86 (d, J = 17.6 Hz, 1H), 5.36 (d, J = 10.5 Hz, 1H), 4.41 (q, J = 7.2 Hz, 2H), 3.10 (q, J = 7.2 Hz, 2H), 1.40 (t, J = 7.2 Hz, 3H), 1.30 (t, J = 7.2 Hz, 3H); ESIMS m / z 205.26 ([M + H] +); IR (thin layer) 1720, 1607, 1263 cm^-1.

Methyl 2-methoxy-4-vinylbenzoate (Al56)

[0201]

<img file="PL2934142T3_D0084.tif" />

The title compound was isolated as a pale yellow liquid (1.2 g, 75%): 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 1.2 Hz, 1H), 6.97 (s, 1H), 6.74 (dd, J = 11.2, 11.2 Hz, 1H), 5.86 (d, J = 17.6 Hz, 1H), 5.39 (d, J = 17.6 Hz, 1H), 3.93 (s, 3H), 3.91 (s, 3H). ESIMS m / z 193.18 ([M + H]⁺); IR (thin layer) 1732 cm^-1,

Example 10 * not according to the invention: Preparation of ethyl (E) -4- (3- (3,5-Dichlorophenyl) -4,4,4-trifluorobut-1-yl) -2-methylbenzoate (Al24)

[0203]

<img file="PL2934142T3_D0085.tif" />

[0204] To a stirred solution of ethyl 2-methyl-4-vinylbenzoate (2.0 g, 10.5 mmol) in 1,2-dichlorobenzene (25 ml) was added 1- (1-bromo-2,2,2-trifluoroethyl) - 3,5-dichlorobenzene (6.44 g, 21.0 mmol), copper (I) chloride (CuCl; 208 mg, 21 mmol) and 2,2-bipyridyl (0.65 g, 4.1 mmol). The reaction mixture was degassed with argon for 30 min and then stirred at 180 ° C for 24 h. After the reaction was judged complete by TLC, the reaction mixture was cooled to 25 ° C and filtered, and the filtrate was concentrated under reduced pressure. Purification by flash chromatography

EP-2934142B1PL (SiO2, 100-200 mesh; eluted with 25-30% EtOAc in petroleum ether) gave the title compound as a solid (1.7 g, 40%): 1H NMR (400MHz, CDCl₃) δ 7.91 (d, J = 8.0 Hz, 1H), 7.37 (m, 1H),

7.27-7.24 (m, 4H), 6.59 (d, J = 16.0 Hz, 1H), 6.59 (dd, J = 16.0, 8.0 Hz, 1H), 4 , 38 (q, J = 7.2 Hz, 2H), 4.08 (m, 1H), 2.62 (s, 3H), 1.42 (t, J = 7.2 Hz, 3H); ESIMS m / z 415.06 ([MH]^-); IR (thin layer) 1717,

1255, 1114 cm-1.

Compounds Al25, Al57-Al68 and AC1-AC5 * not according to the invention (Table 1) were prepared according to the procedures disclosed in Example 10.

(E) -4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-phenyl) -2- (trifluoromethyl) benzoic acid ethyl ester (Al25) [0206]

<img file="PL2934142T3_D0086.tif" />

The product was isolated as a pale brown gummy liquid (500 mg, 40%): 1 H NMR (400 MHz, CDCl₃) δ 7.79 (d, J = 8.0 Hz, 1H), 7.71 (m, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.42 (s, 2H ), 6.70 (d, J = 16.0 Hz, 1H), 6.57 (dd, J = 16.0, 8.0 Hz, 1H), 4.42 (q, J = 7.2 Hz , 2H), 4.19 (m, 1H), 1.40 (t, J = 7.6 Hz, 3H); ESIMS m / z 502.99 ([MH]^-); IR (thin layer) 1730, 1201, 1120, 749 cm^-1.

Ethyl (E) -4- (3- (3,5-Dichlorophenyl) -4,4,4-trifluorobut-1-enyl) -2-fluorobenzoate (Al57)

[0208]

<img file="PL2934142T3_D0087.tif" />

1H NMR (400MHz, CDCl₃) δ 7.38 (s, 1H), 7.26 (s, 3H), 7.21 (d, J = 8.4 Hz, 1H), 7.16 (d, J = 11.6 Hz, 1H ), 6.59 (d, J = 16.0 Hz, 1H), 6.47 (dd, J =, 16.0, 8.0 Hz, 1H), 4.41 (q, J = 6.8 Hz, 2H), 4.18 (m, 1H), 1.41 (t, J = 6.8 Hz, 3H); ESIMS m / z 419.33 ([MH] -); IR (thin layer) 1723, 1115, 802 cm-1.

Ethyl (E) -4- (3- (3,5-Dichlorophenyl) -4,4,4-trifluorobut-1-phenyl) -2-bromobenzoate (Al58)

[0210]

<img file="PL2934142T3_D0088.tif" />

[0211] 1H NMR (400 MHz, CDCl₃) δ 7.79 (d, J = 8.0 Hz, 1H), 7.67 (s, 1H), 7.38 (m, 2H), 7.26 (m, 2H), 6.56 (d , J = 16.0 Hz, 1H), 6.45 (dd, J = 16.0, 7.6 Hz, 1H), 4.42 (q, J = 7.2 Hz, 2H), 4.39 (m, 1H), 1.42 (t, J = 7.2Hz, 3H); ESIMS m / z 481.22 ([MH]^-); IR (thin layer) 1727, 1114, 801.685 cm^-1.

Ethyl (E) -2-Bromo-4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-enyl) benzoate (Al59)

[0212]

<img file="PL2934142T3_D0089.tif" />

[0213] 1H NMR (400 MHz, CDCl₃) δ 7.79 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 1.6 Hz, 1H), 7.40 (s, 2H), 7.36 (d, J = 1.6 Hz, 1H), 6.56 (d, J = 16.0 Hz, 1H), 6.44 (dd, J = 16.0, 7.6 Hz, 1H), 4.42 (q , J = 6.8 Hz, 2H)

EP-2934142B1PL

4.15 (m, 1H), 1.42 (t, J = 6.8 Hz, 3H); ESIMS m / z 514.74 ([MH]^-); IR (thin layer) 1726, 1115, 808,

620 cm^-1.

Ethyl (E) -2-methyl-4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-phenyl) benzoate (Al60) [0214]

<img file="PL2934142T3_D0090.tif" />

[0215] The title compound is isolated as a light brown gummy material: ¹H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 8.8 Hz, 1H), 7.34 (d, J = 6.0 Hz, 2H), 7.25 (d, J = 7 , 2 Hz, 2H), 6.59 (d, J = 16.0 Hz, 1H), 6.42 (dd, J = 16.0, 8.0 Hz, 1H), 4.38 (q, J = 7.2 Hz, 2H), 4.19 (m, 1H), 2.63 (s, 3H), 1.41 (t, J = 7.2 Hz, 3H).

Ethyl (E) -2-Chloro-4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-phenyl) benzoate (Al61) [0216]

<img file="PL2934142T3_D0091.tif" />

1H NMR (400 MHz, CDCl₃) δ 7.87 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 1.6 Hz, 1H), 7.40 (s, 2H), 7.31 (d, J = 1.6 Hz, 1H), 6.57 (d, J = 16.0 Hz, 1H), 6.44 (dd, J = 16.0 Hz, 8.0 Hz, 1H), 4.42 ( q, J = 6.8 Hz, 2H), 4.15 (m, 1H), 1.42 (t, J = 6.8 Hz, 3H); ESIMS m / z 470.73 ([MH] -); IR (thin layer) 1726, 1115, 809, 3072 cm^-1.

Ethyl (E-4- (4,4,4-Trifluoro-3- (3,4,5-trichlorophenyl) but-1-enyl) -2- (trifluoromethyl) benzoate (Al62) [0218]

<img file="PL2934142T3_D0092.tif" />

[0219] The title compound was isolated as a pale brown liquid (1.0 g, 46.3%): 1 H NMR (400 MHz, CDCl₃) δ 7.79 (d, J = 8.0 Hz, 1H), 7.71 (s, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.41 (s, 2H ) 6.65 (d, J = 16.0 Hz, 1H), 6.49 (dd, J = 16.0, 8.0 Hz, 1H), 4.42 (q, J = 7.6 Hz, 2H), 4.15 (m, 1H), 1.42 (t, J = 7.6 Hz, 3H); ESIMS m / z 502.99 ([MH]^-); IR (thin layer) 1730, 1202, 1120, 750 cm^-1.

Ethyl (E-2-Chloro-4- (3- (3,5-dichloro-4-fluorophenyl) -4,4,4-trifluorobut-1-enyl) benzoate (Al63) [0220]

<img file="PL2934142T3_D0093.tif" />

1H NMR (400MHz, CDCl₃) δ 7.85 (d, J = 6.0 Hz, 1H), 7.46 (d, J = 1.8 Hz, 2H), 7.34 (m, 1H), 7.24 (m, 1H ), 6.57 (d, J = 16.2 Hz, 1H), 6.45 (dd, J = 16.2, 7.2 Hz, 1H), 4.43 (q, J = 7.2 Hz , 2H), 4.13 (m, 1H), 1.41 (t, J = 7.2Hz, 3H); ESIMS m / z 455.0 ([M + H] +); IR (thin layer) 1728, 1115, 817 cm-1.

Ethyl (E) -2-Fluoro-4- (3- (3,5-dichloro-4-fluorophenyl) -4,4,4-trifluorobut-1-enyl) benzoate (Al64) [0222]

EP-2934142B1PL

1H NMR (400MHz, CDCl₃) δ 7.93 (t, J = 7.6 Hz, 1H), 7.34 (d, J = 5.6 Hz, 2H), 7.21 (d, J = 8.0 Hz,

1H), 7.16 (d, J = 11.6 Hz, 1H), 6.59 (d, J = 16.0 Hz, 1H), 6.49 (dd, J = 16.0, 7.6 Hz, 1H), 4.42 (q, J = 7.6 Hz,

2H), 4.13 (m, 1H), 1.41 (t, J = 7.6 Hz, 3H); ESIMS m / z 436.81 ([MH] -); IR (thin layer) 1725 cm-1.

Ethyl (E) -2-Bromo-4- (3- (3,5-dichloro-4-fluorophenyl) -4,4,4-trifluorobut-1-enyl) benzoate (Al65)

[0224]

<img file="PL2934142T3_D0094.tif" />

<img file="PL2934142T3_D0095.tif" />

[0225] 1H NMR (400 MHz, CDCl₃) δ 7.94 (d, J = 8.0 Hz, 1H), 7.67 (s, 1H), 7.36 (m, 3H), 6.56 (d, J = 15.6 Hz, 1H ), 6.44 (dd, J = 15.6, 8.0 Hz, 1H), 4.42 (q, J = 6.8 Hz, 2H), 4.10 (m, 1H), 1.42 (t, J = 6.8 Hz, 3H); ESIMS m / z 498.74 ([MH]^-); IR (thin layer) 1726, 1114, 820, 623 cm^-1.

Ethyl (E) -2-methyl-4- (3- (3,5-dichloro-4-fluorophenyl) -4,4,4-trifluorobut-1-enyl) benzoate (Al66) [0226]

<img file="PL2934142T3_D0096.tif" />

[0227] The title compound was isolated as a brown semi-solid: 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 8.8 Hz, 1H), 7.34 (d, J = 6.0 Hz, 2H ), 7.25 (d, J = 7.2 Hz, 2H), 6.59 (d, J = 16.0 Hz, 1H), 6.42 (dd, J = 16.0 Hz, 8.0 Hz, 1H), 4.38 (q, J = 7.2 Hz, 2H), 4.19 (m, 1H), 2.63 (s, 3H), 1.41 (t, J = 7.2 Hz, 3H); ESIMS m / z 432.90 ([MH]^-); IR (thin layer) 1715 cm^-1.

Methyl (E) -2-methoxy-4- (3- (3,5-dichloro-4-fluorophenyl) -4,4,4-trifluorobut-1-enyl) benzoate (Al67) [0228]

<img file="PL2934142T3_D0097.tif" />

1H NMR (400MHz, CDCl₃) δ 7.80 (d, J = 8.4 Hz, 1H), 7.35 (d, J = 6.0 Hz, 2H), 7.03 (d, J = 1.2 Hz, 1H), 6.92 (s, 1H), 6.59 (d, J = 15.6 Hz, 1H), 6.42 (dd, J = 15.6, 8.0 Hz, 1H), 4.13 (m , 1H), 3.93 (s, 3H), 3.88 (s, 3H); ESIMS m / z 437.29 ([M + H] +); IR (thin layer) 1724 cm-1.

Ethyl (E) -2-ethyl-4- (3- (3,5-dichloro-4-fluorophenyl) -4,4,4-trifluorobut-1-enyl) benzoate (Al68) [0230]

<img file="PL2934142T3_D0098.tif" />

[0231] ¹H NMR (400 MHz, CDCl₃) δ 7.85 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 9.6 Hz, 2H), 7.26 (m, 1H), 7.24 (m, 1H ), 6.60 (d, J = 15.6 Hz, 1H), 6.42 (dd, J = 15.6, 8.0 Hz, 1H), 4.38 (q, J = 7.2 Hz , 2H), 4.14 (m, 1H), 3.01 (q, J = 7.6 Hz 2H), 1.41 (t, J = 7.2 Hz, 3H), 1.26 (t, J = 7.6 Hz, 3H); ESIMS m / z 447.05 ([MH] -); IR (thin layer) 1715, 1115, 817 cm^-1.

EP-2934142B1PL

Example 11 * not according to the invention: Preparation of (E) -4- (3- (3,5-dichlorophenyl) -4,4,4-trifluorobut-1-enyl) -2-methylbenzoic acid (Al32)

[0232]

<img file="PL2934142T3_D0099.tif" />

To a stirred solution of ethyl (E) -4- (3- (3,5-dichlorophenyl) -4,4,4-trifluorobut-1-enyl) -2-methylbenzoate (1.7 g, 4.0 mmol ) in 1,4-dioxane (10 ml), 11N HCl (30 ml) was added, and the reaction mixture was heated at 100 ° C for 48 h. The reaction mixture was cooled to 25 ° C and concentrated under reduced pressure. The residue was diluted with H 2 O and extracted with chloroform (CHCl 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure, and the crude compound was washed with n-hexane to provide the title compound as a white solid (0.7 g, 50%): mp 142-143 ° C; 1 H NMR (400 MHz, DMSO-d6) δ 12.62 (br s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.66 (s, 3H), 7.52- 7.44 (m, 2H), 6.89 (dd, J = 16.0, 8.0 Hz, 1H), 6.78-6.74 (d, J = 16.0 Hz, 1H), 4 . 84 (m, 1H); 2.50 (s, 3H); ESIMS m / z 387.05 ([MH]^-); IR (thin layer) 3448, 1701, 1109, 777 cm^-1.

[0234] The following compounds * not according to the invention were prepared according to the procedures disclosed in Example 11.

(E) -2-methyl-4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-enyl) benzoic acid (Al26) [0235]

<img file="PL2934142T3_D0100.tif" />

[0236] The product was isolated as a pale brown gummy liquid (1 g, 46%): ¹H NMR (400 MHz, CDCl 3) δ 7.97 (d, J = 8.0 Hz, 1H), 7.77 (s, 1H), 7.65 (m, 1H), 7.41 (s, 2H ), 6.68 (d, J = 16.0 Hz, 1H), 6.53 (dd, J = 16.0, 8.0 Hz, 1H), 4.16 (m, 1H), 2.50 (s, 3H); ESIMS m / z 422.67 ([MH]^-).

(E) -2-chloro-4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-enyl) benzoic acid (Al27)

[0237]

<img file="PL2934142T3_D0101.tif" />

[0238] The product was isolated as an off-white semi-solid (1 g, 45%): ¹H NMR (400 MHz, CDCl 3) δ 7.99 (d, J = 8.4 Hz, 1H), 7.50 (m, 1H), 7.40 (s, 1H), 7.36 (m, 2H ), 6.59 (d, J = 15.6 Hz, 1H), 6.48 (dd, J = 15.6, 7.6 Hz, 1H), 4.14 (m, 1H); ESIMS m / z 442.72 ([MH]^-); IR (thin layer) 3472, 1704, 1113, 808 cm^-1.

(E) -2-bromo-4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-phenyl) benzoic acid (Al28) [0239]

<img file="PL2934142T3_D0102.tif" />

EP-2934142B1PL

[0240] The product was isolated as a brown solid (1 g, 45%): mp 70-71 ° C; ¹H NMR (400 MHz,

CDCl₃) δ 7.99 (d, J = 8.0 Hz, 1H), 7.72 (s, 1H), 7.40 (m, 3H), 6.58 (d, J = 16.0 Hz, 1H ), 6.48 (dd, J = 16.0,

8.0 Hz, 1H), 4.14 (m, 1H); ESIMS m / z 484.75 ([MH]^-); IR (thin layer) 3468, 1700 cm^-1.

(E) -2-Cyano-4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-phenyl) benzoic acid (Al29)

[0241]

<img file="PL2934142T3_D0103.tif" />

[0242] The product was isolated as an off-white solid (500 mg, 45%): mp 100-101 ° C; ¹H NMR (400 MHz, CDCl₃) δ 7.90 (s, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.65 (br s, 1H), 7.42 (s, 2H), 6.73 (d, J = 16.0 Hz, 1H), 6.58 (dd, J = 16.0, 8.0 Hz, 1H), 4, 19 (m, 1H); ESIMS m / z 431.93 ([MH] -).

(E) -4- (3- (3,4-dichlorophenyl) -4,4,4-trifluorobut-1-phenyl) -2-methylbenzoic acid (Al30)

[0243]

<img file="PL2934142T3_D0104.tif" />

The product was isolated as a pale brown liquid (500 mg, 46%): ¹H NMR (400 MHz, CDCl3) δ 8.03 (m, 1H), 7.49 (m, 2H), 7.29 (m, 1H), 7.22 (m, 2H), 6.73 (d , J = 16.0 Hz, 1H), 6.58 (dd, J = 16.0, 7.8 Hz, 1H), 4.16 (m, 1H), 2.64 (s, 3H); ESIMS m / z 386.84 ([MH] -); IR (thin layer) 3428, 1690, 1113, 780 cm^-1.

(E) -4- (3- (3,5-Dichloro-4-fluorophenyl) -4,4,4-trifluorobut-1-phenyl) -2-methylbenzoic acid (Al31) [0245]

<img file="PL2934142T3_D0105.tif" />

The product was isolated as a white solid (500 mg, 50%): mp 91-93 ° C; 1 H NMR (400 MHz, CDCl₃) δ 8.02 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 5.6 Hz, 1H), 7.30 (m, 3H), 6.61 (d, J = 16.0 Hz, 1H), 6.48 (dd, J = 16.0, 8.0 Hz, 1H), 4.13 (m, 1H), 2.65 (s, 3H); ESIMS m / z 406.87 ([MH]^-).

(E) -4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-enyl) -2- (trifluoromethyl) benzoic acid (Al33)

[0247]

<img file="PL2934142T3_D0106.tif" />

The product was isolated as a white solid (500 mg, 45%): mp 142-143 ° C; 1 H NMR (400 MHz, CDCl₃) δ 7.97 (d, J = 8.0 Hz, 1H), 7.77 (s, 1H), 7.65 (m, 1H), 7.41 (s, 2H), 6.68 (d , J = 16.0 Hz, 1H), 6.53 (dd, J = 16.0, 8.0 Hz, 1H), 4.16 (m, 1H); ESIMS m / z 474.87 ([MH] -).

(E) -2-bromo-4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-phenyl) benzoic acid (Al69)

[0249]

EP-2934142B1PL

[0250] The title compound was isolated as a brown solid (0.8 g, 28%): ¹H NMR (400 MHz,

CDCl₃) δ 13.42 (br, 1H), 7.98 (d, J = 1.5 Hz, 1H), 7.94 (m, 2H), 7.75 (d, J = 8.1 Hz, 1H ), 7.65 (m, 1H),

7.06 (dd, J = 15.9, 9.0 Hz, 1H), 6.80 (d, J = 15.9 Hz, 1H), 4.91 (m, 1H); ESIMS m / z 484.75 ([MH] -); IR (thin layer) 3469, 1700 cm^-1.

<img file="PL2934142T3_D0107.tif" />

(E) -2-bromo-4- (3- (3,5-dichloro-4-fluorophenyl) -4,4,4-trifluorobut-1-enyl) benzoic acid (Al70)

[0251]

<img file="PL2934142T3_D0108.tif" />

The title compound was isolated as a yellow liquid (0.3 g, crude): 1 H NMR (300 MHz, CDCl 3) δ 7.79 (d, J = 8.1 Hz, 1H), 7.67 (s, 1H ), 7.34 (m, 3H), 6.56 (d, J = 15.9 Hz, 1H), 6.45 (dd, J = 15.9, 7.6 Hz, 1H), 4.43 (m, 1H); ESIMS m / z 471.0 ([MH] -).

(E) -4- (3- (3,5-Dichloro-4-fluorophenyl) -4,4,4-trifluorobut-1-phenyl) -2-ethylbenzoic acid (Al71)

[0253]

<img file="PL2934142T3_D0109.tif" />

The title compound was isolated as a brown gummy material (0.2 g, crude): 1 H NMR (300 MHz, DMSO-d₆) δ 12.5 (br, 1H), 7.85 (d, J = 6.3 Hz, 2H), 7.75 (d, J = 8.1 Hz, 1H), 7.52 (m, 2H ), 6.96 (dd, J = 8.7, 8.7 Hz, 1H), 6.78 (d, J = 15.6 Hz, 1H), 4.80 (m, 1H), 4.06 (q, J = 7.2 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H); ESIMS m / z 419.06 ([MH] -).

(E) -2-chloro-4- (3- (3,5-dichloro-4-fluorophenyl) -4,4,4-trifluorobut-1-enyl) benzoic acid (Al72) [0255]

<img file="PL2934142T3_D0110.tif" />

[0256] The title compound was isolated as a yellow liquid (0.7 g, 95%): ¹H NMR (300 MHz, CDCl3) δ 7.85 (d, J = 6.0 Hz, 1H), 7.46 (d, J = 1.8 Hz, 1H), 7.41 (s, 3H), 6.57 (d, J = 16.0 Hz, 1H), 6.45 (dd, J = 16.0, 8.0 Hz, 1H), 4.16 (m, 1H); ESIMS m / z 455.0 ([M + H] +); IR (thin layer) 1728, 1115, 817 cm^-1.

(E) -4- (3- (3,5-Dichloro-4-fluorophenyl) -4,4,4-trifluorobut-1-enyl) -2-methylbenzoic acid (Al73) [0257]

<img file="PL2934142T3_D0111.tif" />

The title compound was isolated as a light brown gummy material (0.7 g, 38%): mp 91-93 ° C; 1 H NMR (400 MHz, CDCl₃) δ 8.02 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 5.6 Hz, 1H), 7.30 (m, 3H), 6.10 (d, J = 16.0 Hz, 1H), 6.46 (dd, J = 16.0, 8.0 Hz, 1H), 4.03 (m, 1H), 2.65 (s, 3H); ESIMS m / z 406.87 ([MH] -).

EP-2934142B1PL

(E) -4- (3- (3,5-Dichlorophenyl) -4,4,4-trifluorobut-1-phenyl) -2-fluorobenzoic acid (Al74)

[0259]

<img file="PL2934142T3_D0112.tif" />

[0260] The title compound was isolated as a light brown liquid (0.3 g, crude): ESIMS m / z 393.15 ([MH]^-).

(E) -2-bromo-4- (3- (3,5-dichlorophenyl) -4,4,4-trifluorobut-1-enyl) benzoic acid (Al75)

[0261]

<img file="PL2934142T3_D0113.tif" />

The title compound is isolated as a light brown liquid (0.35 g, crude): ESIMS m / z 451.91 ([MH]^-).

[0263] It was anticipated that Al34, Al36-Al41, Al44-Al45 (Table 1) could be made according to the procedures disclosed in Example 10, or Examples 10 and 11.

Example 12 * not according to the invention: Preparation of (E) -4- (3- (3,5-Dichlorophenyl) -4,4,4-trifluorobut-1-yl) -2-methyl-N- (2,2,2-trifluoroethyl) ) benzamide (AC6) [0264]

<img file="PL2934142T3_D0114.tif" />

[0265] 2,2,2-Trifluoroethylamine was added to a mixed solution of (E) -4- (3- (3,5-dichlorophenyl) -4,4,4-trifluorobut-1-enyl) -2-methylbenzoic acid in DMF. , 1-hydroxybenzotriazole hydrate (HOBt.H2O), N- (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride (EDC.HCl) and DIPEA, and the reaction mixture was stirred at 25 ° C for 18 h. The reaction mixture was diluted with H 2 O and extracted EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; eluting with hexane: EtOAc gave a white semi-solid (110 mg, 50%): 1 H NMR (400 MHz, CDCl₃) 7.40 (m, 2H), 7.26 (m, 3H), 6.56 (d, J = 16.0 Hz, 1H), 6.48 (dd, J = 16.0, 8.0 Hz, 1H), 5.82 (br s, 1H), 4.08 (m, 3H), 2.52 (s, 3H); ESIMS m / z 468.40 ([MH] -); IR (thin layer) 1657, 1113, 804 cm^-1.

Compounds AC7-AC38, AC40-AC58, AC110-AC112, AC117, and AC118 * not according to the invention (Table 1) were prepared according to the procedures disclosed in Example 12.

Example 13 * not according to the invention: Preparation of 4 - ((E) -3- (3,5-Dichlorophenyl) -4,4,4-trifluorobut-1-phenyl) -2-methyl-N - ((pyrimidin-5-yl) methyl) benzamide (AC39)

[0267]

<img file="PL2934142T3_D0115.tif" />

[0268] To a stirred solution of (pyrimidin-5-yl) methanamine (0.15 g, 1.43 mmol) in CH2Cl2 (10 mL) was added trimethylaluminum (2 M solution in toluene; 0.71 mL, 1.43 mmol) dropwise. ), and the reaction mixture

The mixture was stirred at 25 ° C for 30 min. A solution of ethyl 4 - ((E) 3- (3,5-dichlorophenyl) -4,4,4-trifluorobut-1-enyl) -2-methylbenzoate (0.3 g, 0.71 mmol) was added dropwise to the reaction mixture. in CH2Cl2 at 25 ° C. The reaction mixture was stirred at reflux for 18 h, cooled to 25 ° C, quenched with 0.5 N HCl solution (50 ml) and extracted with EtOAc (2 x 50 ml). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude compound was purified by flash chromatography (SiO2, 100-200 mesh; eluted with 40% EtOAc in n-hexane) to afford the title compound (0.18 g, 55%): mp 141 144 ° C; 1H (400MHz, CDCl₃) δ 9.19 (s, 1H), 8.79 (s, 2H), 7.37 (m, 2H), 7.23 (m, 2H), 7.21 (m, 1H), 6.57 (d, J = 16.0 Hz, 1H), 6.40 (dd, J = 16.0, 7.6 Hz, 1H), 6.21 (m, 1H), 4.65 (s, 2H), 4.11 (m, 1H), 2.46 (s, 3H); ESIMS m / z 477.83 ([MH] -).

Example 14 * not according to the invention: Preparation of (E) -2-Chloro-N- (2-oxo-2 - ((2,2,2-trifluoroethyl) amino) ethyl) -4- (4,4,4-trifluoro -3- (3,4,5-trichlorophenyl) but-1-en-1-yl) benzamide (AC64)

[0269]

<img file="PL2934142T3_D0116.tif" />

[0270] To a stirred solution of glycine amide (0.15 g, 0.58 mmol) in CH2Cl2 (5 mL) was added trimethylaluminum (2 M toluene solution; 1.45 mL, 2.91 mmol) dropwise, and the reaction mixture was stirred. at 28 ° C for 30 min. A solution of ethyl (E) -2-chloro-4 (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-enyl) benzoate (0.3 g , 58 mmol) in CH2Cl2 (5 mL) at 28 ° C. The reaction mixture was stirred at reflux for 18 h, cooled to 25 ° C, quenched with 1 N HCl solution (50 ml) and extracted with CH2Cl2 (2 x 50 ml). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude compound was purified by flash chromatography (SiO2, 100-200 mesh; eluted with 40% EtOAc in n-hexane) to provide the title compound as a yellow solid (0.15 g, 50%): mp 83-85 ° C; 1 H NMR (400 MHz, CDCl₃) δ 7.72 (d, J = 8.0 Hz, 1H), 7.44 (s, 1H), 7.40 (s, 2H), 7.36 (d, J = 6.8 Hz, 1H ), 7.05 (t, J = 5.2 Hz, 1H), 6.70 (t, J = 5.2 Hz, 1H), 6.57 (d, J = 15.6 Hz, 1H), 6.44 (dd, J = 15.6, 8.0 Hz, 1H), 4.23 (d, J = 5.6 Hz, 2H), 4.15 (m, 1H), 4.01 (m , 2H); ESIMS m / z 580.72 ([MH] -).

Compounds AC59-AC75 * not according to the invention (Table 1) were prepared according to the procedures disclosed in Example 14.

Example 15 * not according to the invention: Preparation of (E) -2-Bromo-4- (3- (3,5-dichloro-4-fluorophenyl) 4,4,4-trifluorobut-1-en-1-yl) -N - (2-oxo-2 - ((2,2,2-trifluoroethyl) amino) ethyl) benzamide (AC79) [0272]

<img file="PL2934142T3_D0117.tif" />

To a stirred solution of (E) -2-bromo-4- (3- (3,5-dichloro-4-fluorophenyl) -4,4,4-trifluorobut-1-enyl) benzoic acid (300 mg, 0.638 mmol) in CH2Cl2 (5.0 mL) was added 2-amino-N- (2,2,2-trifluoroethyl) acetamide (172 mg, 0.638 mmol) followed by benzotriazol-1-yl-oxytripyrrolidine phosphonium hexafluorophosphate (PyBOP) (364, 5 mg, 0.701 mmol) and DIPEA (0.32 mL, 1.914 mmol), and the resulting mixture

The reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with water and extracted with CH2Cl2. The combined CH2Cl2 layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification by flash column chromatography (SiO2, 100-200 mesh; eluted with 40% ethyl acetate / petroleum ether) gave the title compound as an off-white solid (121mg, 31%): 1H NMR (400MHz, CDCl₃) δ 8.69 (t, J = 6.0 Hz, 1H), 8.58 (t, J = 6.0 Hz, 1H), 7.92 (s, 1H), 7.87 (d, J = 6.4 Hz, 2H), 7.62 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.0 (m, 1H), 6.76 (d, J = 15.6 Hz, 1H), 4.83 (t, J = 8.0 Hz, 1H), 3.98 (m, 4H); ESIMS m / z 610.97 ([M + H] +); IR (thin layer) 3303, 1658, 1166, 817 cm^-1.

Compounds AC76-AC80, AC96-AC102, and AC113 * not according to the invention (Table 1) were prepared according to the procedures disclosed in Example 15.

Example 16 * not according to the invention: Preparation of (E) -4- (3- (3,5-Dichlorophenyl) -4,4,4-trifluorobut-1-en-1-yl) -N- (1,1-dioxydothiethane-3 -yl) -2-fluorobenzamide (AC83)

[0275]

<img file="PL2934142T3_D0118.tif" />

To a mixed solution of (E) -4- (3- (3,5-dichlorophenyl) -4,4,4-trifluorobut-1-enyl) -2-fluoro-N (thietan-3-yl) benzamide ( 100 mg, 0.2159 mmol) in acetone / water (1: 1, 5.0 mL) was added Oxone (266 mg, 0.4319 mmol) and the resulting reaction mixture was stirred at ambient temperature for 4 h. The reaction mixture was diluted with water. and extracted with ethyl acetate. The combined ethyl acetate layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; eluted with 30% ethyl acetate / petroleum ether) gave the title compound as an off-white solid (70.0mg, 66%): ¹H NMR (400 MHz, CDCl₃) δ 8.07 (t, J = 8.4 Hz, 1H), 7.39 (t, J = 1.6 Hz, 1H), 7.31 (d, J = 1.2 Hz, 1H), 7.26 (m, 2H), 7.23 (m, 2H), 7.19 (d, J = 1.6 Hz, 1H), 6.60 (d, J = 16.8 Hz, 1H), 6.49 (dd, J = 16.8, 7.6 Hz, 1H), 4.90 (m, 1H), 4.64 (m, 2H), 4.14 (m, 2H); ESIMS m / z 493.83 ([MH]^-); IR (thin layer) 1527, 1113, 801, 1167, 1321 cm-¹.

Compounds AC81-AC87 * not according to the invention (Table 1) were prepared according to the procedures disclosed in Example 16.

Example 17 * not according to the invention: Preparation of (E) -N - ((5-Cyclopropyl-1,3,4-oxadiazol-2-yl) methyl) -4- (3- (3,5-dichlorophenyl) -4,4, 4-trifluorobut-1-en-1-yl) -2-methylbenzamide (AC89) [0278]

<img file="PL2934142T3_D0119.tif" />

A solution of (E) -N- (2- (2- (cyclopropanecarbonyl) hydrazinyl) -2-oxoethyl) -4- (3- (3,5-dichlorophenyl) 4,4,4-trifluorobut-1-enyl ) -2-methylbenzamide (200 mg, 0.379 mmol) in POCl3 (2.0 mL) was stirred at ambient temperature for 10 min, then the resulting reaction mixture was heated to 50 ° C for 1 h. ° C and extracted with ethyl acetate. The combined ethyl acetate layers were washed with saturated NaHCO3 solution and brine solution,

The EP-2934142B1PL was dried over anhydrous NapSO4, and concentrated under reduced pressure. Purification by flash column chromatography (SiO₂, 100-200 mesh; eluted with 50% ethyl acetate / petroleum ether) gave the title compound as a light brown gummy material (70.0 mg, 36%):¹H NMR (400 MHz, CDCl₃) δ 7.43 (m, 2H), 7.27 (m, 2H), 7.23 (m, 2H), 6.58 (d, J = 16.0 Hz, 1H), 6.41 (dd , J = 16.0, 7.6 Hz, 1H), 4.79 (d, J = 5.6 Hz, 2H), 4.14 (m, 1H), 2.48 (s, 3H), 2 . 18 (m, 1H), 1.16 (m, 4H); ESIMS m / z 509.89 ([M + H] +); IR (thin layer) 1666, 1166, 1112, 800 cm^-1.

Example 18 * not according to the invention: Preparation of (E-2-Bromo-N- (2-thioxo-2 - ((2,2,2-trifluoroethyl) amino) ethyl) -4- (4,4,4-trifluoro 3- (3,4,5-trichlorophenyl) but-1-en-1-yl) benzothioamide (AC90) [0280]

<img file="PL2934142T3_D0120.tif" />

To a stirred solution of (E) -2-bromo-N- (2-oxo-2 - ((2,2,2-trifluoroethyl) amino) ethyl) -4- (4,4,4-trifluoro-3 - (3,4,5-trichlorophenyl) but-1-en-1-yl) benzamide (400 mg, 0.638 mmol) in 5 mL of THF at ambient temperature 2,4-bis (4-methoxyphenyl) -1.3 , 2,4-Dithiadiphosphetane-2,4-disulfide (Lawesson's reagent) (336 mg, 0.830 mmol) in one portion. The resulting reaction mixture was stirred for 18 h. TLC showed the reaction was incomplete so additional Lawesson's reagent (168 mg, 0.415 mmol) was added and the reaction was stirred for 48 h. After the reaction was judged complete by TLC, the reaction mixture was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 230-400 mesh; eluted with 20% EtOAc in hexane) gave the title compound as a yellow glass oil (188 mg, 44.7%): 1H NMR (400 MHz, CDCl3) δ 8.34 (m, 1H), 8.27 (m, 1H), 7.60 (d, J = 1.6Hz, 1H), 7.49 (d, J = 8.0Hz, 2H), 7.40 (s, 2H), 7.36 (dd, J = 8.2, 1.7 Hz, 1H), 6.53 (d, J = 16.0 Hz, 1H), 6.38 (dd, J = 15.9, 7.9 Hz, 1H), 4.89 (d, J = 8.4, 5.5 Hz, 2H), 4.48 (qd, J = 9.0, 6.0 Hz, 2H ), 4.11 (m, 1H); ESIMS m / z 656.9 ([MH] -).

Example 19 * not according to the invention: Preparation of (E) -2- (2-Bromo-4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-en-1-yl) phenylthioamido ) -N- (2,2,2-trifluoroethyl) acetamide (AC91)

[0282]

<img file="PL2934142T3_D0121.tif" />

To a stirred solution of (E) -2-bromo-N- (2-oxo-2 - ((2,2,2-trifluoroethyl) amino) ethyl) -4- (4,4,4-trifluoro-3- ( 3,4,5-trichlorophenyl) but-1-en-1-yl) benzamide (400 mg, 0.638 mmol) in 5 mL of THF at ambient temperature was added Lawesson's reagent (64.5 mg, 0.160 mmol) in one portion. After the resulting reaction mixture was stirred for 18 h, the reaction mixture was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 230-400 mesh; eluted with 20% EtOAc in hexane) gave the title compounds as a yellow oil (18.5mg, 4.51%): ¹H NMR (400 MHz, CDCl₃) δ 8.18 (t, J = 5.0 Hz, 1H), 7.58 (d, J = 1.6 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.40 (s, 2H), 7.34 (dd, J = 8.1, 1.6 Hz, 1H), 6.52 (m, 2H), 6.37 (dd, J = 15.9, 7.9 Hz, 1H), 4.54 (d, J = 4.9 Hz, 2H), 4.12 (m, 1H), 3.99 (qd, J = 8.9, 6.5 Hz, 2H); ESIMS m / z 640.9 ([MH] -).

[0284] The following compound * not according to the invention was prepared according to the procedures disclosed in Example 19.

EP-2934142B1PL (E) -2-Bromo-N- (2-thioxo-2 - ((2,2,2-trifluoroethyl) amino) ethyl) -4- (4,4,4-trifluoro-3- (3) , 4,5-trichlorophenyl) but-1-en-1-yl) benzamide (AC92)

[0285]

<img file="PL2934142T3_D0122.tif" />

The product was isolated as a colorless oil (17.9 mg, 4.36%): 1 H NMR (400 MHz, CDCl₃) δ 9.16 (d, J = 6.1 Hz, 1H), 7.65 (d, J = 1.6 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.41 (m, 3H), 7.21 (t, J = 5.6 Hz, 1H), 6.55 (d, J = 15.9 Hz, 1H), 6.41 (dd, J = 15 , 9, 7.8 Hz, 1H), 4.59 (d, J = 5.6 Hz, 2H), 4.45 (qd, J = 9.0, 6.0 Hz, 2H), 4.12 (q, J = 7.2 Hz, 1H); ESIMS m / z 640.9 ([MH] -).

Example 106 * not according to the invention: Preparation of ethyl (Z) -2-Bromo-4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-en-1-yl) benzoate (AI76)

[0287]

<img file="PL2934142T3_D0123.tif" />

[0288] The title compound was prepared according to the procedure disclosed in Example 88 and isolated as a yellow viscous oil (416mg, 23%): 1H NMR (400MHz, CDCl₃) δ 7.80 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 1.7 Hz, 1H), 7.35 (s, 2H), 7.12 (dd, J = 8.0, 1.7 Hz, 1H), 6.86 (d, J = 11.4 Hz, 1H), 6.23 - 5.91 (m, 1H), 4.42 (q, J = 7.1 Hz, 2H), 4.33-4.10 (m, 1H), 1.42 (t, J = 7.2 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ -69.34 (d, J = 8.3 Hz); EIMS m / z 514.10 ([M]^-); IR (thin layer) 2983, 1727, 1247, 1204, 1116 cm-¹.

Example 107 * not according to the invention: Preparation of (Z) -2-bromo-4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-en-1-yl) benzoic acid (Al77 )

[0289]

<img file="PL2934142T3_D0124.tif" />

[0290] To a stirred solution of ethyl (Z) -2-bromo-4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-en-1-yl) benzoate (360 mg, 0.70 mmol) in CH3CN (1.0 mL) was added iodotrimethylsilane (0.28 mL, 2.8 mmol). The reaction mixture was refluxed for 20 h, allowed to cool to ambient temperature and partitioned between CH2Cl2 and aq. 10% Na2S2O3. The organic phase was washed once with aq. 10% Na2S2O3 and dried over MgSO4 and concentrated in vacuo. Passing the material through a silica pad using 10% EtOAc in hexane followed by 20% MeOH in CH2Cl2 as eluents provided the title compound as a yellow foam (143 mg, 42%): mp 54-64 ° C; ¹H NMR (400 MHz, CDCl 3) δ 11.36 (s, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.43 (s, 1H), 7.30 (s, 2H ), 7.14 (d, J = 7.9 Hz, 1H), 6.85 (d, J = 11.4 Hz, 1H), 6.15 (t, J = 10.9 Hz, 1H), 4.36 - 4.09 (m, 1H); ¹⁹F NMR (376 MHz, CDCl3) δ 69.30.

Example 108 * not according to the invention: Preparation of (Z) -2-Bromo-N- (2-oxo-2 - ((2,2,2-trifluoroethyl) amino) ethyl) -4- (4,4,4-trifluoro -3- (3,4,5-trichlorophenyl) but-1-en-1-yl) benzamide (AC95)

EP-2934142B1PL

[0291]

<img file="PL2934142T3_D0125.tif" />

[0292] To a stirred solution of (Z) -2-bromo-4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-en-1-yl) benzoic acid (200 mg, 0.41 mmol) in anhydrous THF (5.0 mL) was added DCI (82 mg, 0.51 mmol). The mixture was heated in a 50 ° C oil bath for 1.5 h, treated with 2-amino-N (2,2,2-trifluoroethyl) acetamide hydrochloride (109 mg, 057 mmol) and the resulting mixture was heated at reflux for 8 h. After cooling to ambient temperature, the mixture was dissolved in Et2O and washed twice with aq. 5% NaHSO4 (2X) and sat. Once. NaCl (1X). After drying over MgSO4, concentration in vacuo, and purification by medium pressure silica chromatography with EtOAc / hexane as eluents, the title compound was obtained as a white foam (160 mg, 41%) mp 48-61 ° C: 1H NMR (400 MHz, CDCl₃) δ 7.58 (d, J = 7.9 Hz, 1H), 7.44 - 7.29 (m, 3H), 7.14 (dd, J = 7.9, 1.6 Hz, 1H) , 6.86 (d, J = 11.4 Hz, 1H), 6.76 (t, J = 5.9 Hz, 1H), 6.59 (br s, 1H), 6.21 - 6.04 (m, 1H), 4.23 (d, J = 5.5 Hz, 1H), 3.98 (qd, J = 9.0, 6.5 Hz, 2H); 19f NMR (376 MHz, CDCl₃) δ -69.31, -72.3; EIMS m / z 626.9 ([M + 1]). +

Example 109a * not according to the invention: Preparation of (E) -2-Bromo-N- (piperidin-4-yl) -4- (4,4,4trifluoro-3- (3,4,5-trichlorophenyl) but-1 - en-1-yl) benzamide (AC114)

[0293]

<img file="PL2934142T3_D0126.tif" />

Tert-butyl (E) -4- (2-Bromo-4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-enyl) benzamido) piperidine-1-carboxylate (0.75 g, 1.11 mmol) was added to dioxane * HCl (10 mL) at 0 ° C and stirred for 18 h. The reaction mixture was concentrated under reduced pressure and triturated with diethyl ether to give the compound as a light brown solid ( 0.6 g, 88%).

Example 109b * not according to the invention: Preparation of (E) - N- (1-Acetylpiperidin-4-yl) -2-bromo-4 · (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-en-1-yl) benzamide (AC103)

[0295]

<img file="PL2934142T3_D0127.tif" />

[0296] To a stirred solution of (E) -2-bromo-N- (piperidin-4-yl) -4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1- enyl) benzamide (0.1 g, 0.16 mmol) in CH2Cl2 (10.0 mL) was added TEA (0.046 mL, 0.35 mmol) and stirred for 10 min. Then acetyl chloride (0.014, 0.18 mmol) was added and stirred for 16 h at ambient temperature. The reaction mixture was diluted with CH2Cl2 and washed with saturated NaHCO3 and brine solution. The combined CH2Cl2 layer was dried over Na2SO4 and concentrated under reduced pressure

Under reduced pressure to obtain the crude compound. The crude compound was washed with 5% diethyl ether / n pentane to afford the title compound as a white solid (0.054 g, 50%).

Example 110 * not according to the invention: Preparation of (E) -2-Bromo-4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-en-1-yl) -N- ( 1- (3,3,3-trifluoropropanoyl) piperidin-4-yl) benzamide (AC104)

[0297]

<img file="PL2934142T3_D0128.tif" />

[0298] To a stirred solution of 3,3,3-trifluoropropanoic acid (0.02 g, 0.16 mmol) in CH2Cl2 (10.0 mL), (E) -2-bromo-N- (piperidin-4- yl) -4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-enyl) benzamide (0.1 g, 0.16 mmol), PYBOP (0.09 g, 0.17 mmol), and DIPEA (0.06 g, 0.48 mmol) at ambient temperature. The reaction mixture was stirred at ambient temperature for 5 h. The reaction mixture was diluted with CH2Cl2. The combined CH2Cl2 layer was washed with 3N HCl and saturated NaHCO3 solution, the separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain a crude compound. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; eluted with 2% MeOH in CH2Cl2) to afford the title compound as an off-white gummy material (0.035 g, 29.%).

Example 111 * not according to the invention: Preparation of (E) -2-Bromo-4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-en-1-yl) -N - (1- (2,2,2-trifluoroethyl) piperidin-4-yl) benzamide (AC105) [0299]

<img file="PL2934142T3_D0129.tif" />

[0300] To a stirred solution of (E) -2-bromo-N- (piperidin-4-yl) -4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1- enyl) benzamide (0.1 g, 0.16 mmol) in THF (5.0 mL) was added TEA (0.06 mL, 0.64 mmol) and stirred for 10 min. Then 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.03, 0.16 mmol) was added and stirred for 16 h at ambient temperature. The reaction mixture was diluted with ethyl acetate and washed with saturated NaHCO3 solution and brine solution. The combined ethyl acetate layers were dried over Na2SO4 and concentrated under reduced pressure to provide the title compound as a tan solid (0.05 g, 44%).

Example 112 * not according to the invention: Preparation of (E) -2-Bromo-N- (1-methylpiperidin-4-yl) -4 (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but -1-en-1-yl) benzamide (AC106) [0301]

<img file="PL2934142T3_D0130.tif" />

EP-2934142B1PL

Solution of (E) -2-bromo-N- (piperidin-4-yl) -4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-enyl) benzamide (0.1 g, 0.16 mmol), formaldehyde (30% in water) (0.1 ml, 0.16 mmol) and acetic acid (0.01 ml) in MeOH (5.0 ml) were stirred in ambient temperature for 30 min. Then NaBH3CN (0.01 g, 0.16 mmol) was added at 0 ° C and the reaction was stirred for 8 h at ambient temperature. The solvent was removed under reduced pressure to give a residue which was diluted with ethyl acetate and washed with saturated aqueous NaHCO3 and brine solution. The combined ethyl acetate layers were dried over Na₂SO4 and concentrated under reduced pressure to afford a residue which was triturated with diethyl ether / pentane to afford the title compound as a pale yellow gummy material (0.06 g, 59%).

Example 113 * not according to the invention: Preparation of ((E) -2-Bromo-N- (1- (cyanomethyl) piperidin-4-yl) -4- (4,4,4-trifluoro-3- (3,4,5-) trichlorophenyl) but-1-en-1-yl) benzamide (AC107)

[0303]

<img file="PL2934142T3_D0131.tif" />

To a mixed solution of (E) -2-bromo-N- (piperidin-4-yl) -4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-enyl) benzamide (0.25 g, 0.43 mmol) in THF (10.0 mL) was added TEA (0.16 mL, 1.29 mmol) and the reaction was stirred for 10 min. Then 2-bromoacetonitrile (0.07, 0.65 mmol) was added and the reaction was stirred for 8 h at ambient temperature. The reaction mixture was diluted with ethyl acetate and washed with saturated brine. The combined ethyl acetate layers were dried over Na2SO4 and concentrated under reduced pressure to provide the title compound as an off-white solid (0.125 g, 46.8%).

Example 114 * not according to the invention: Preparation of (E) -2-Bromo-N- (1- (oxetan-3-yl) piperidin-4-yl) -4- (4,4,4-trifluoro-3- (3, 4,5-trichlorophenyl) but-1-en-1-yl) benzamide (AC108)

[0305]

<img file="PL2934142T3_D0132.tif" />

[0306] Solution of (E) -2-bromo-N- (piperidin-4-yl) -4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-enyl) benzamide (0.2 g, 0.35 mmol), oxetan-3-one (0.027 g, 0.38 mmol) and acetic acid (0.01 ml) in MeOH (5.0 ml) were stirred at ambient temperature for 30 min. Then NaBH3CN (0.022 g, 0.35 mmol) was added slowly in portions at 0 ° C over a period of 10 min and the reaction was stirred for 8 h at ambient temperature. The solvent was removed under reduced pressure to give a residue which was diluted with ethyl acetate and washed with saturated NaHCO3 and brine solution. The combined ethyl acetate layers were dried over Na2SO4 and concentrated in vacuo to give a residue which was triturated with diethyl ether / pentane to afford the title compound as an off white solid (0.05 g, 23%).

EP-2934142B1PL

Example 115 * not according to the invention: Preparation of (E) -2-Bromo-N- (1- (2-hydroxyethyl) piperidin-4-yl) -4- (4,4,4-trifluoro-3- (3,4,5 -trichlorophenyl) but-1-en-1-yl) benzamide (AC109)

[0307]

<img file="PL2934142T3_D0133.tif" />

To a stirred solution of (E) -2-bromo-N- (piperidin-4-yl) -4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1- enyl) benzamide (0.25 g, 0.43 mmol) in THF (10.0 mL) was added TEA (0.16 mL, 1.29 mmol) and the reaction was stirred for 10 min. Then 2-chloroethanol (0.05, 0.65 mmol) was added and the reaction was stirred for 8 h at ambient temperature. The reaction mixture was diluted with ethyl acetate and washed with saturated brine. The combined ethyl acetate layers were dried over Na2SO4 and concentrated under reduced pressure to provide the title compound as an off-white solid (0.09 g, 34%).

Example 116 * not according to the invention: Preparation of (E) -2- (2-bromo-4- (4,4,4-trifluoro-3 (3,4,5-trichlorophenyl) but-1-en-1-yl) acid ) benzamido) acetic acid (AI78)

[0309]

<img file="PL2934142T3_D0134.tif" />

[0310] To a stirred solution of (E) -2- (2-bromo-4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-enyl) benzamido) acetate, butyl (440 mg, 0.734 mmol) in CH2Cl2 (36.0 mL), TFA (4.0 mL) was added and the reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue that was washed with n- pentane to give the title compound as an off-white solid (310 mg, 78%): ¹H NMR (400 MHz, CDCl3) δ 13.0 (s, 1H), 8.75 (t, J = 5.7 Hz, 1H), 7.93 (m, 2H), 7.62 (d, J = 7.5 Hz, 1H), 7.40 (d, J = 8.1 Hz, 1H), 6.96 (dd, J = 15.3, 9.3 Hz, 1H), 6.78 (d , J = 15.3 Hz, 1H), 4.83 (m, 1H), 3.90 (d, J = 5.7 Hz, 2H); ESIMS m / z 543.61 ([M + H] +); IR (thin layer) 3429, 1635, 1114, 772 cm^-1.

Example 117 * not according to the invention: Preparation of (E) -N - ((6-Chloropyridin-3-yl) methyl) -4- (3- (3,5-dichlorophenyl) -4,4,4-trifluorobut-1-en- 1-yl) -2-methylbenzothioamide (AC115) [0311]

<img file="PL2934142T3_D0135.tif" />

To a mixed solution of (E) -N - ((6-chloropyridin-3-yl) methyl) -4- (3- (3,5-dichlorophenyl) -4,4,4 trifluorobut-1-enyl) -2 -methylbenzamide (0.06 g, 0.117 mmol) in toluene (3 mL) was added Lawesson's reagent (0.14 g, 0.351 mmol) and the reaction was irradiated at 100 ° C for 1 h, then cooled to ambient temperature and concentrated under reduced pressure. pressure to give the crude compound. The crude product was purified by preparative HPLC to give the product as a yellow solid (0.03 g, 49%).

EP-2934142B1PL

Example 118 * not according to the invention: Preparation of (E) -4- (3- (3,5-Dichloro-4-fluorophenyl) -4,4,4 trifluorobut-1-en-1-yl) -N- (2- oxo-2 - ((2,2,2-trifluoroethyl) amino) ethyl) -2 (trifluoromethoxy) benzamide (AC116)

[0313]

<img file="PL2934142T3_D0136.tif" />

Step 1. 2- (trifluoromethoxy) -4-vinylbenzoic acid (Al79): To a stirred solution of 4-bromo-2- (trifluoromethoxy) benzoic acid (1 g, 3.67 mmol) in DMSO (20 mL) was added Potassium vinyl trifluoroborate (1.47 g, 11.02 mmol) and potassium carbonate (1.52 g, 11.02 mmol). The reaction mixture was degassed with argon for 30 min. Palladium bistriphenylphosphine (diphenylphosphinoferrocene) dichloride (0.13 g, 0.18 mmol) was added and the reaction mixture was heated to 80 ° C for 1 h. The reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (2 x 50 mL), washed with brine, and dried over Na2SO4. Concentration under reduced pressure gave the crude compound which was purified by flash column chromatography to give the product as a pale yellow gummy material (0.4 g, 47%): 1H NMR (400MHz, CDCl₃) δ 8.05 (d, J = 8.1 Hz, 1H), 7.44 (d, J = 1.8 Hz, 1H), 7.35 (s, 1H), 6.78 (dd, J = 17.4.1, 11.1 Hz, 1H), 5.92 (d, J = 17.4 Hz, 1H), 5.51 (d, J = 10.8 Hz, 1H); ESIMS m / z 232.97 ([M + H] +).

Step 2. (E) -4- (3- (3,5-Dichloro-4-fluorophenyl) -4,4,4-trifluorobut-1-enyl) -2- (trifluoromethoxy) benzoic acid (Al80) 1- (1-Bromo-2,2,2-trifluoroethyl) -3,5- was added to a stirred solution of 2- (trifluoromethoxy) -4-vinylbenzoic acid (0.356 g, 1.53 mmol) in N-methylpyrrolidine (5.0 ml). dichloro-4-fluorobenzene (1.0 g, 3.07 mmol), copper (I) chloride (CuCl; 0.03 g, 0.307 mmol), and 2,2-bipyridyl (0.095 g, 0.614 mmol). The reaction mixture was stirred at 150 ° C for 1 h. After the reaction was judged complete by TLC, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2X 50 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give a crude compound which was purified by flash column chromatography to give the product as a pale yellow gummy material (0.3 g, 21%): 1H NMR (400MHz, CDCl₃) δ 8.08 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 1.6 Hz, 1H), 7.35 (s, 3H), 6.63 (d, J = 16.0 Hz, 1H), 6.50 (dd, J = 16.0, 8.0 Hz, 1H), 4.15 (m, 1H); ESIMS m / z 474.81 ([MH]^-).

Step 3. (E) -4- (3- (3,5-Dichloro-4-fluorophenyl) -4,4,4-trifluorobut-1-enyl) -N- (2-oxo-2- ( 2,2,2-trifluoroethylamino) ethyl) -2- (trifluoromethoxy) benzamide (AC116): A mixture of (E) -4- (3- (3,5-dichloro-4-fluorophenyl) -4,4,4-trifluorobut-1- enyl) -2- (trifluoromethoxy) benzoic acid (0.25 g, 0.52 mmol), 2-amino-N- (2,2,2-trifluoroethyl) acetamide (0.158 g, 0.62 mmol), PyBOP (0 , 40 g, 0.78 mmol) and DIPEA (0.134 g, 1.04 mmol) in CH2Cl2 (10.0 mL) was stirred at ambient temperature for 16 h. The reaction mixture was diluted with water and extracted with CH2Cl2. The combined CH2Cl2 layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification by flash column chromatography (SiO2, 100-200 mesh; eluted with 20% ethyl acetate / petroleum ether) gave the title compound as a pale yellow gummy material (0.15 g, 47%).

[0317] The following molecules * not according to the invention were made according to the procedures disclosed in Example 118, Step 2

EP-2934142B1PL

(E) -4- (3- (3,5-Dibromophenyl) -4,4,4-trifluorobut-1-en-1-yl) -2-methylbenzoic acid

[0318]

<img file="PL2934142T3_D0137.tif" />

[0319] The title molecule was isolated as a brown solid: ¹H NMR (400 MHz, DMSO-d6) δ 12.90 (bs, 1H), 7.85 (s, 1H), 7.78-7.75 (m, 3H), 7.47-7.41 ( m, 2H), 6.89 (dd, J = 15.6, 9.2 Hz, 1H), 6.72 (d, J = 15.6 Hz, 1H), 4.80-4.75 (m , 1H), 2.33 (s, 3H); ESIMS m / z 474.90 ([MH]^-); IR (thin layer) 3437, 1689, 1165, 579 cm^-1.

(E) -4- (3- (3,5-Dibromophenyl) -4,4,4-trifluorobut-1-en-1-yl) -2- (trifluoromethyl) benzoic acid

[0320]

<img file="PL2934142T3_D0138.tif" />

[0321] The title molecule was isolated as a brown solid: ¹H NMR (300 MHz, DMSO-d6) δ 13.5 (bs, 1H), 8.03 (s, 1H), 7.95-7.85 (m, 4H), 7.81 (d, J = 7.8 Hz, 1H), 7.14 (dd, J = 15.6, 9.6 Hz, 1H), 6.90 (d, J = 15.9 Hz, 1H), 4.86-4, 79 (m, 1H); ESIMS m / z 528.82 ([MH] +); IR (thin layer) 3437, 1707, 1153, 555 cm^-1.

(E) -4- (3- (4-bromo-3,5-dichlorophenyl) -4,4,4-trinuorobut-1-en-1-yl) -2- (trifluoromethyl) benzoic acid

[0322]

<img file="PL2934142T3_D0139.tif" />

The title molecule was isolated as a brown gum: 1H NMR (300MHz, DMSO-d6) δ 13.6 (bs, 1H) 8.03 (s, 1H), 7.95 (d, J = 8.4Hz , 1H), 7.88 (s, 2H), 7.81 (d, J = 8.1 Hz, 1H), 7.13 (dd, J = 16.2, 7.5 Hz, 1H), 6 , 91 (d, J = 15.9 Hz, 1H), 4.89 - 4.83 (m, 1H); ESIMS m / z 532.0 ([M + H] +).

(E) -4- (3- (3,5-dichloro-4-fluorophenyl) -4,4,4-trifluorobut-1-en-1-yl) -2- (trifluoromethyl) benzoic acid

[0324]

<img file="PL2934142T3_D0140.tif" />

EP-2934142B1PL

[0325] The title molecule isolated as an off-white solid: mp 140-143 ° C; ¹H NMR (400

MHz, DMSO) δ13.60 (bs, 1H), 8.02 (s, 1H), 7.94 - 7.90 (m, 1H), 7.88 -7.86 (m, 2H), 7, 81 - 7.79 (m, 1H),

7.12 (dd, J = 15.6, 8.8 Hz, 1H), 6.89 (d, J = 15.6 Hz, 1H), 4.86 - 4.81 (m, 2H); ESIMS m / z 458.88 ([MH]^-).

Example 20: * not according to the invention Preparation of 5-Vinyl-2,3-dihydro-1H-inden-1-one (BI1) [0326]

<img file="PL2934142T3_D0141.tif" />

To a stirred solution of 5-bromo-2,3-dihydro-1H-inden-1-one (5 g, 23.7 mmol) in toluene was added vinylboronic acid anhydride-pyridine complex (8.55 g, 35.54 mmol), Pd (PPh3) 4 (0.1 g, 0.094 mmol), K2CO3 (22.88 g, 165.83 mmol). The resulting reaction mixture was refluxed for 16 h. The reaction mixture was cooled to 25 ° C and filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with EtOAc and washed with H 2 O and brine. The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by flash column chromatography (SiO2, 5% EtOAc in petroleum ether) gave the title compound as a solid (1.8 g, 48%):¹H NMR (400 MHz, CDCl₃) δ 7.74 (d, J = 7.2 Hz, 1H), 7.49 (br s, 1H), 7.44 (d, J = 7.2 Hz, 1H), 6.82 (m, 1H), 5.90 (d, J = 7.4Hz, 1H), 5.42 (d, J = 6.4Hz, 1H), 3.20 (m, 2H), 2.70 (m, 2H); ESIMS m / z 159.06 ([M + H] -).

[0328] The following compound * not according to the invention was prepared according to the procedures disclosed in Example 20.

6-Vinyl-3,4-dihydronaphthalen-1 (2H) -one (BI2)

[0329]

<img file="PL2934142T3_D0142.tif" />

[0330] The product was isolated as an off-white solid (5 g, 48%): 1H NMR (400 MHz, DMSO) δ 7.85 (d, J = 8.4 Hz, 1H), 7.48 (m, 2H), 6.82 (m, 1H), 6.02 (d, J = 7.4 Hz, 1H), 5.44 (d, J = 6.4 Hz, 1H), 2.95 (m, 2H), 2.60 (m, 2H), 2.00 (m, 2H); ESIMS m / z 173.14 ([MH] -); IR (thin layer) 1681 cm-1.

Example 21 * not according to the invention: Preparation of (E) -5- (4,4,4-Trifluoro-3- (3,4,5-trichlorophenyl) but1-enyl) -2,3-dihydro-1H-inden- 1-one (BI3)

[0331]

<img file="PL2934142T3_D0143.tif" />

5- (1-Bromo-2,2,2-trifluoroethyl) -1,2,3-trichlorobenzene (4 g, 11.7 mmol), 5-vinyl-2,3-dihydro-1 Hinden-1 -one (0.92 g, 5.8 mmol), CuCl (0.115 g, 1.171 mmol) and 2,2-bipyridyl (0.053 g, 0.34 mmol) in 1,2-dichlorobenzene (25 mL) was heated at 180 ° C C for 16 h. The reaction mixture was cooled to 25 ° C and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 5% EtOAc in petroleum ether) to provide the title compound as a liquid (1.28 g, 25%): 1 H NMR (400 MHz, CDCl₃) δ 7.76 (d, J = 7.4 Hz, 1H), 7.52 (m, 3H), 6.68 (d, J = 7.4 Hz, 1H), 6.52 (m, 1H ), 4.18 (m, 1H), 3.18 (m, 2H), 2.75 (m, 2H); ESIMS m / z 419.14 ([M + H]^-); IR (thin layer) 1708.94, 1113.60, 807.77 cm^-1.

EP-2934142B1PL

The following compound * not according to the invention was prepared according to the procedures disclosed in

Example 21.

(E) -5- (3- (3,5-Dichloro-4-fluorophenyl) -4,4,4-trifluorobut-1-en-1-yl) -2,3-dihydro-1H- inden-1 -on (BI4)

[0334]

<img file="PL2934142T3_D0144.tif" />

[0335] The product was isolated as a brown semi-solid (1.2 g, 16%): ¹H NMR (400 MHz, CDCl 3) δ 7.76 (d, J = 7.4 Hz, 1H), 7.54 (m, 3H), 7.30 (s, 1H), 6.68 (d, J = 7.4 Hz, 1H), 6.52 (m, 1H), 4.18 (m, 1H), 3.18 (m, 2H), 2.75 (m, 2H); ESIMS m / z 400.84 ([MH]^-); IR (thin layer) 815, 1113, 1709 cm^-1.

(E) -6- (4,4,4-Trifluoro-3- (3,4,5-trichlorophenyl) but-1-enyl) -3,4-dihydronaphthalen-1 (2H) -one (BI5)

[0336]

<img file="PL2934142T3_D0145.tif" />

[0337] The product was isolated as a pale yellow semi-solid (1.2 g, 30%): ¹H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 8.0 Hz, 1H), 7.42 (s, 2H), 7.35 (m, 1H), 7.24 (m, 2H ), 6.62 (d, J = 16Hz, 1H), 6.46 (m, 1H), 4.18 (m, 1H), 2.95 (m, 2H), 2.65 (m, 2H ). 2.19 (m, 2H); ESIMS m / z 432.94 ([MH] -); IR (thin layer) 1680, 1113, 808 cm^-1.

Example 22 * ​​not according to the invention: Preparation of (E) -5- (3- (3,5-Dichloro-4-fluorophenyl) -4,4,4 trifluorobut-1-en-1-yl) -2-fluoro-2, 3-dihydro-1H-inden-1-one (BI6) [0338]

<img file="PL2934142T3_D0146.tif" />

To a mixed solution of (E) -5- (3- (3,5-dichloro-4-fluorophenyl) -4,4,4-trifluorobut-1-enyl) -2,3-dihydro-1H-inden-1 -one (0.5 g, 1.24 mmol) in acetonitrile (20 mL), Selectfluor® (0.52 g, 1.48 mmol) was added and the reaction was heated at reflux for 16 h. The reaction mixture was cooled to ambient temperature. , concentrated under reduced pressure and diluted with CH2Cl2. The solution was washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give a crude product which was purified by flash column chromatography (SiO2, 100-200 mesh; 15% EtOAc in petroleum ether) to afford the title compound as a pale yellow semisolid. (0.1 g, 24%): 1 H NMR (400 MHz, CDCl₃) δ 7.80 (m, 1H), 7.48 (m, 2H), 7.32 (m, 2H), 6.65 (d, J = 16.0 Hz, 1H), 6.54 (dd , J = 16.0, 8.0 Hz, 1H), 5.38 (m, 1H), 4.18 (m, 1H), 3.62 (m, 1H), 3.32 (m, 1H) ; ESIMS m / z 419.06 ([MH]^-); IR (thin layer) 1728, 1114, 817 cm^-1.

Example 23 * not according to the invention: Preparation of (E) -5- (3- (3,5-Dichloro-4-fluorophenyl) -4,4,4 trifluorobut-1-en-1-yl) -N- (3.3 , 3-trifluoropropyl) -2,3-dihydro-1H-inden-1-amine (BC10) [0340]

EP-2934142B1PL

<img file="PL2934142T3_D0147.tif" />

To a mixed solution of (E) -5- (3- (3,5-dichloro-4-fluorophenyl) -4,4,4-trifluorobut-1-enyl) -2,3-dihydro-1H-inden-1 -one (0.15 g, 0.35 mmol) in DCE (10 ml), trifluoropropylamine (0.048 g, 0.42 mmol) and sodium cyanoborohydride (0.055 g, 0.875 mmol) were added with cooling and the reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was diluted with DCE, washed with water and brine, and dried over anhydrous sodium sulfate. Concentration in vacuo gave the crude compound which was purified by flash column chromatography (SiO2, 100-200 mesh; 10-15% EtOAc in petroleum ether) to afford the title compound as a colorless gummy material (0.042 g, 24%): 1H NMR (400 MHz , CDCl₃) δ 7.38-7.20 (m, 5H), 6.62 (d, J = 16.0 Hz, 1H), 6.34 (dd, J = 16.0, 8.0 Hz, 1H) , 5.83 (br, 1H), 5.52 (m, 1H), 4.12 (m, 1H), 3.02 (m, 3H), 2.82 (m, 1H), 2.50 ( m, 2H), 1.82 (m, 1H), 1.42 (m, 1H); ESIMS m / z 497.98 ([MH]^-); IR (thin layer) 3027, 1654, 815 cm^-1.

Example 24 * not according to the invention: Preparation of Oxime 6 - ((E) -4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-enyl) -3,4-dihydronaphthalene-1 ( 2H) -one (BI5a)

[0342]

<img file="PL2934142T3_D0148.tif" />

[0343] To a stirred solution of ((E) -6- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-enyl) -3,4-dihydronaphthalene-1 (2H ) -one (0.4 g, 0.92 mmol) in EtOH (50 mL) were added hydroxylamine hydrochloride (0.128 g, 1.85 mmol) and sodium acetate (0.23 g, 2.77 mmol), and the reaction mixture was heated at reflux for 3 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with H 2 O and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude compound which was purified by flash column chromatography (SiO2, 100-200 mesh; 10-15% EtOAc in petroleum ether). The title compound was isolated as a solid (0.3 g, 73%): mp 155-158 ° C;¹H NMR (400 MHz, CDCl₃) δ 7.89 (d, J = 8.4 Hz, 1H), 7.41 (s, 2H), 7.24 (m, 1H), 7.17 (m, 1H), 6.57 (d , J = 16Hz, 1H), 6.46 (dd, J = 16.0, 8.0Hz, 1H), 4.13 (m, 1H), 2.82 (m, 4H), 2.04 (m, 2H); ESIMS m / z 445.95 ([MH] -).

Example 25 * not according to the invention: Preparation of (E) -5- (4,4,4-Trifluoro-3- (3,4,5-trichlorophenyl) but1-enyl) -2,3-dihydro-1H-indene 1-amines (BI5b)

[0344]

<img file="PL2934142T3_D0149.tif" />

To a stirred solution of (E) -5- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-enyl) -2,3-dihydro-1H-inden-1-one (1 g, 2.39 mmol) in MEOH (10 mL) were added ammonium acetate (1.84 g, 23.9 mmol) and sodium cyanoborohydride (NaCNBH3; 0.44 g, 7.17 mmol,) and the reaction mixture was heated. in temperature

Reflux for 16 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with H 2 O and extracted with EtOAc. The combined organic extracts were washed with H.₂O and saturated aqueous sodium bicarbonate (sat. Aq. NaHCO3), dried over anhydrous Na2SO4, and concentrated under reduced pressure to provide the title compound as a liquid (500 mg, crude): 1H NMR (400 MHz, DMSO-d₆) δ 7.85 (s, 2H), 7.40 (s, 1H), 7.30 (s, 2H), 6.71 (s, 2H), 4.78 (m, 1H), 4.2 (m, 1H), 2.80 (m, 1H), 2.73 (m, 1H), 1.60 (m, 2H); ESIMS m / z 419.02 ([M + H] +); IR (thin layer) 2924, 1552, 1112, 807 cm^-1.

The following compound * not according to the invention was prepared according to the procedures disclosed in Example 25.

(E) -5- (3- (3,5-Dichloro-4-fluorophenyl) -4,4,4-trifluorobut-1-en-1-yl) -2,3-dihydro-1H-indene-1 -amine (BI7)

[0347]

<img file="PL2934142T3_D0150.tif" />

[0348] The product was isolated as a light brown gummy material taken as is for the next step (0.15 g, crude compound): ESIMS m / z 401.97 ([MH]^-).

(E) -5- (3- (3,5-Dichloro-4-fluorophenyl) -4,4,4-trifluorobut-1-en-1-yl) -2-fluoro-2,3-dihydro-1H -indeno1-amine (BI8)

[0349]

<img file="PL2934142T3_D0151.tif" />

[0350] The product was isolated as a light brown gummy material taken as is for the next step (0.15 g, crude compound): ESIMS m / z 420.15 ([MH]^-).

(E) -6- (4,4,4-Trilluoro-3- (3,4,5-trichlorophenyl) but-1-enyl) -1,2,3,4-tetrahydronaphthalen-1-amine (BI9) [ 0351]

<img file="PL2934142T3_D0152.tif" />

[0352] The product was isolated as a pale yellow liquid (500 mg of crude product).

Example 26 * not according to the invention: Preparation of (E) -1-Methyl-3- (5- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) -but-1-enyl) -2,3 -dihydro-1H-inden-1-yl) thiourea (BC1) [0353]

<img file="PL2934142T3_D0153.tif" />

EP-2934142B1PL

To a stirred solution of (E) -5- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-enyl) -2,3-dihydro-1H-inden-1-amine (0.1 g, 0.23 mmol) in Et₂O (5 mL) was added methyl isothiocyanate (0.026 g, 0.35 mmol), and the mixture was stirred for 2 h at 25 ° C. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography (SiO2, 20% EtOAc in petroleum ether). The title compound was isolated as a liquid (65 mg, 50%):¹H NMR (400 MHz, CDCl₃) δ 7.39 (s, 2H), 7.25-7.18 (m, 3H), 6.58 (d, J = 16.0 Hz, 1H), 6.30 (dd, J = 16, 0.4Hz, 1H), 5.91 5.70 (br, 2H), 4.05 (m, 1H), 3.05 - 2.80 (m, 6H), 2.70 (m, 1H), 1.81 (m, 1H); ESIMS m / z 492.17 ([M + H] +); IR (thin layer) 3211, 1569, 1113, 806 cm^-1.

Compounds BC2 - BC3 * not according to the invention in Table 1 were prepared according to the procedures disclosed in Example 26.

Example 27 * not according to the invention: Preparation of (E) -3,3,3-Trifluoro-N- (5- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-enyl) - 2,3-dihydro-1H-inden-1-yl) propanamide (BC4)

[0356]

<img file="PL2934142T3_D0154.tif" />

To a stirred solution of (E) -5- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-enyl) -2,3-dihydro-1H-inden-1-amine (0.1 g, 0.23 mmol) in CH2Cl2 (10 mL) added trifluoropropionic acid (0.044 g, 0.34 mmol), EDC^.HCl (0.038 g, 0.35 mmol), HOBt^.H 2 O (0.07 g, 0.46 mmol) and DIPEA (0.074 g, 0.57 mmol), and the reaction mixture was stirred for 16 h at 25 ° C. The reaction mixture was diluted with CH2Cl2 and washed with H2O. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude material was purified by flash column chromatography (SiO2, 15% EtOAc in petroleum ether) to afford the title compound as a liquid (65 mg, 65%): 1 H NMR (400 MHz, CDCl₃) δ 7.39 (s, 2H), 7.25-7.20 (m, 3H), 6.34 (d, J = 16.0 Hz, 1H), 6.30 (dd, J = 16, 0.81 (br, 1H), 5.48 (m, 1H), 4.10 (m, 1H), 3.10 (m, 2H), 2.86- 3.07 (m, 2H), 2.86 (m, 1H), 1.81 (m, 1H); ESIMS m / z 529.02 ([M + H]⁺); IR (thin layer) 3283, 1652, 1241.811 cm^-1.

[0358] Compounds BC5 - BC9, BC11 * not according to the invention in Table 1 were prepared according to the procedures disclosed in Example 27.

Example 28 * not according to the invention: Preparation of tert-butyl 5-vinylindoline-1-carboxylate (BI10)

[0359]

<img file="PL2934142T3_D0155.tif" />

Step 1. 5-Bromo-indoline (BI11): To 5-bromo-1H-indole (2.5g, 12.82mmol) in acetic acid (10.0ml), NaCNBH3 (2 , 38 g, 38.46 mmol) at 10 ° C for a period of 20 min. The reaction mixture was then stirred at ambient temperature for 3 h. The reaction mixture was diluted with water and extracted with diethyl ether. The organic layer was washed with saturated

EP-2934142B1PL with NaHCO3 solution, water and brine solution. The combined ether layer was dried over anhydrous

NapSO4 and concentrated under reduced pressure to provide the title compound as a pale yellow semi-solid (1.8 g, 71%).

Step 2. tert-Butyl 5-Bromoindoline-1-carboxylate (BI12): To a stirred solution of 5-bromoindoline (3.0 g, 15 mmol) in acetonitrile (100 mL), DMAP (0.185 g, 1.522 mmol) was added ) and di-tert-butyl dicarbonate (3.98 g, 18.3 mmol) and the reaction was stirred at ambient temperature for 16 h. The reaction mixture was concentrated in vacuo to give a residue which was diluted with diethyl ether and washed with water and brine solution (2X ). The combined ether layer was dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude product as an off-white solid that was used in the next step without further purification (3.0 g).

Step 3. tert-Butyl 5-vinylindoline-1-carboxylate (BI10): Mixed solution of tert-butyl 5-bromoindoline-1-carboxylate (2.0 g, 6.73 mmol), potassium vinyl trifluoroborate (2.6 g, 20.20 mmol) and K2CO3, (2.78 g, 20.2 mmol) in DMSO (50.0 ml), degassed with argon for 20 min at ambient temperature. PdCl2 (dppf) (0.49 g, 0.67 mmol) was added at ambient temperature then the reaction mixture was heated to 100 ° C for 3 h. The reaction mixture was cooled to ambient temperature and filtered through a celite pad under reduced pressure and washed with diethyl ether. The reaction mixture was extracted with diethyl ether. The combined diethyl ether layer was dried over Na2SO4 and concentrated under reduced pressure to give the crude product. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; eluted with 2% ethyl acetate / petroleum ether) to afford the title compound as an off-white solid (1.2 g, 73%): Mp 85.5 88.6 ° C; 1 H NMR (400 MHz, CDCl₃) δ 7.23 (m, 3H), 6.69 (dd, J = 17.4, 10.8 Hz, 1H), 5.64 (d, J = 10.5 Hz, 1H), 5.13 (d, J = 10.5 Hz, 1H), 4.00 (t, J = 9.0 Hz, 2H), 3.10 (t, J = 9.0 Hz, 2H), 1.55 (bs , 9H).

Example 29 * not according to the invention: Preparation of tert- (E) -5- (3- (3,5-Dichloro-4-fluorophenyl) -4,4,4 trifluorobut-1-en-1-yl) indoline-1-carboxylate butyl (BI13)

[0363]

<img file="PL2934142T3_D0156.tif" />

To a stirred solution of tert-butyl 5-vinylindoline-1-carboxylate (1.28 g, 5.23 mmol) in 1,2-dichlorobenzene (10.0 mL), 5- (1-bromo-2,2, 2-trifluoroethyl) -1,3-dichloro-2-fluorobenzene (3.4 g, 10 mmol), CuCl (103 mg, 1.05 mmol) and 2,2-bipyridyl (0.326 g, 2.092 mmol) and the resulting mixture the reaction was degassed with argon for 30 min and heated to 150 ° C for 1 h. The reaction mixture was cooled to ambient temperature and filtered and the filtrate was concentrated under reduced pressure. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 2% ethyl acetate / petroleum ether) to afford the title compound as a pale yellow gummy solid (0.3 g, 61%): 1 H NMR (400 MHz, CDCl₃) δ 7.34 (d, J = 6.0 Hz, 2H), 7.22 (s, 2H), 7.16 (d, J = 8.4 Hz, 1H), 6.52 (d, J = 16.0 Hz, 1H), 6.21 (dd, J = 16.0, 7.6 Hz, 1H), 4.07 (m, 3H), 3.10 (t, J = 8.4 Hz , 2H). 1.55 (s, 9H); ESIMS m / z 433.79 ([MH] -); IR (thin layer) 1168,858 cm-1.

Example 30 * not according to the invention: Preparation of (E) -5- (3- (3,5-Dichloro-4-fluorophenyl) -4,4,4-trifluorobut-1-en-1-yl) indoline-1-amine (BI14 )

[0365]

EP-2934142B1PL

<img file="PL2934142T3_D0157.tif" />

Step 1. (E) -5- (3- (3,5-Dichloro-4-fluorophenyl) -4,4,4-trifluorobut-1-enyl) indoline (BI15) To the stirred solution of (E) - Tert-butyl 5- (3- (3,5-dichloro-4-fluorophenyl) -4,4,4-trifluorobut-1-enyl) indoline-1 carboxylate (0.2 g, 0.4 mmol) in CH2Cl2 ( 10.0 mL) TFA (0.6 mL) was added and the reaction was stirred at ambient temperature for 2 h. The reaction mixture was diluted with CH2Cl2, washed with saturated aqueous NaHCO3 solution, water, and brine solution. The separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude product as a light brown gummy material which was used in the next step without further purification (0.12 g): 1H NMR (400 MHz, CDCl₃) δ 7.33 (d, J = 6.4 Hz, 2H), 7.21 (s, 1H), 7.02 (d, J = 8.0 Hz, 1H), 6.57 (d, J = 8.4 Hz, 1H), 6.49 (d, J = 15.6 Hz, 1H), 6.21 (dd, J = 15.6, 8.4 Hz, 1H), 4.07 (m , 1H), 3.61 (t, J = 8.4 Hz, 2H), 3.05 (t, J = 8.4 Hz, 2H); ESIMS m / z 389.89 ([M + H] +); IR (thin layer) 3385, 1112, 816 cm-1.

Step 2. 5- (3- (3,5-Dichloro-4-fluorophenyl) -4,4,4-trifluorobut-1-enyl) -1-nitrosoindoline (BI16): To (E) -5- (3- (3,5-dichloro-4-fluorophenyl) -4,4,4-trifluorobut-1-enyl) indolines (0.2 g, 0.5 mmol) in concentrated HCl (5.0 mL) at a temperature of 5 ° C, NaNO2 in water was added slowly and allowed to stir the reaction at ambient temperature for 2 h. The reaction mixture was diluted with CH2Cl2, and the CH2Cl2 layer was washed with water and brine solution. The separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product as a pale yellow solid which was used in the next step without further purification (0.2 g): 1H NMR (400 MHz, CDCl3) δ 7.33 (d , J = 8.4 Hz, 1H), 7.39 (m, 4H), 6.61 (d, J = 16.0 Hz, 1H), 6.35 (dd, J = 16.0, 8, 4 Hz, 1H), 4.07 (m, 3H), 3.23 (t, J = 8.4 Hz, 2H); ESIMS m / z 418.82 ([M + H]⁺); IR (thin layer) 1488, 1112, 860 cm^-1.

Step 3. (E) -5- (3- (3,5-Dichloro-4-fluorophenyl) -4,4,4-trifluorobut-1-en-1-yl) indoline-1-amine (BI14 ): Do (E) -5- (3- (3,5-dichloro-4-fluorophenyl) -4,4,4-trifluorobut-1-enyl) -1-nitrosoindoline (0.1 g, 0.2 mmol ) in MeOH (10.0 ml) zinc dust (77.5 mg) and NH4Cl (36.9 mg, 0.69 mmol) in water (2.0 ml) were added. The reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was diluted with CH2Cl2 and the CH2Cl2 layer was washed with water and brine solution. The separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated in vacuo to give a crude compound which was purified by column chromatography (SiO2, 100-200 mesh; eluted with 2% ethyl acetate / petroleum ether) to afford the title compound as a light brown gummy material ( 0.08 g): ESIMS m / z 404.86 ([M + H] +).

Example 31 * not according to the invention: Preparation of (E) -N- (5- (3- (3,5-Dichloro-4-fluorophenyl) -4,4,4 trifluorobut-1-en-1-yl) indolin-1- yl) -3,3,3-trifluoropropanamide (BC12) [0369]

<img file="PL2934142T3_D0158.tif" />

To a stirred solution of (E) -5- (3- (3,5-dichloro-4-fluorophenyl) -4,4,4-trifluorobut-1-enyl) indolin-1-amine (0.1 g, 0.247 mmol ) in CH2Cl2 (10.0 mL), 3,3,3-trifluoropropanoic acid (0.038 g, 0.297 mmol), PyBOP (0.192 g, 0.370 mmol) and DIPEA (0.047 g, 0.370 mmol) were added and the reaction was stirred at temperature

For 18 h. The reaction mixture was diluted with CH2Cl2, and the separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 2025% ethyl acetate / petroleum ether) to afford the title compound as a light brown gummy material (0.12 g, 33%): 1H NMR (400MHz, CDCl₃) δ 7.32, (d, J = 6.0 Hz, 2H) 7.28 (m, 1H), 7.20 (d, J = 8.0, 1H), 7.14 (d, J = 8.8, 1H), 6.70 (d, J = 8.0 Hz, 1H), 6.60 (m, 2H), 4.15 (m, 1H), 3.85 (m, 1H), 3.65 (m, 1H), 3.46 (m, 2H), 3.19 (m, 2H); ESIMS m / z 514.86 ([M + H] +); IR (thin layer) 3428, 1112, 857 cm^-1.

Example 32 * not according to the invention: Preparation of tert-butyl 5-vinyl-1H-indole-1-carboxylate (BI17)

[0371]

<img file="PL2934142T3_D0159.tif" />

Step 1. 5-Vinyl-1H-indole (BI18): A mixture of 5-bromo-1H-indole (2.5 g, 12.82 mmol), potassium vinyl trifluoroborate (2.57 g, 19.2 mmol), Cs2CO3 (12.53 g, 38.46 mmol) and triphenylphosphine (201 mg, 0.769 mmol) in THF / water (9: 1, 75 mL) degassed with argon for 20 min, then PdCl2 (45.3 mg, 0.256 mmol). The reaction mixture was refluxed for 16 h, then cooled to ambient temperature, filtered through a celite pad and washed with ethyl acetate. The filtrate was back extracted with ethyl acetate, and the combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure to provide the crude compound. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 2% ethyl acetate / petroleum ether) to afford the title compound as a light brown gummy material (1.5 g, 83%): 1 H NMR (400 MHz, CDCl₃) δ 8.20 (br, 1H), 7.68 (s, 1H), 7.45 (s, 2H), 7.21 (m, 1H), 6.90 (dd, J = 16.0, 10.8 Hz, 1H), 6.55 (m, 1H), 5.75 (d, J = 10.5 Hz, 1H), 5.21 (d, J = 10.5 Hz, 1H); ESIMS m / z 142.05 ([MH] -).

Step 2. tert-Butyl 5-vinyl-1H-indole-1-carboxylate (BI17): To a stirred solution of 5-vinyl-1H-indole (0.7g, 4.89mmol) in acetonitrile (20ml) DMAP (59.65 mg, 0.489 mmol) and di-tert-butyl dicarbonate (1.38 g, 6.36 mmol) were added, and the reaction was stirred at ambient temperature for 3 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was diluted with CH2Cl2 and washed with water and brine solution. The combined CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude compound. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 2% ethyl acetate / petroleum ether) to provide the title compound as an off-white semi-solid (0.7 g, 59%):¹H NMR (400 MHz, CDCl₃) δ 8.15 (d, J = 8.0 Hz, 1H), 7.60 (s, 2H), 7.30 (d, J = 8.4 Hz, 1H), 7.21 (m, 1H ), 6.90 (dd, J = 16.0, 10.8 Hz, 1H), 6.59 (s, 1H), 5.75 (d, J = 10.5 Hz, 1H), 5.21 (d, J = 10.5 Hz, 1H), 1.65 (s, 9H); ESIMS m / z 242.10 ([MH]^-); IR (thin layer) 1630 cm^-1.

Example 33 * not according to the invention: Preparation of (E) -5- (3- (3,5-Dichloro-4-fluorophenyl) -4,4,4 trifluorobut-1-en-1-yl) -1H-indole-1- tert-butyl carboxylate (BI19)

[0374]

EP-2934142B1PL

<img file="PL2934142T3_D0160.tif" />

[0375] To a stirred solution of tert-butyl 5-vinyl-1H-indole-1-carboxylate (0.65 g, 2.67 mmol) in 1,2-dichlorobenzene (10.0 mL) was added 5- (1 -bromo-2,2,2-trifluoroethyl) -1,3-dichloro-2-fluorobenzene (1.74 g, 5.37 mmol), CuCl (53 mg, 0.537 mmol) and 2,2-bipyridyl (167 mg , 1.07 mmol). The resulting reaction mixture was degassed with argon for 30 min and heated to 150 ° C for 2 h. The reaction mixture was cooled to ambient temperature and filtered, and the filtrate was concentrated under reduced pressure. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 2% ethyl acetate / petroleum ether) to afford the title compound as a light brown gummy material (0.25 g, 10%): 1 H NMR (400 MHz, CDCl₃) δ 8.20 (d, J = 8.0 Hz, 1H), 7.60 (m, 2H), 7.39 (m, 3H), 6.69 (d, J = 16.0 Hz, 1H ), 6.55 (d, J = 10.5 Hz, 1H), 6.36 (dd, J = 16.0, 8.0 Hz, 1H), 4.10 (m, 1H), 1.65 (s, 9H); ESIMS m / z 485.91 ([MH]^-); IR (thin layer) 1165,854 cm^-1.

Example 34 * not according to the invention: Preparation of (E-5- (3- (3,5-Dichloro-4-fluorophenyl) -4,4,4 trifluorobut-1-en-1-yl) -1H-indole (BI20)

[0376]

<img file="PL2934142T3_D0161.tif" />

To a mixed solution of tert-butyl (E) - 5- (3- (3,5-dichloro-4-fluorophenyl) -4,4,4-trifluorobut-1-enyl) -1H-indole-1-carboxylate (0 , 2 g, 0.40 mmol) in CH2Cl2 (10.0 mL) was added TFA (70 mg, 0.61 mmol) and the reaction was stirred at ambient temperature for 2 h. The reaction mixture was diluted with CH2Cl2 and washed with saturated NaHCO3 solution, water and brine solution. The CH2Cl2 was separated, the layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to provide the title compound as a light brown solid (0.2 g, 97%): mp 132.9-138.8 ° C; 1 H NMR (400 MHz, CDCl 3) δ 11.19 (br, 1H), 8.20 (d, J = 8.0 Hz, 1H), 7.60 (m, 2H), 7.39 (m, 3H ), 6.69 (d, J = 16.0 Hz, 1H), 6.55 (d, J = 10.5 Hz, 1H), 6.36 (dd, J = 16.0, 8.0 Hz , 1H); 4.82 (m, 1H); ESIMS m / z 387.98 ([M + H] +).

Example 35 * not according to the invention: Preparation of 4-nitrophenyl 2 - ((tert-Butoxycarbonyl) amino) acetate (BI21)

[0378]

<img file="PL2934142T3_D0162.tif" />

[0379] To a stirred solution of 4-nitrophenol (1.0 g, 7.19 mmol) in CH2Cl2 (20.0 mL) was added N-Bocglycine (1.38 g, 7.91 mmol) and EDC.HCl (2, 05 g, 10.785 mmol) and the reaction was stirred at ambient temperature for 24 h. The reaction mixture was diluted with CH2Cl2 and washed with water and saturated brine. The separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the title compound as a light brown gummy material which was used in the next step without further purification (1.1 g): ¹H NMR (400 MHz, CDCl 3) δ 8.29 (d, J = 9.2 Hz, 2H), 7.33 (d, J = 8.8 Hz, 2H), 5.07 (br, 1H), 4.20 (s, 2H), 1.47 (s, 9H); ESIMS m / z 296.27 ([M + H] +).

EP-2934142B1PL

Example 36 * not according to the invention: Preparation of (E) - (2- (5- (3- (3,5-Dichloro-4-fluorophenyl) -4,4,4trifluorobut-1-en-1-yl) -1H tert-butyl-indol-1-yl) -2-oxoethyl) carbamate (BI22)

[0380]

CF

<img file="PL2934142T3_D0163.tif" />

To a stirred solution of (E) -5- (3- (3,5-dichloro-4-fluorophenyl) -4,4,4-trifluorobut-1-enyl) -1 Hindol (0.1 g, 0.258 mmol ) in acetonitrile (5.0 ml), 4-nitrophenyl acetate (0.114 g, 0.387 mmol), potassium fluoride (0.03 g, 0.516 mmol), 18-crown-6 ether (0.075 g, 0.283 mmol) and DIPEA (0.0332 g, 0.258 mmol) and the reaction was stirred at ambient temperature for 16 h. The reaction mixture was concentrated to a residue which was diluted with CH2Cl2 and washed with water and brine solution. The separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude title compound as a light brown gummy material which was used in the next step without further purification (0.1 g): ESIMS m / z 545.23 ([M + H] +).

Example 37 * not according to the invention: Preparation of (E) - N- (2- (5- (3- (3,5-Dichloro-4-fluorophenyl) -4,4,4trifluorobut-1-en-1-yl) - 1H- indol-1-yl) -2-oxoethyl) -3,3,3-trifluoropropanamide (BC13)

[0382]

<img file="PL2934142T3_D0164.tif" />

Step 1. (E) -2-Amino-1- (5- (3- (3,5-dichloro-4-fluorophenyl) -4,4,4-trifluorobut-1-enyl) -1Hindol-1 -yl) ethanone (BI23): For a mixed solution of (E) -2- (5- (3- (3,5-dichloro-4-fluorophenyl) -4,4,4trifluorobut-1-enyl) -1H-indole Tert-butyl -1-yl) -2-oxoethylcarbamate (0.05 g, 0.09 mmol) in CH2Cl2 (5.0 mL) was added TFA (0.01 mL) and the reaction was stirred at ambient temperature for 16 h. the reaction was diluted with CH2Cl2 and washed with saturated NaHCO3 solution, water and brine solution. The separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude title compound which was used in the next step without further purification (50 mg).

Step 2. (E) -N- (2- (5- (3- (3,5-Dichloro-4-fluorophenyl) -4,4,4-trifluorobut-1-en-1-yl) - 1H-indol-1-yl) -2-oxoethyl) -3,3,3-trifluoropropanamide (BC13): For a mixed solution of (E) -2-amino-1- (5- (3 (3,5-dichloro-4) -fluorophenyl) -4,4,4-trifluorobut-1-enyl) -1H-indol-1-yl) ethanone (0.04 g, 0.09 mmol) in CH2Cl2 (5.0 ml) added acid 3.3 , 3-trifluoropropane (17.5 mg, 0.136 mmol), PyBOP (70 mg, 0.135 mmol) and DIPEA (29 mg, 0.225 mmol) and the reaction was stirred at ambient temperature for 16 h. The reaction mixture was diluted with CH2Cl2, and the CH2Cl2 layer was washed with water and saturated brine. The separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude compound which was purified by column chromatography (SiO2, 100-200 mesh; 10% ethyl acetate / petroleum ether) to afford the title compound as an off-white solid (30mg, 60%): mp 121-126 ° C; 1 H NMR (400 MHz, CDCl₃) δ 8.33 (br, 1H), 7.59 (s, 1H), 7.45 (m, 4H), 6.72 (d, J = 3.6 Hz, 3H), 6.39 (m , 1H), 4.71 (t, J = 7.2 Hz, 2H), 4.15 (m, 1H), 3.51 (m, 1H), 3.28 (m, 1H); ESIMS m / z 553.06 ([MH] -).

EP-2934142B1PL

Example 38 * not according to the invention: Preparation of ethyl 2- (1-Oxo-6-vinylphthalazin-2 (1H) -yl) acetate (BI24)

[0385]

<img file="PL2934142T3_D0165.tif" />

Step 1. 5-Bromo-3-hydroxyisoindolin-1-one (BI25): A mixture of Zn dust (1.73 g, 26.154 mmol), copper (II) sulfate pentahydrate (0.02 g, 0.08 mmol) ) and 2M aq NaOH (27 ml) cooled to 0 ° C. 5-Bromoisoindoline-1,3-dione (5 g, 22 mmol) was added at the same temperature over a period of 30 min. The reaction mixture was stirred at 0 ° C for 30 min and 3 h at ambient temperature. The reaction mixture was filtered and the filtrate was neutralized with concentrated HCl. The reaction mixture was diluted with ethanol and extracted with ethyl acetate. The combined ethyl acetate layers were dried over Na2SO4 and concentrated in vacuo to give the crude title compound as a brown solid which was used in the next step without further purification (1.3 g): mp 258-261 ° C;¹1 H NMR (400 MHz, DMSO-d₆) δ 9.03 (br, 1H), 7.81 (m, 2H), 7.69 (m, 1H), 6.44 (m, 1H), 5.88 (d, J = 9.3 Hz , 1H); ESIMS m / z 225.83 ([MH]^-); IR (thin layer) 1684, 3246, 606 cm^-1.

Step 2. 6-Bromophthalazin-1 (2H) -one (BI26): To a stirred solution of 5-bromo-3-hydroxyisoindolin-1-one (1.0 g, 4.40 mmol) in water, was added hydrazine hydrate ( 0.45 g, 8.80 mmol) and heated to 95 ° C for 5 h. The reaction mixture was cooled to ambient temperature, filtered and washed with diethyl ether and pentane (1: 1) to provide the title compound as a white solid which was used for the next step without further purification (0.5 g): ESIMS m / z 225.15 ([M + H] +).

Step 3. 6-Vinylphthalazin-1 (2H) -one (BI27): A solution of 6-bromophthalazin-1 (2H) -one (0.25 g, 1.11 mmol), potassium vinyl trifluoroborate (0.446 g, 3 , 33 mmol) and K2CO3 (0.46 g, 3.33 mmol) in DMSO (2 mL) was degassed with argon for 20 min at ambient temperature. PdCl2 (dppf) (0.04 g, 0.055 mmol) was added at ambient temperature, and the reaction mixture was heated to 80 ° C for 2 h. The reaction mixture was cooled to ambient temperature and filtered through a celite pad under reduced pressure and washed with ethyl acetate. The reaction mixture was extracted with ethyl acetate and the combined ethyl acetate layers were dried over Na2SO4 and concentrated under reduced pressure to give the crude product. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 50% ethyl acetate / petroleum ether) to afford the title compound as a tan solid (0.12 g, 63%): 1H NMR (400MHz, DMSO-d₆) δ 13.61 (br, 1H), 8.33 (m, 1H), 8.19 (m, 1H), 8.01 (m, 2H), 6.97 (m, 1H), 6.15 (m, 1H), 5.56 (d, J = 10.8 Hz, 1H); ESIMS m / z 172.93 ([M + H] +); IR (thin layer) 1748, 1655, 3241 cm^-1.

Step 4. Ethyl 2- (1-Oxo-6-vinylphthalazin-2 (1H) -ylacetate (BI24): For a mixed solution of 6-vinylphthalazin-1 (2H) -one (0.5 g, 2.90 mmol) in DMF (5.0 mL) Cs2CO3 (0.94 g, 2.90 mmol) was added and the reaction was stirred for 10 min. Ethyl bromoacetate (0.48 g, 2.90 mmol) was added to the reaction mixture at ambient temperature and stirred for 8 h at ambient temperature The reaction mixture was diluted and extracted with ethyl acetate, and the ethyl acetate layer was washed with water and brine solution (2X). The separated ethyl acetate layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude product. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 25% ethyl acetate / petroleum ether) to afford the title compound as a tan solid (0.34 g, 45%): 1H NMR (400MHz, DMSO-d₆) δ 8.45 (m, 1H), 8.24 (m, 1H), 8.04 (m,

EP-2934142B1PL

2H), 7.01 (m, 1H), 6.17 (d, J = 2.1 Hz, 1H), 5.56 (d, J = 10.8 Hz, 1H), 4.92 (s, 2H), 4.19 (m, 2H), 1.23 (m,

3H). ESIMS m / z 259.10 ([M + H]⁺); IR (thin layer) 1750, 1660 cm^-1.

Example 39 * not according to the invention: Preparation of (E) -2- (6- (3- (3,5-Dichloro-4-fluorophenyl) -4,4,4trifluorobut-1-en-1-yl) -1-oxophthalazine -2 (1H) -yl) ethyl acetate (BI28)

[0390]

<img file="PL2934142T3_D0166.tif" />

[0391] To a stirred solution of ethyl-2- (1-oxo-6-vinylphthalazin-2 (1H) -yl acetate (0.07 g, 0.27 mmol) in 1,2-dichlorobenzene (1.0 mL) 5- (1-bromo-2,2,2-trifluoroethyl) -1,3-dichloro-2-fluorobenzene (0.17 g, 0.54 mmol), CuCl (0.005 g, 0.05 mmol) and 2 , 2-bipyridyl (0.016 g, 0.10 mmol) and the resulting reaction mixture was degassed with argon for 30 min and heated to 180 ° C for 12 h. The reaction mixture was cooled to ambient temperature and filtered, and the filtrate was concentrated under reduced pressure. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 1015% ethyl acetate / petroleum ether) to afford the title compound as a tan solid (40mg, 29%): 1H NMR (400MHz, DMSO-d₆) δ 8.40 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 1.5 Hz, 1H), 7.65 (s, 1H), 7.37 (d, J = 6.3 Hz, 2H), 6.76 (d, J = 16.0 Hz, 1H), 6.59 (dd, J = 16.0, 8.0 Hz, 1H), 4.96 (s , 2H), 4.29 (m, 3H), 1.31 (t, J = 7.2 Hz, 3H); ESIMS m / z 503.0 ([M + H]⁺); IR (thin layer) 1660, 1114, 817 cm^-1.

Example 40 * not according to the invention: Preparation of (E) -2- (6- (3- (3,5-Dichloro-4-fluorophenyl) 4,4,4-trifluorobut-1-en-1-yl) -1 -oxophthalazin-2 (1H) -yl) acetic acid (BI29) [0392]

<img file="PL2934142T3_D0167.tif" />

Solution of (E) -2- (6- (3- (3,5-dichloro-4-fluorophenyl) -4,4,4-trifluorobut-1-enyl) -1-oxophthalazin-2 (1H) yl) ethyl acetate (0.04 g, 0.07 mmol) in HCl (0.5 mL) and acetic acid (0.5 mL) was heated to 100 ° C for 3 h. The solvent was removed under reduced pressure and the residue was diluted with water . The aqueous layer was extracted with ethyl acetate, and the separated ethyl acetate layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude compound. The crude compound was triturated with diethyl ether-pentane to give the title compound as a brown solid (0.03 g): 1 H NMR (400 MHz, DMSO-d₆) δ 13.0 (br s, 1H), 8.43 (m, 1H), 8.23 ​​(d, J = 8.1 Hz, 1H), 8.14 (m, 2H), 7.91 ( m, 2H), 7.16 (dd, J = 16.0, 8.0 Hz, 1H), 6.99 (d, J = 16.0 Hz, 1H), 4.96 (m, 3H); ESIMS m / z 473.0 ([MH]^-); IR (thin layer) 1629, 1168, 817 cm^-1.

Example 41 * not according to the invention: Preparation of (E) -2- (6- (3- (3,5-Dichloro-4-fluorophenyl) -4,4,4trifluorobut-1-en-1-yl) -1-oxophthalazine -2 (1H) -yl) -N- (2,2,2-trifluoroethyl) acetamide (BC14) [0394]

<img file="PL2934142T3_D0168.tif" />

EP-2934142B1PL

To a mixed solution of the acid (E-2- (6- (3- (3,5-dichloro-4-fluorophenyl) -4,4,4-trifluorobut-1-yl) -1-oxophthalazin-2 (1H) -yl) acetic acid (0.15 g, 0.31 mmol) in CH₂Cl2 (20.0 mL) added 2.2,2-trifluoroethanamine (0.03 g, 0.31 mmol), PyBOP (0.17 g, 0.34 mmol), and DIPEA (0.15 mL, 0.93 mmol) at ambient temperature, and the reaction was stirred for 18 h. The reaction mixture was diluted with CH2Cl2 and washed with 3N HCl (2 x 20 mL), NaHCO3 (2 x 20 mL), and brine solution (2x). The separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 20-25% ethyl acetate / petroleum ether) to afford the title compound as a tan solid (0.11 g): mp 172-175 ° C; 1 H NMR (400 MHz, CDCl₃) δ 8.83 (t, J = 6.6 Hz, 1H), 8.42 (t, J = 14.7 Hz, 1H), 8.22 (d, J = 8.1 Hz, 1H), 8.13 (t, J = 6.3 Hz, 1H), 7.98 - 7.86 (m, 2H), 7.16 - 7.07 (m, 1H), 7.01 - 6.93 ( m, 1H), 4.96 - 4.81 (m, 3H), 4.00 - 3.88 (m, 2H); ESIMS m / z 554.0 ([MH]^-).

Example 42 * not according to the invention: Preparation of 2- (4-Vinylbenzyl) isoindoline-1,3-dione (Cl1)

[0396]

<img file="PL2934142T3_D0169.tif" />

To a stirred solution of 1- (chloromethyl) -4-vinylbenzene (10 g, 66 mmol) in DMF (100 mL) was added potassium phthalimide (13.3 g, 72.1 mmol), and the resulting reaction mixture was heated to room temperature 70 ° C for 16 h. The reaction mixture was diluted with H 2 O and extracted with CHCl 3. The combined CHCl3 layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. Recrystallization from MEOH gave the title compound as an off-white solid (8 g, 46%): 1 H NMR (400 MHz, CDCl₃) δ 7.83 (m, 2H), 7.71 (m, 2H), 7.39 (m, 4H), 6.65 (dd, J = 17.6, 10.8 Hz, 1H), 5 , 72 (d, J = 17.6 Hz, 1H), 5.21 (d, J = 10.8 Hz, 1H), 4.82 (s, 2H); GCMS m / z 263.2 ([M] +); IR (thin layer) 3420, 1133, 718 cm^-1.

Example 43 * not according to the invention: Preparation of (E) -2- (4- (3- (3,5-Dichlorophenyl) -4,4,4-trifluorobut-1-en-1-yl) benzyl) isoindoline-1,3- dione (CI2)

[0398]

<img file="PL2934142T3_D0170.tif" />

Following the procedure of Example 10 using 2- (4-vinylbenzyl) isoindoline-1,3-dione and 1- (1-bromoethyl) -3,5-dichlorobenzene as starting materials, the title compound was isolated as an off-white solid (0, 3 g, 40-50%): mp 142-145 ° C; 1 H NMR (400 MHz, CDCl₃) δ 7.86 (m, 2H), 7.74 (m, 2H), 7.42 (m, 2H), 7.36 (m, 3H), 7.27 (m, 2H), 6.58 (d, J = 16.0 Hz, 1H), 6.32 (dd, J = 16.0, 8.0 Hz, 1H), 4.82 (s, 2H), 4.05 (m, 1H) ; ESIMS m / z 488.17 ([MH] -).

[0400] The following compound * not according to the invention was prepared according to the procedures disclosed in Example 43.

(E) -2- (4- (4,4,4-Trifluoro-3- (3,4,5-trichlorophenyl) but-1-en-1-yl) benzyl) isoindoline-1,3-dione (CI3 ) [0401]

EP-2934142B1PL

<img file="PL2934142T3_D0171.tif" />

[0402] The title compound was isolated as an off-white solid (0.3 g, 56%): mp 145-146 ° C; 1 H NMR (400 MHz, CDCl₃) δ 7.86 (m, 2H), 7.74 (m, 2H), 7.42-7.31 (m, 6H), 6.58 (d, J = 16.0 Hz, 1H), 6 , 53 (dd, J = 16.0, 8.0 Hz, 1H), 4.82 (s, 2H), 4.05 (m, 1H); ESIMS m / z 522.2 ([MH] -); IR (thin layer) 1716, 1110, 712 cm^-1.

[0403] It was anticipated that CI4-CI5 compounds (Table 1) could be prepared according to the procedures disclosed in Example 43.

Example 44 * not according to the invention: Preparation of (E) - (4- (3,5-Dichlorophenyl) -4,4,4-trifluorobut-1-en-1-yl) phenyl) methanamine (CI6)

[0404]

<img file="PL2934142T3_D0172.tif" />

[0405] To a mixed solution of (E) -2- (4- (3- (3,5-dichlorophenyl) but-1-en-1-yl) benzyl) -isoindoline-1,3-dione (1.2 g, 2 , 45 mmol) in EtOH, hydrazine hydrate (0.61 g, 12 mmol) was added, and the resulting reaction mixture was heated at 90 ° C for 1 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was dissolved in CH2Cl2, washed with brine, dried over Na2SO4, and concentrated under reduced pressure to provide the crude title compound as a gummy liquid (0.9 g) which was used without further purification.

[0406] The following compounds * not according to the invention were prepared according to the procedures disclosed in Example 44.

(E) - (4- (4,4,4-Trifluoro-3- (3,4,5-trichlorophenyl) but-1-en-1-yl) phenyl) methanamine (CI7) [0407]

<img file="PL2934142T3_D0173.tif" />

[0408] The title compound was isolated and used without further purification. It was anticipated that CI8-CI9 * compounds not according to the invention (Table 1) could be prepared according to the procedures disclosed in Example 44.

Example 45 * not according to the invention: Preparation of 4- (Bromomethyl) -3-chlorobenzonitrile (Cl10) [0409]

<img file="PL2934142T3_D0174.tif" />

To a stirred solution of 3-chloro-4-methylbenzonitrile (5 g, 25.4 mmol) in carbon tetrachloride (CCl4; 50 mL) under argon, NBS (5.16 g, 29 mmol) was added, and the mixture was degassed for 30 min. Azobisisobutyronitrile (AIBN; 0.3 g, 1.8 mmol) was added thereto, and the resulting reaction mixture was heated under reflux for 4 h. The reaction mixture was cooled to

Ambient temperature, washed with water, and extracted with CH2Cl2. The combined CH2Cl2 layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (SiO2, 100-200 mesh; 5% EtOAc in n-hexane) to provide the title compound as a white solid (4.8 g, 68%): mp 87-88 ° C; 1 H NMR (400 MHz, CDCl 3) δ 7.71 (s, 1H), 7.59 (s, 2H), 4.60 (s, 2H); ESIMS m / z 229.77 ([M + H] +); IR (thin layer) 2235, 752, 621 cm^-1.

[0411] The following compounds * not according to the invention were prepared according to the procedures disclosed in Example 45.

4- (Bromomethyl) -3- (trifluoromethyl) benzonitrile (CI11)

[0412]

NC

ΧΥ- cf₃

Br

[0413] The title compound was isolated as an off-white gummy material (5 g, 66%): ¹H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 4.62 (s. 2H); ESIMS m / z 262.11 ([MH]^-); IR (thin layer) 2236, 1132, 617 cm^-1.

3-Bromo-4- (bromomethyl) benzonitrile (CI12)

[0414]

NC &lt;^ Λ-Βγ

Br

[0415] The title compound was isolated as an off-white solid (5 g, 67%): mp 82-83 ° C; ¹H NMR (400 MHz, CDCl 3) δ 7.90 (s, 1H), 7.61 (m, 2H), 4.62 (s, 2H); EIMS m / z 272.90; IR (thin layer) 2229.618 cm^-1.

4- (Bromomethyl) -3-fluorobenzonitrile (CI13)

[0416]

NC

Kf ^ Br

[0417] The title compound was isolated as an off-white solid (2 g, 60%): mp 79-81 ° C; 1 H NMR (400 MHz, CDCl 3) δ 7.54 (t, J = 8.0 Hz, 1H), 7.48 (dd, J = 8.0 Hz, 8.0, 1H), 7.38 (dd , J = 5Hz, 1H), 4.5 (s, 2H); EIMS m / z 215.

Example 46 * not according to the invention: Preparation of 4- (Bromomethyl) -3-chlorobenzaldehyde (CI14)

[0419] To a stirred solution of 4- (bromomethyl) -3-chlorobenzonitrile (4.8 g, 17 mmol) in toluene (50 mL) at 0 ° C was added diisobutylaluminum hydride (DIBAL-H, 1.0 M solution in toluene; 23.9 mL), and the reaction mixture was stirred at 0 ° C for 1 h. 10 M HCl in water (5 mL) was added until the reaction mixture turned to a white slurry, then additional 1 N HCl was added

EP-2934142B1PL (20 ml). The organic layer was collected and the aqueous layer was extracted with CHCl3. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (SiO2, 100-200 mesh; 5% EtOAc in hexane) to provide the title compound as a white solid (3.8 g, 80%): mp 64-66 ° C; 1H NMR (400 MHz, CDCl₃) δ 10.00 (s, 1H), 7.92 (s, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H ). 4.60 (s, 2H); ESIMS m / z 232.78 ([M + H] +).

[0420] The following compounds * not according to the invention were prepared according to the procedures disclosed in Example 46.

4- (Bromomethyl) -3- (trifluoromethyl) benzaldehyde (CI15) [0421]

<img file="PL2934142T3_D0175.tif" />

[0422] The title compound was isolated as a pale yellow low melting solid (5 g, 60%): 1H NMR (400 MHz, CDCl₃) δ 10.09 (s, 1H), 8.19 (s, 1H), 8.09 (m, 1H), 7.81 (m, 1H), 4.61 (s, 2H); ESIMS m / z 265.04 ([MH]^-); IR (thin layer) 1709, 1126, 649 cm^-1.

3-Bromo-4- (bromomethyl) benzaldehyde (CI16)

[0423]

<img file="PL2934142T3_D0176.tif" />

[0424] The title compound was isolated as a pale yellow solid (5 g, 62%): mp 94-95 ° C; 1 H NMR (400 MHz, CDCl₃) δ 9.96 (s, 1H), 8.05 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H ). 4.60 (s, 2H); EIMS m / z 275.90.

4- (Bromomethyl) -3-fluorobenzaldehyde (CI17)

[0425]

<img file="PL2934142T3_D0177.tif" />

[0426] The title compound was isolated as an off-white solid (5 g, 61%): mp 43-45 ° C; 1 H NMR (400 MHz, CDCl₃) δ 9.1 (s, 1H), 7.54 (t, J = 8 Hz, 1H), 7.48 (d, J = 8 Hz, 1H), 7.38 (d, J = 5 Hz, 1H), 4.5 (s, 2H); EIMS m / z 216.

Example 47 * not according to the invention: Preparation of 3-Chloro-4 - ((1,3-dioxoisoindolin-2-yl) methyl) benzaldehyde (CI18)

[0427]

<img file="PL2934142T3_D0178.tif" />

EP-2934142B1PL

To a stirred solution of 4- (bromomethyl) -3-chlorobenzaldehyde (3.8 g, 14 mmol) in DMF (40 mL) was added potassium phthalimide (3.54 g, 19.14 mmol), and the mixture was heated to room temperature. 60 ° C for 6 h. The reaction mixture was cooled to ambient temperature and diluted with H 2 O (100 mL). The resulting solid was separated by filtration and dried in vacuo to provide the title compound as a white solid (2.8 g, 60%): mp 123-126 ° C; 1 H NMR (400 MHz, CDCl₃) δ 9.95 (s, 1H), 8.21 (s, 1H), 7.91 (m, 3H), 7.80 (m, 2H), 7.20 (m, 1H), 5.05 (s. 2H); ESIMS m / z 298.03 ([MH]^-).

[0429] The following compounds * not according to the invention were prepared according to the procedures disclosed in Example 47.

4 - ((1,3-Dioxoisoindolin-2-yl) -3- (trifluoromethyl) benzaldehyde (CI19)

[0430]

<img file="PL2934142T3_D0179.tif" />

[0431] The title compound was isolated as an off-white solid (1 g, 62%): mp 142-143 ° C; 1 H NMR (400 MHz, CDCl₃) δ 10.05 (s, 1H), 8.15 (s, 1H), 7.91 (m, 2H), 7.80 (m, 3H), 7.27 (m, 1H), 5.19 (s. 2H); ESIMS m / z 332.03 ([MH] -).

3-Bromo-4 - ((1,3-dioxoisoindolin-2-yl) methyl) benzaldehyde (Cl2O)

[0432]

<img file="PL2934142T3_D0180.tif" />

[0433] The title compound was isolated as an off-white solid (0.5 g, 64%): mp 159-161 ° C; 1 H NMR (400 MHz, CDCl₃) δ 9.95 (s, 1H), 8.21 (s, 1H), 7.91 (m, 3H), 7.80 (m, 2H), 7.20 (m, 1H), 5.05 (s. 2H); ESIMS m / z 314.00 ([M-CHO] -).

4 - ((1,3-Dioxoisoindolin-2-yl) -3-fluorobenzaldehyde (CI21)

[0434]

<img file="PL2934142T3_D0181.tif" />

[0435] The title compound was isolated as a white solid (2 g, 60%): mp 154-156 ° C; ¹H NMR (400 MHz, CDCl₃) δ 9.95 (s, 1H), 7.9 (m, 2H), 7.75 (m, 2H), 7.6 (m, 2H), 7.5 (t, J = 7.6 Hz , 1H), 5.05 (s, 2H); EIMS m / z 283.1.

Example 48 * not according to the invention: Preparation of 2- (2-Chloro-4-vinylbenzyl) isoindoline-1,3-dione (CI22)

[0436]

EP-2934142B1PL

<img file="PL2934142T3_D0182.tif" />

[0437] To a stirred solution of 3-chloro-4 - ((1,3-dioxoisoindolin-2-yl) methyl) benzaldehyde (2.8 g, 8.2 mmol) in 1,4-dioxane (30 mL) was added K2CO3 (1.68 g, 12.24 mmol) and methyltriphenylphosphonium bromide (4.37 g, 12.24 mmol) at ambient temperature. The resulting reaction mixture was then heated at 100 ° C for 18 h. After the reaction was judged complete by TLC, the reaction mixture was cooled to ambient temperature and filtered, and the resulting filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 100-200 mesh; 20% EtOAc in n-hexane) to provide the title compound as a white solid (1.94 g, 70%): mp 141-143 ° C; 1 H NMR (400 MHz, CDCl₃) δ 7.85 (m, 2H), 7.70 (m, 2H), 7.41 (m, 1H), 7.21 (m, 2H), 6.71 (dd, J = 17.6, 10.8 Hz, 1H), 5.72 (d, J = 17.6 Hz, 1H), 5.23 (d, J = 10.8 Hz, 1H), 4.92 (s, 2H); ESIMS m / z 298.10 ([MH] -).

[0438] The following compounds * not according to the invention were prepared according to the procedures disclosed in Example 48.

2- (2- (Trifluoromethyl) -4-vinylbenzyl) isoindoline-1,3-dione (CI23)

[0439]

<img file="PL2934142T3_D0183.tif" />

[0440] The title compound was isolated as a light brown solid (0.5 g, 60%): mp 134-135 ° C; 1 H NMR (400 MHz, CDCl₃) δ 7.92 (m, 2H), 7.80 (m, 2H), 7.71 (s, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.16 (d , J = 8.0 Hz, 1H), 6.65 (m, 1H), 5.80 (d, J = 17.8 Hz, 1H), 5.19 (d, J = 10.8 Hz, 1H ). 5.09 (s. 2H); ESIMS m / z 332.10 ([M + H] +).

2- (2-Bromo-4-vinylbenzyl) isoindoline-1,3-dione (CI24)

[0441]

<img file="PL2934142T3_D0184.tif" />

[0442] The title compound was isolated as an off-white solid (0.5 g, 62%): mp 126-128 ° C; 1 H NMR (400 MHz, CDCl₃) δ 7.92 (m, 2H), 7.79 (m, 2H), 7.62 (s, 1H), 7.21 (m, 1H), 7.16 (d, J = 8.0 Hz , 1H), 6.62 (m, 1H), 5.72 (d, J = 17.8 Hz, 1H), 5.15 (d, J = 10.8 Hz, 1H), 4.95 (s , 2H); EIMS mlz 341.10.

2- (2-Fluoro-4-vinylbenzyl) isoindoline-1,3-dione (CI25)

[0443]

EP-2934142B1PL

<img file="PL2934142T3_D0185.tif" />

The title compound was isolated as a white solid (0.5 g, 61%): mp 140-142 ° C; ¹H NMR (400 MHz, CDCl₃) δ 7.85 (m, 2H), 7.72 (m, 2H), 7.25 (m, 1H), 7.11 (m, 2H), 6.63 (m, 1H), 5.80 (d, J = 17.6 Hz, 1H), 5.28 (d, J = 10.8 Hz, 1H), 4.92 (s, 2H); EIMS m / z 282.08.

Example 49 * not according to the invention: Preparation of (E) -2- (2-Chloro-4- (3- (3,5-dichlorophenyl) -4,4,4-trifluorobut-1-en-1-yl) benzyl) isoindoline- 1,3-dione (CI26) [0445]

<img file="PL2934142T3_D0186.tif" />

[0446] To a stirred solution of 2- (2-chloro-4-vinylbenzyl) isoindoline-1,3-dione (2.0 g, 6.51 mmol) in 1,2-dichlorobenzene (25 mL) was added 1- (1 -bromo-2,2,2-trifluoroethyl) -3,5-dichlorobenzene (3.48 g, 11.36 mmol), CuCl (112 mg, 1.13 mmol) and 2,2-bipyridyl (0.35 g ). The resulting reaction mixture was degassed with argon for 30 min and then stirred at 180 ° C for 24 h. After the reaction was judged complete by TLC, the reaction mixture was cooled to ambient temperature and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 100-200 mesh; 25-30% EtOAc in n-hexane) to provide the title compound as a solid (1.3 g, 50%): mp 141-143 ° C;¹H NMR (400 MHz, CDCl3) δ 7.92 (m, 2H), 7.79 (m, 2H), 7.42 (m, 2H), 7.24 (m, 2H), 7.20 (m , 2H), 6.54 (d, J = 16.0 Hz, 1H), 6.34 (dd, J = 16.0, 8.0 Hz, 1H), 5.00 (s, 2H), 4 . 1. 10 (m, 1H); ESIMS m / z 524.07 ([M + H] +).

[0447] The following compounds * not of the invention were prepared according to the procedures disclosed in Example 49.

(E) -2- (2-Chloro-4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-en-1-yl) benzyl) isoindoline-1,3-dione (CI27)

[0448]

<img file="PL2934142T3_D0187.tif" />

The title compound was isolated as a pale white solid (0.2 g, 55%): mp 128-129 ° C; 1 H NMR (400 MHz, CDCl₃) δ 7.92 (m, 2H), 7.79 (m, 2H), 7.42 (m, 3H), 7.22 (m, 2H), 6.52 (d, J = 16.0 Hz , 1H), 6.32 (dd, J = 16.0, 8.0 Hz, 1H), 5.00 (s, 2H), 4.05 (m, 1H); ESIMS m / z 557.99 ([M + H] +).

EP-2934142B1PL (E) -2- (2-Chloro-4- (3- (3,5-dichloro-4-fluorophenyl) -4,4,4-trifluorobut-1-en-1-yl) benzyl) isoindoline , 3-dione (CI28)

[0450]

<img file="PL2934142T3_D0188.tif" />

[0451] The title compound was isolated as an off-white solid (0.2 g, 54%): mp 177-180 ° C; ¹H NMR (400 MHz, CDCl₃) δ 7.90 (m, 2H), 7.77 (m, 2H), 7.42 (s, 1H), 7.32 (d, J = 8.0 Hz, 2H), 7.21 (m , 2H), 6.52 (d, J = 16.0 Hz, 1H), 6.32 (dd, J = 16.0, 8.0 Hz, 1H), 5.00 (s, 2H), 4 .05 (m, 1H); ESIMS m / z 540.08 ([MH]^-); IR (thin layer) 1716 cm^-1.

(E) -2- (2-Chloro-4- (3- (3,4-dichlorophenyl) -4,4,4-trifluorobut-1-en-1-yl) benzyl) isoindoline-1,3-dione ( CI29)

[0452]

<img file="PL2934142T3_D0189.tif" />

[0453] The title compound was isolated as an off-white solid (0.2 g, 59%): ¹H NMR (400 MHz, CDCl₃) δ 7.89 (m, 2H), 7.76 (m, 2H), 7.47 (m, 3H), 7.21 (m, 3H), 6.50 (d, J = 16.0 Hz , 1H), 6.32 (dd, J = 16.0, 7.6 Hz, 1H), 4.97 (s, 2H), 4.11 (m, 1H); ESIMS m / z 522.27 ([MH] -); IR (thin layer) 3064, 1717, 1111, 715 cm^-1.

(E) -2- (4- (3- (3,5-Dichlorophenyl) -4,4,4-trifluorobut-1-en-1-yl) -2- (trifluoromethyl) benzyl) isoindoline-1,3- dione (CI30)

[0454]

<img file="PL2934142T3_D0190.tif" />

[0455] The title compound was isolated as an off-white solid (0.2 g, 54%): mp 141-142 ° C; 1 H NMR (400 MHz, CDCl₃) 7.94 (m, 2H), 7.80 (m, 2H), 7.69 (s, 1H), 7.44 (m, 1H), 7.38 (m, 1H), 7.24 ( m, 2H), 7.19 (m, 1H), 6.60 (d, J = 16.0 Hz, 1H), 6.39 (dd, J = 16.0, 7.6 Hz, 1H), 5.10 (s, 2H); 4.11 (m, 1H); ESIMS m / z 556.00 ([MH]^-).

(E) -2- (4- (4,4,4-Trifluoro-3- (3,4,5-trichlorophenyl) but-1-en-1-yl) -2- (trifluoromethyl) benzyl) isoindoline-1 , 3-dione (CI31)

[0456]

EP-2934142B1PL

<img file="PL2934142T3_D0191.tif" />

[0457] The title compound was isolated as an off-white solid (0.2 g, 56%): mp 130-132 ° C; ¹H NMR (400 MHz, CDCl₃) δ 7.94 (m, 2H), 7.80 (m, 2H), 7.69 (s, 1H), 7.44 (m, 3H), 7.19 (m, 1H), 6.61 (d, J = 16.0 Hz, 1H), 6.38 (dd, J = 16.0, 7.6 Hz, 1H), 5.10 (s, 2H), 4.12 (m, 1H) ; ESIMS m / z 589.57 ([M-2H]^-).

(E) -2- (2-Bromo-4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-en-1-yl) benzyl) -isoindoline-1, 3dion (CI32)

[0458]

<img file="PL2934142T3_D0192.tif" />

The title compound was isolated as a pale yellow solid (0.2 g, 55%): mp 160-162 ° C; 1 H NMR (400 MHz, CDCl₃) δ 7.92 (m, 2H), 7.80 (m, 2H), 7.62 (s, 1H), 7.39 (s, 2H), 7.24 (m, 1H), 7.16 (m, 1H), 6.52 (d, J = 16.0 Hz, 1H), 6.32 (dd, J = 16.0, 8.0 Hz, 1H), 4.98 (s, 2H) . 4.12 (m, 1H); ESIMS m / z 599.78 ([MH]^-).

(E) -2- (2-Fluoro-4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-en-1-yl) benzyl) -isoindoline-1, 3dion (CI33)

[0460]

<img file="PL2934142T3_D0193.tif" />

[0461] The title compound was isolated as an off-white solid (0.2 g, 55%): mp 72-74 ° C; 1 H NMR (400 MHz, CDCl₃) δ 7.88 (m, 2H), 7.74 (m, 2H), 7.38 (s, 2H), 7.34 (m, 1H), 7.18 (m, 2H), 6.54 (d, J = 16.0 Hz, 1H), 6.32 (dd, J = 16.0, 8.0 Hz, 1H), 4.91 (s, 2H), 4.08 (m, 1H) ; ESIMS m / z 539.89 ([MH]^-); IR (thin layer) 1773 cm^-1.

[0462] It was anticipated that CI34-CI41 * compounds not according to the invention (Table 1) could be prepared according to the procedures disclosed in Example 49.

Example 50 * not according to the invention: Preparation of (E) - (2-Chloro-4- (3- (3,5-dichlorophenyl) -4,4,4-trifluorobut-1-en-1-yl) phenyl) methanamine ( CI42)

[0463]

EP-2934142B1PL

<img file="PL2934142T3_D0194.tif" />

[0464] To a mixed solution of (E) -2- (2-chloro-4- (3- (3,5-dichlorophenyl) -4,4,4-trifluorobut-1-en-1-yl) benzyl) isoindoline- 1,3-dione (0.4 g, 0.76 mmol) in EtOH was added hydrazine hydrate (0.38 g, 7.6 mmol), and the resulting reaction mixture was heated at 80 ° C for 2 h. The reaction mixture was filtered. and the filtrate was concentrated. The residue was dissolved in CH2Cl2, washed with brine, dried over Na2SO4, and concentrated under reduced pressure to provide the title compound as a gummy liquid (0.3 g) which was carried on to the next step without further purification.

[0465] The following compounds * not according to the invention were prepared according to the procedures disclosed in Example 50.

(E) - (2-Chloro-4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-en-1-yl) phenyl) -methanamine (CI43) [0466 ]

<img file="PL2934142T3_D0195.tif" />

[0467] The product obtained in this reaction was taken to the next step without further purification.

(E) - (2-Chloro-4- (3- (3,4-dichlorophenyl) -4,4,4-trilluorobut-1-en-1-yl) phenyl) -methanamine (CI44)

[0468]

<img file="PL2934142T3_D0196.tif" />

[0469] The product obtained in this reaction was taken to the next step without further purification. ¹H NMR (400 MHz, CDCl₃) δ 7.48 (d, J = 8.4 Hz, 2H), 7.39 (m, 2H), 7.23 (m, 2H), 6.52 (d, J = 16.0 Hz, 1H ), 6.38 (dd, J = 16.0, 7.6 Hz, 1H), 4.12 (m, 1H), 3.90 (s, 2H); ESIMS m / z 391.90 ([MH] -); IR (thin layer) 3370, 3280, 1111, 817 cm^-1.

(E) - (4- (4,4,4-Trifluoro-3- (3,4,5-trichlorophenyl) but-1-en-1-yl) -2 (trifluoromethyl) phenyl) methanamine (CI45)

[0470]

<img file="PL2934142T3_D0197.tif" />

[0471] The title compound was isolated as a gummy material. The product obtained in this reaction was taken to the next step without further purification.

(E) - (2-Bromo-4- (3- (3,5-dichlorophenyl) -4,4,4-trifluorobut-1-en-1-yl) phenyl) methanamine (CI46)

[0472]

<img file="PL2934142T3_D0198.tif" />

EP-2934142B1PL

[0473] The title compound was isolated as a gummy material: The product obtained in this reaction was taken to the next step without further purification.

(E) - (2-Bromo-4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-en-1-yl) phenyl) methanamine (CI47)

[0474]

[0475] The title compound was isolated as a gummy material. The product obtained in this reaction was taken to the next step without further purification.

(E) - (2-Fluoro-4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-en-1-yl) phenyl) methanamine (CI48)

[0476] cf₃ nh₂

[0477] The title compound is isolated as a gummy material: ¹H NMR (400 MHz, CDCl3) δ 7.40 (s, 2H), 7.33 (t, J = 7.6 Hz, 1H), 7.13 (m, 2H), 6.56 (d, J = 16.0 Hz, 1H), 6.33 (dd, J = 16.0, 7.6 Hz, 1H), 4.08 (m, 1H), 3.90 (s, 2H); ESIMS m / z 413.84 ([M + H] +); IR (thin layer) 3368, 3274, 1114, 808 cm^-1.

[0478] It was anticipated that CI49-CI57 * compounds not according to the invention (Table 1) could be prepared according to the procedures disclosed in Example 50.

Example 51 * not according to the invention: Preparation of 3-Chloro-4 - ((pyridin-2-ylamino) methyl) benzaldehyde (CI58)

[0479]

H, N.

[0480] To a stirred solution of 4- (bromomethyl) -3-chlorobenzaldehyde (2 g, 9 mmol) in N, N-dimethylacetamide (DMA; 20 mL) was added K2CO3 (2.36 g, 17.16 mmol) and 2- aminopyridine (0.84 g, 8.58 mmol), and the reaction mixture was stirred at ambient temperature for 4 h. The reaction mixture was diluted with H 2 O and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 100-200 mesh; 20% EtOAc in n-hexane) to provide the title compound as an off-white solid (1.05 g, 50%): mp 122-123 ° C; 1 H NMR (400 MHz, CDCl₃) δ 9.94 (s, 1H), 8.11 (s, 1H), 7.88 (s, 1H), 7.72 (d, J = 4.8 Hz, 1H), 7.62 (d , J = 5.7 Hz, 1H), 7.4 (m, 1H), 6.64 (d, J = 3.9 Hz, 1H), 6.38 (d, J = 6.3 Hz, 1H ), 5.04 (br s, 1H), 4.71 (s, 2H); ESIMS m / z 246.97 ([M + H]⁺).

Example 52 * not according to the invention: Preparation of N- (2-Chloro-4-vinylbenzyl) pyridin-2-amine (CI59)

[0481]

EP-2934142B1PL

To a stirred solution of 3-chloro-4 - ((pyridin-2-ylamino) methyl) benzaldehyde (1 g, 4. mmol) in 1,4-dioxane (20 mL) was added K2CO3 (0.84 g, 6 , 09 mmol) and methyltriphenylphosphonium bromide (2.17 g, 6.09 mmol) at ambient temperature. The resulting reaction mixture was then heated at 100 ° C for 18 h. After the reaction was judged complete by TLC, the reaction mixture was cooled to ambient temperature and filtered, and the resulting filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 100-200 mesh; 10% EtOAc in n-hexane) to provide the title compound as a white solid (0.5 g, 50%): mp 119-121 ° C; 1 H NMR (400 MHz, CDCl₃) δ 8.12 (s, 1H), 7.42 - 7.40 (m, 3H), 7.26 (s, 1H), 6.66 (m, 2H), 6.36 (d, J = 6.3 Hz, 1H), 5.75 (d, J = 13.2 Hz, 1H), 4.92 (br s, 1H), 4.60 (s, 2H); ESIMS m / z 245.05 ([M + H] +).

Example 53 * not according to the invention: Preparation of ethyl 2-Amino-2- (5-bromo-3-chloropyridin-2-yl) acetate (CI60)

[0483]

<img file="PL2934142T3_D0199.tif" />

[0484] Ethyl 2- (diphenylmethyleneamino) acetate (10.2 g, 38.2 mmol) was added to sodium hydride (NaH; 3.18 g, 133.52 mmol) in DMF (50 mL) at 0 ° C. and the mixture was stirred for 30 min. Thereto was added 5-bromo-2,3-dichloropyridine (12.9 g, 57.23 mmol), and the reaction mixture was stirred for 3 h at ambient temperature. The reaction mixture was quenched with 2 N HCl solution, then stirred for 4 h at ambient temperature. The mixture was extracted with EtOAc. The combined EtOAc layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (20-30% EtOAc in hexanes) gave the title compound as a liquid (1.3 g, 20%): 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 7.89 (s, 1H), 5.09 (s 1 H), 4.23 (m, 2H), 2.27 (br s, 2H), 1.26 (m, 3H); ESIMS m / z 293.05 ([M + H] +); IR (thin layer) 3381, 3306, 1742, 759, 523 cm^-1.

Example 54 * not according to the invention: Preparation of (5-Bromo-3-chloropyridin-2-yl) methanamine hydrochloride (CI61)

[0485]

N [0486] A mixed solution of ethyl 2-amino-2- (5-bromo-3-chloropyridin-2-yl) acetate (0.5 g, 1.7 mmol) in 3 N HCl (25 mL) was heated to reflux. for 4 h. The reaction mixture was washed with diethyl ether and H20. The combined ether layer was concentrated under reduced pressure to provide the title compound as an off-white solid (400mg, 65%):¹H NMR (400 MHz, CDCl 3) δ 8.78 (s, 1H), 8.70 (br s, 2H), 8.45 (s, 1H), 4.56 (m, 2H); ESIMS m / z 221.15 ([M + H] +).

Example 55 * not according to the invention: Preparation of 2 - ((5-Bromo-3-chloropyridin-2-yl) methyl) isoindoline-1,3-dione (CI62)

[0487]

EP-2934142B1PL

<img file="PL2934142T3_D0200.tif" />

To a stirred solution of (5-bromo-3-chloropyridin-2-yl) methanamine hydrochloride (0.3 g, 1.4 mmol) in toluene (40 mL) was added TEA (0.41 g, 4.08 mmol) ) and phthalic anhydride (0.24 g, 1.63 mmol), and the reaction mixture was heated at reflux for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water and extracted with EtOAc. The combined EtOAc layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (20-30% EtOAc in hexane) to provide the title compound as a white solid (0.25 g, 65%): ¹H NMR (400 MHz, CDCl3) δ 8.78 (s, 1H), 8.45 (s, 1H), 7.88 (m, 2H), 7.74 (m, 2H), 4.56 (m , 2H); ESIMS m / z 349 ([MH] -); IR (thin layer) 3307, 1665, 1114, 813 cm^-1.

Example 56 * not according to the invention: Preparation of 2 - ((3-Chloro-5-vinylpyridin-2-yl) methyl) iso indoline-1,3-dione (CI63) [0489]

<img file="PL2934142T3_D0201.tif" />

[0490] To a stirred solution of 2 - ((5-bromo-3-chloropyridin-2-yl) methyl) isoindoline-1,3-dione (0.23 g, 0.65 mmol) in toluene (10 mL) was added Pd (PPh3) 4 (3.7 mg, 0.003 mmol), K2CO3 (0.269 g, 1.95 mmol) and vinylboronic acid anhydride-pyridine complex (0.78 g, 3.28 mmol), and the reaction mixture was heated to reflux. for 16 h. The reaction mixture was filtered and the filtrate was washed with H 2 O and brine, dried over anhydrous Na 2 SO 4, and concentrated under reduced pressure. Purification by flash column chromatography (20-30% EtOAc in hexanes) provided the title compound as an off-white solid (0.2 g, 65%): ¹H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 7.91 (m, 2H), 7.77 (m, 3H), 7.72 (m, 1H), 6.63 (m , 1H), 5.79 (d, J = 16.0 Hz, 1H), 5.39 (d, J = 16.0 Hz, 1H), 5.12 (s, 2H); ESIMS m / z 299.20 (LM + H] +).

Example 57 * not according to the invention: Preparation of (E) -2 - ((3-Chloro-5- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-en-1-yl) pyridin-2-yl) methyl) isoindoline-1,3-dione (CI64)

[0491]

<img file="PL2934142T3_D0202.tif" />

To a stirred solution of 2 - ((3-chloro-5-vinylpyridin-2-yl) methyl) isoindoline-1,3-dione (0.35 g, 1.17 mmol) in 1,2-dichlorobenzene (10 ml) added 5- (1-bromo-2,2,2-trifluoroethyl) -1,2,3-trichlorobenzene

EP-2934142B1PL (0.8 g, 2.3 mmol), CuCl (23 mg, 0.12 mmol), 2,2-bipyridyl (0.073 g, 0.234 mmol), and the reaction mixture was heated at 180 ° C for 16 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (20-30% EtOAc in hexane) to provide the title compound as a liquid (0.4 g, 50%): mp 79-82 ° C; 1 H NMR (400 MHz, CDCl 3) δ 8.27 (s, 1H), 7.91 (m, 2H), 7.77 (m, 3H), 7.36 (s, 2H), 6.51 (d , J = 15.6 Hz, 1H), 6.32 (dd, J = 15.6, 8.0 Hz, 1H), 5.30 (s, 2H), 4.13 (m, 1H); ESIMS m / z 559 ([M + H] +).

Example 58 * not according to the invention: Preparation of (E) - (3-Chloro-5- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-en-1-yl) pyridines -2-yl) methanamine (CI65)

[0493]

<img file="PL2934142T3_D0203.tif" />

[0494] To a stirred solution of (E) -2 - ((3-chloro-5- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-en-1-yl) pyridin- 2-yl) methyl) isoindoline-1,3-dione (200 mg, 0.358 mmol) in EtOH (5 mL) was added hydrazine hydrate (89.6 mg, 1.79 mmol), and the reaction mixture was heated to reflux for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in CH2Cl2. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to provide the title compound as a solid (100 mg). The product obtained in this reaction was taken to the next step without further purification.

Example 59 * not according to the invention: Preparation of 4- (Bromomethyl) -1-naphtonitrile (CI66) [0495]

<img file="PL2934142T3_D0204.tif" />

NBS (6.06 g, 34.09 mmol) was added to a stirred solution of 4-methyl-1-naphtonitrile (5 g, 30 mmol) in CCl4 (50 mL) under argon, and the reaction mixture was degassed for 30 min. . AIBN (0.3 g, 2.1 mmol) was added, and the resulting reaction mixture was refluxed for 4 h. The reaction mixture was cooled to ambient temperature, diluted with H 2 O and extracted with CH 2 Cl 2 (3 x 100 mL). The combined CH2Cl2 layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 100-200 mesh; 5% EtOAc in n-hexane) to provide the title compound as a white solid (3.8 g, 52%): mp 131-133 ° C;¹H NMR (400 MHz, CDCl₃) δ 8.33 (m, 1H), 8.24 (m, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.78 (m, 2H), 7.62 (d , J = 8.0 Hz, 1H), 4.95 (s, 2H); ESIMS m / z 245.92 ([M + H] +); IR (thin layer) 2217 cm^-1.

Example 60 * not according to the invention: Preparation of 4- (Bromomethyl) -1-naphthaldehyde (CI67) [0497]

<img file="PL2934142T3_D0205.tif" />

EP-2934142B1PL

[0498] To a stirred solution of 4- (bromomethyl) -1-naphtonitrile (8 g, 33 mmol) in toluene (100 mL) at 0 ° C was added DIBAL-H (1.0 M solution in toluene; 43 mL) dropwise. , and the reaction mixture was stirred at 0 ° C for 1 h. To the mixture was added 3 N HCl in H 2 O (50 mL) until it became a white suspension, then additional 1 N HCl (20 mL) was added. The organic layer was collected and the aqueous layer was extracted with EtOAc (3 x100 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; 5% EtOAc in petroleum ether) gave the title compound as a white solid (7 g, 88%): mp 115-116 ° C; 1 H NMR (400 MHz, CDCl₃) δ 10.41 (s, 1H), 9.35 (m, 1H), 8.22 (m, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.75 (m , 3H), 4.95 (s, 2H); ESIMS m / z 248.88 ([M + H] +).

Example 61 * not according to the invention: Preparation of 4 - ((1,3-Dioxoisoindolin-2-yl) methyl) -1-naphtaldehyde (CI68)

[0499]

<img file="PL2934142T3_D0206.tif" />

[0500] To a stirred solution of 4- (bromomethyl) -1-naphthaldehyde (7 g, 28. mmol) in DMF (100 mL) was added potassium phthalimide (7.3 g, 39.5 mmol), and the mixture was heated to 85 ° C for 2 h. The reaction mixture was cooled to ambient temperature and diluted with water (100 mL). The resulting solid was separated by filtration and dried under reduced pressure to provide the title compound as a white solid (8.8 g, 98%): mp 190-192 ° C; 1 H NMR (400 MHz, CDCl 3) δ 10.39 (s, 1H), 9.25 (m, 1H), 8.41 (m, 1H), 8.10 (d, J = 8.0 Hz, 1H ), 7.95 (m, 4H), 7.80 (m, 4H), 7.61 (m, 4H), 5.39 (s, 2H); ESIMS mlz 316.09 ([M + H] +); IR (thin layer) 1708 cm-1.

Example 62 * not according to the invention: Preparation of 2 - ((4-Vinylnaphthalen-1-yl) methyl) isoindoline-1,3-dione (CI69)

[0501]

<img file="PL2934142T3_D0207.tif" />

To a stirred solution of 4 - ((1,3-dioxoisoindolin-2-yl) methyl) -1-naphthaldehyde (9 g, 28.5 mmol) in 1,4-dioxane (100 mL) was added K2CO3 (6 g , 42.8 mmol) and methyltriphenylphosphonium bromide (15.3 g, 35.7 mmol) at ambient temperature. The reaction mixture was heated at 100 ° C for 14 h and then cooled to ambient temperature. The reaction mixture was filtered, and the obtained filtrate was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 100-200 mesh; 20% EtOAc in petroleum ether) gave the title compound as a white solid (6 g, 67%): mp 146-147 ° C; 1 H NMR (400 MHz, CDCl₃) δ 8.35 (m, 2H), 7.95 (m, 4H), 7.65 (m, 4H), 7.39 (m, 1H), 5.81 (m, 1H), 5.45 (m, 1H); 5.21 (s, 2H); ESIMS m / z 314.13 ([M + H]⁺).

EP-2934142B1PL

Example 63 * not according to the invention: Preparation of (E) -2 - ((4- (4,4,4-Trifluoro-3- (3,4,5-trichlorophenyl) but-1-en-1-yl) naphthalene- 1-yl) methyl) isoindoline-1,3-dione (CI70)

[0503]

<img file="PL2934142T3_D0208.tif" />

To a stirred solution of 2 - ((4-vinylnaphthalen-1-yl) methyl) isoindoline-1,3-dione (1.5 g, 4.79 mmol) in 1,2-dichlorobenzene (15 mL) was added 1 - (1-bromo-2,2,2-trifluoroethyl) -3,4,5-trichlorobenzene (3.2 g, 9.5 mmol), CuCl (24 mg, 0.24 mmol) and 2,2-bipyridyl (0.149 g, 0.95 mmol), and the resulting reaction mixture was degassed with argon for 30 min, then stirred at 180 ° C for 14 h. After the reaction was judged complete by TLC, the reaction mixture was cooled to ambient temperature and filtered, and the filtrate was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 100-200 mesh; 25-30% EtOAc in petroleum ether) gave the title compound as an off-white solid (1.5 g, 56%): mp 158-160 ° C; 1 H NMR (400 MHz, CDCl 3) δ 8.40 (m, 1H), 7.89 (m, 2H), 7.74 (m, 2H), 7.64 (m, 2H), 7.58 (m , 2H), 7.46 (s, 2H), 7.36 (m, 2H), 6.31 (m, 1H), 5.30 (s, 2H), 4.21 (m, 1H); ESIMS m / z 572.08 ([MH]^-).

Example 64 * not according to the invention: Preparation of (E) - (4- (4,4,4-Trifluoro-3- (3,4,5-trichlorophenyl) but-1-en-1-yl) naphthalen-1-yl) methanamine (CI71)

[0505]

<img file="PL2934142T3_D0209.tif" />

To a stirred solution of (E) -2 - ((4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-en-1-yl) naphthalen-1-yl) methyl) isoindoline-1,3-dione (0.4 g, 0.7 mmol) in EtOH was added hydrazine hydrate (0.18 g, 3.5 mmol), and the resulting reaction mixture was heated at 80 ° C for 2 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was dissolved in CH2Cl2, and the solution was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The title compound was isolated as a gummy liquid (150 mg, 50%). The product obtained in this reaction was taken to the next step without further purification.

Example 65 * not according to the invention: Preparation of 2 - ((4-Bromophenyl) amino) isoindoline-1,3-dione (CI72)

[0507]

<img file="PL2934142T3_D0210.tif" />

<img file="PL2934142T3_D0211.tif" />

[0508] To a stirred solution of (4-bromophenyl) hydrazine hydrochloride (0.5 g, 2.2 mmol) in glacial acetic acid (8 mL) was added phthalic anhydride (0.398 g, 2.690 mmol), and the reaction mixture was stirred at 130 ° C for 1 h under nitrogen atmosphere. The reaction mixture was quenched with saturated aqueous NaHCO3 solution and filtered to give a solid.

EP-2934142B1PL

Purification by column chromatography (SiO2, 0-10% EtOAc in petroleum ether) gave the title compound as a solid (60 mg, 84%): mp 205-206 ° C; 1 H NMR (400 MHz, CDCl 3) δ 8.71 (s, 1H),

7.99 (m, 4H), 7.32 (d, J = 8.8 Hz, 2H), 6.79 (d, J = 8.8 Hz, 2H); ESIMS m / z 314.95 ([MH]^-).

Example 66 * not according to the invention: Preparation of 2 - ((4-Vinylphenyl) amino) isoindoline-1,3-dione (CI73)

[0509]

<img file="PL2934142T3_D0212.tif" />

[0510] To a solution of 2- (4-bromophenylamino) isoindoline-1,3-dione (2 g, 6.mmol) in 1,2-dimethoxyethane (20 mL) and H 2 O (4 mL) was added vinylboronic acid anhydride-pyridine complex. (4.57 g, 18.98 mmol) and K2CO3 (1.3 g, 9.5 mmol) followed by Pd (PPh3) 4 (0.219 g, 0.189 mmol). The resulting reaction mixture was heated at 150 ° C in a microwave reactor for 30 min and then concentrated under reduced pressure. Purification by column chromatography (SiO2, 15% EtOAc in petroleum ether) gave the title compound as a solid (200 mg, 13%): mp 174-176 ° C; ¹H NMR (400 MHz, CDCl₃) δ 8.65 (s, 1H), 7.94 (m, 4H), 7.29 (d, J = 8.4 Hz, 2H), 6.72 (d, J = 8.4 Hz, 2H ), 6.61 (m, 1H), 5.61 (d, J = 17.6 Hz, 1H), 5.05 (d, J = 11.2 Hz, 1H); ESIMS m / z 263.18 ([MH]^-).

Example 67 * not according to the invention: Preparation of (E) -2 - ((4- (4,4,4-Trifluoro-3- (3,4,5-trichlorophenyl) but-1-en-1-yl) phenyl) amino) isoindoline-1,3-dione (CI74)

[0511]

<img file="PL2934142T3_D0213.tif" />

[0512] To a stirred solution of 2- (4-vinylphenylamino) isoindoline-1,3-dione (0.3 g, 1.1 mmol) in 1,2-dichlorobenzene (5 mL) was added CuCl (0.022 g, 0.273 mmol), 2 , 2-bipyridyl (0.07 g, 0.46 mmol) and 5- (1-bromo-2,2,2-trifluoroethyl) -1,2,3-trichlorobenzene (0.77 g, 2.27 mmol). The reaction mixture was degassed with argon for 30 min and heated at 180 ° C for 2 h. The reaction mixture was then concentrated under reduced pressure, and the residue was purified by column chromatography (SiO 2, 0-30% EtOAc in petroleum ether) to afford the title compound as a solid (450 mg, 75%): mp 187-189 ° C; 1 H NMR (400 MHz, CDCl₃) δ 8.75 (s, 1H), 7.96 (m, 4H), 7.82 (s, 2H), 7.37 (d, J = 8.8 Hz, 1H), 6.73 (d , J = 8.4 Hz, 2H), 6.61 (m, 2H), 6.58 (m, 1H), 4.59 (m, 1H); ESIMS m / z 523.05 ([MH] -).

Example 68 * not according to the invention: Preparation of (E) - (4- (4,4,4-Trifluoro-3- (3,4,5-trichlorophenyl) but-1-en-1-yl) phenyl) hydrazine (CI75)

[0513]

<img file="PL2934142T3_D0214.tif" />

EP-2934142B1PL

To a mixed solution of (E) -2- (4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-enyl) phenylamino) isoindoline-1,3-dione (0.16 g, 0.31 mmol) in EtOH (5 mL), hydrazine hydrate (0.076 g, 1.52 mmol) was added, and the reaction mixture was heated at 85 ° C for 1 h. The reaction mixture was cooled to ambient temperature and filtered, and the filtrate was concentrated under reduced pressure to provide the title compound as a solid (0.08 g, 66%) which was taken to the next step without further purification.

Example 69 * not according to the invention: Preparation of 2- (4-Vinylphenoxy) isoindoline-1,3-dione (CI76) [0515]

<img file="PL2934142T3_D0215.tif" />

[0516] To a mixed solution of 4-vinylphenylboronic acid (2 g, 13 mmol), 2-hydroxyisoindoline-1,3-dione (3.63 g, 24.53 mmol), and CuCl (1.214 g 12.26 mmol) in 1, 2-Dichloroethane (50 mL) was added pyridine (1.065 g, 13.48 mmol), and the resulting reaction mixture was stirred at ambient temperature for 48 h. The reaction mixture was diluted with H 2 O and extracted with CHCl 3. The combined CHCl3 layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification by flash column chromatography (SiO2; 20% EtOAc in petroleum ether) gave the title compound as a white solid (2 g, 63%): mp 129-131 ° C; 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 2.0 Hz, 2H), 7.82 (d, J = 3.2 Hz, 2H), 7.38 (d, J = 2 .0 Hz, 2H), 7.14 (d, J = 2.0 Hz, 2H), 6.70 (m, 1H), 5.83 (d, J = 16.0 Hz, 1H), 5, 22 (d, J = 10.8 Hz, 1H); ESIMS m / z 266.12 ([M + H] +).

Example 70 * not according to the invention: Preparation of (E) -2- (4- (4,4,4-Trifluoro-3- (3,4,5-trichlorophenyl) but-1-en-1-yl) phenoxy) isoindoline-1 , 3-dione (CI77)

[0517]

<img file="PL2934142T3_D0216.tif" />

1- (1-Bromoethyl) -3 was added to a stirred solution of 2- (4-vinylphenoxy) isoindoline-1,3-dione (0.3 g, 1.1 mmol) in 1,2-dichlorobenzene (10 ml). 4,5-trichlorobenzene (769 mg, 2.26 mmol), CuCl (22 mg, 0.22 mmol), and 2,2-bipyridyl (35 mg, 0.44 mmol), and the resulting reaction mixture was degassed with argon for 30 min and heated to 180 ° C for 24 h. The reaction mixture was cooled to ambient temperature and filtered, and the filtrate was concentrated under reduced pressure. The crude material was purified by column chromatography (SiO2, 100-200 mesh; 20% EtOAc in petroleum ether) to afford the title compound as a solid (0.29 g, 50%): 1H NMR (400 MHz, CDCl3) δ 7.90 (m, 1H), 7.62 (m, 2H), 7.50 (m, 1H), 7.40 (s, 2H), 7.12 (s, 1H), 6.90 (m, 2H) , 6.60 (m, 2H), 6.20 (m, 1H), 4.08 (m, 1H); ESIMS m / z 524.09 ([MH] -).

Example 71 * not according to the invention: Preparation of (E) - O- (4- (4,4,4-Trifluoro-3- (3,4,5-trichlorophenyl) but-1-en-1-yl) phenyl) hydroxylamine (CI78 )

[0519]

EP-2934142B1PL

<img file="PL2934142T3_D0217.tif" />

[0520] To a mixed solution of (E) -2- (4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-enyl) phenoxy) isoindoline-1,3-dione Hydrazine hydrate (0.1 g, 1.9 mmol) in EtOH was added, and the resulting reaction mixture was heated at 90 ° C for 1 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was dissolved in CH2Cl2. washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give the crude title compound as a gummy liquid (0.08 g, 53%): ¹H NMR (400 MHz, CDCl₃) δ 7.40 (s, 2H), 6.98 (s, 1H), 6.82 (s, 2H), 6.48 (m, 1H), 6.20 (m, 1H), 5.02 (s, 1H). 4.08 (m, 1H); ESIMS m / z 394.94 ([MH]^-).

Example 72 * not according to the invention: Preparation of (E) -N- (4- (3- (3,5-Dichlorophenyl) -4,4,4 trifluorobut-1-enyl) benzyl) acetamide (CC1)

[0521]

<img file="PL2934142T3_D0218.tif" />

To a mixed solution of (E) - (2-chloro-4- (3- (3,5-dichlorophenyl) -4,4,4-trifluorobut-1-en-1-yl) phenyl) methanamine (0.3 g , 0.8 mmol) in CH2Cl2 (10 mL) were added acetic anhydride (0.12 mL, 1.14 mmol), and TEA (0.217 mL, 1.52 mmol), and the resulting reaction mixture was stirred at ambient temperature for 6 h. The reaction mixture was diluted with water and extracted with CH2Cl2. The combined CH2Cl2 layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; 30-50% ethyl acetate in hexane) provided the title compound as an off-white solid (0.2 g, 60%) mp 107-109 ° C; 1 H NMR (400 MHz, CDCl₃) δ 7.37 (m, 3H), 7.28 (m, 4H), 6.60 (d, J = 16.0 Hz, 1H), 6.36 (dd, J = 16.0, 8, 0 Hz, 1H), 5.75 (br s, 1H), 4.46 (d, J = 6 Hz, 2H), 4.01 (m, 1H), 2.11 (s, 3H); ESIMS m / z 402.00 ([M + H] +).

Compounds CC2 - CC6 * not according to the invention in Table 1 were prepared according to the procedures disclosed in Example 72. Furthermore, compound DC56 * not according to the invention

[0524] in Table 1, DC55 was made according to the procedures disclosed in Example 72.

Example 73 * not according to the invention: Preparation of (E) - N- (2-Chloro-4- (3- (3,5-dichlorophenyl) -4,4,4-trifluorobut-1-en-1-yl) benzyl) acetamide ( CC7)

[0525]

<img file="PL2934142T3_D0219.tif" />

To a mixed solution of (E) - (2-chloro-4- (3- (3,5-dichlorophenyl) -4,4,4-trifluorobut-1-en-1-yl) phenyl) methanamine (0.3 g , 0.8 mmol) in DMF (5 mL) added 2,2,2-trifluoro-propanoic acid (97 mg, 0.76 mmol), HOBPH2O (174 mg, 1.14 mmol) and EDC-HCl (217 mg , 1.14 mmol) and DIPEA (196 mg, 1.52 mmol), and the resulting reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with H 2 O and extracted with EtOAc. The combined EtOAc layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. Purification by chromatography

EP-2934142B1PL flash column (SiO2, 100-200 mesh; ethyl acetate in hexane (30-50%) provided the title compound as an off-white solid (0.2 g, 60%): mp 127-128 ° C; 1H NMR ( 400 MHz, CDCl3) δ 7.42 (m, 4H),

7.24 (m, 2H), 6.53 (d, J = 16.0 Hz, 1H), 6.36 (dd, J = 16.0, 8.0 Hz, 1H), 5.86 (br s, 1H), 4.51 (d, J = 6.0

Hz, 2H), 4.05 (m, 1H), 2.02 (s, 3H); ESIMS m / z 436.03 ([M + H] +).

Compounds CC8 - CC28 * not according to the invention in Table 1 were prepared according to the procedures disclosed in Example 73.

Example 74 * not according to the invention: Preparation of (E) - N- (Pyridin-2-ylmethyl) -N- (4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-enyl ) -2- (trifluoromethyl) benzyl) cyclopropanecarboxamide (CC29)

[0528]

<img file="PL2934142T3_D0220.tif" />

Step 1: (E) -1- (Pyridin-2-yl) -N- (4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-enyl ) -2 (trifluoromethyl) benzyl) methanamine. (E) - (4- (4,4,4-Trifluoro-3- (3,4,5-trichlorophenyl) but-1-en-1-yl) -2 (trifluoromethyl) phenyl) methanamine (0.46 g , 1 mmol) was dissolved in MEOH (3 mL). Thereto was added pyridine-2-carbaldehyde (0.107 g, 1 mmol). The reaction mixture was stirred for 1 h. After 1 h, NaBH4 (0.076 g, 2 mmol) was added and left at ambient temperature for 3 h. The reaction mixture was concentrated to give an oily residue. Purification by flash column chromatography (SiO2, 100-200 mesh; 30-50% EtOAc in hexane) gave the title compound as a pale yellow liquid (0.22 g, 40%): 1 H NMR (400 MHz, CDCl₃) δ 8.58 (d, J = 4.8 Hz, 1H), 7.74 (m, 1H), 7.62 (m, 2H), 7.52 (m, 1H), 7.4 (s , 2H), 7.3 (m, 1H), 7.2 (m, 2H), 6.60 (d, J = 16.0 Hz, 1H), 6.38 (dd, J = 16.0, 8.0 Hz, 1H), 4.10 (m, 1H), 4.02 (s, 2H), 3.96 (s, 2H); ESIMS m / z 552.95 ([M + H] +); IR (thin layer) 3338, 1114, 808 cm^-1.

Step 2: (E) -N- (Pyridin-2-ylmethyl) -N- (4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-phenyl) - 2- (trifluoromethyl) benzyl) cyclopropanecarboxamide. (E) -1- (Pyridin-2-yl) -N- (4- (4,4,4trifluoro-3- (3,4,5-trichlorophenyl) but-1-en-1-yl) -2- (trifluoromethyl) benzyl) methanamine (0.27 g, 0.05 mmol) was dissolved in CH2Cl2 (3 mL). To this was added TEA (0.14 mL, 0.1 mmol). The reaction mixture was stirred for 10 min. After 10 min, the reaction mixture was cooled to 0 ° C, and cyclopropylcarbonyl chloride (0.08 mL, 0.075 mmol) was added. The reaction mixture was stirred at ambient temperature for 1 h, then washed with H 2 O and sat. aq. NaHCO3 solution. The organic layer was dried over anhydrous Na2SO4 and evaporated to give a pale yellow gummy material (0.15 g, 50%): 1H NMR (400MHz, CDCl₃) δ 8.58 (d, J = 4.6 Hz, 1H), 7.74 (m, 1H), 7.62 (m, 2H), 7.52 (m, 1H), 7.4 (s , 2H), 7.3 (m, 1H), 7.2 (m, 2H), 6.60 (d, J = 16.0 Hz, 1H), 6.38 (dd, J = 16.0, 8.0 Hz, 1H), 5.02 (s, 1H), 4.8 (s, 1H), 4.8 (d, J = 10Hz, 2H), 4.10 (m, 1H), 1 . 8 (m, 1H), 1.2 (m, 2H), 0.6 (m, 2H); ESIMS m / z 620.86 ([MH]); IR (thin layer) 1645, 1115, 808 cm^-1.

Example 75 * not according to the invention: Preparation of (E) -N- (2-Chloro-4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-en-1-yl) benzyl ) -3- (methylsulfonyl) propanamide (CC30) [0531]

EP-2934142B1PL

<img file="PL2934142T3_D0221.tif" />

[0532] (E) -N- (2-Chloro-4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-en-1-yl) benzyl) -3 - (Methylthio) propanamide (0.15 g, 0.28 mmol) was treated with Oxone reagent (0.175 g, 0.569 mmol) in 1: 1 acetone: water (20 ml) for 4 h at ambient temperature. The acetone was evaporated to give a white solid (0.095 g, 60%): mp 101-104 ° C;¹H NMR (400 MHz, CDCl₃) δ 7.41 (m, 4H), 7.24 (m, 1H), 6.53 (d, J = 16.0 Hz, 1H), 6.35 (dd, J = 16.0, 8, 0Hz, 1H), 6.12 (br s, 1H), 4.53 (m, 2H), 4.10 (m, 1H), 3.42 (m, 2H), 2.91 (s, 3H ). 2.78 (m, 2H); ESIMS m / z 559.75 ([MH]^-).

Example 76 * not according to the invention: Preparation of (E-1- (2-Chloro-4- (3- (3,5-dichlorophenyl) -4,4,4-trifluorobut-1-en-1-yl) benzyl) -3- ethyl urea (CC31)

[0533]

<img file="PL2934142T3_D0222.tif" />

To a mixed solution of (E) - (2-chloro-4- (3- (3,5-dichlorophenyl) -4,4,4-trifluorobut-1-en-1-yl) phenyl) methanamine (0.2 g , 0.5 mmol) in CH2Cl2 (5 mL) at 0 ° C, TEA (0.141 mL, 1 mmol) and ethyl isocyanate (0.053 g, 0.75 mmol) were added, and the reaction mixture was stirred for 1 h at 0 ° C. . The reaction mixture was diluted with CH2Cl2. The organic layer was washed with H 2 O and brine, dried over Na 2 SO 4, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 30-50% EtOAc in hexanes) provided the title compound as a solid (0.141 g, 60%): mp 177-178 ° C; 1 H NMR (400 MHz, CDCl₃) δ 7.58 (m, 2H), 7.41 (m, 3H), 7.24 (m, 1H), 6.53 (d, J = 16.0 Hz, 1H), 6.35 (dd , J = 16.0, 8.0 Hz, 1H), 4.70 (br s, 1H), 4.43 (s, 2H), 4.08 (m, 1H), 3.21 (m, 2H ). 1.25 (m, 3H); ESIMS m / z 463 ([MH] -).

Compounds CC32 - CC35 * not according to the invention in Table 1 were prepared according to the procedures disclosed in Example 76.

Example 77 * not according to the invention: Preparation of (E) -3- (2-Chloro-4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-en-1-yl) benzyl ) -1,1-dimethylurea (CC36)

[0536]

<img file="PL2934142T3_D0223.tif" />

To a mixed solution of (E) - (2-chloro-4- (3- (3,4,5-trichlorophenyl) -4,4,4-trifluorobut-1-en-1-yl) phenyl) methanamine ( 0.2 g, 0.5 mmol) in CH2Cl2 (5 mL) at 0 ° C were added TEA (0.141 mL, 1 mmol) and N, N-dimethylcarbamoyl chloride (0.08 g, 0.075 mmol), and the reaction mixture stirred for 1 h at 0 ° C. The reaction mixture was diluted with CH2Cl2. The organic layer was washed with H 2 O and brine, dried over Na 2 SO 4, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 30-50% EtOAc in hexanes) provided the title compound as a solid (0.15 g, 60%): 1H NMR (400 MHz, CDCl₃) δ 7.39 (m, 4H), 7.28 (m, 1H), 6.54 (d, J =

EP-2934142B1PL

16.0 Hz, 1H), 6.34 (dd, J = 16.0, 8.0 Hz, 1H), 4.97 (br s, 1H), 4.38 (d, J = 6.0 Hz , 2H), 4.10 (m, 1H), 2.9 (s, 3H), 2.7 (s, 3H); ESIMS m / z497 ([MH]^-); IR (thin layer) 3350, 1705, 1114, 808 cm^-1.

Example 78 * not according to the invention: Preparation of (E) -1- (2-Chloro-4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-en-1-yl) benzyl ) -3-ethylthiourea (CC37)

[0538]

<img file="PL2934142T3_D0224.tif" />

To a mixed solution of (E) - (2-chloro-4- (3- (3,4,5-trichlorophenyl) -4,4,4-trifluorobut-1-en-1-yl) phenyl) methanamine ( 0.2 g, 0.5 mmol) in CH2Cl2 (5 ml) at 0 ° C were added TEA (0.141 ml, 1 mmol) and ethyl isothiocyanate (0.053 g, 0.75 mmol), and the reaction mixture was stirred for 1 h at at 0 ° C. The reaction mixture was diluted with CH2Cl2. The organic layer was washed with H 2 O and brine, dried over Na 2 SO 4, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 30-50% EtOAc in hexanes) provided the title compound as a solid (0.14 g, 60%): mp 88-91 ° C; 1 H NMR (400 MHz, CDCl₃) δ 7.49 (d, J = 8 Hz, 1H), 7.41 (d, J = 7.2 Hz, 2H), 7.26 (m, 2H), 6.50 (d, J = 16 Hz, 1H), 6.35 (dd, J = 16.0, 8.0 Hz, 1H), 6.0 (br s, 1H), 5.73 (br s, 1H), 4.80 (br s, 2H), 4.09 (m, 1H), 1.23 (m, 3H); ESIMS m / z 515.01 ([M + H] +).

Compound CC38 * not of the invention in Table 1 was prepared according to the procedures disclosed in Example 78.

Example 79 * not according to the invention: Preparation of (E) - (2-Chloro-4- (3- (3,5-dichlorophenyl) -4,4,4-trifluorobut-1-en-1-yl) benzyl) -3-ethyl urea tert-butyl (CC39)

[0541]

<img file="PL2934142T3_D0225.tif" />

To a mixed solution of (E) - (2-chloro-4- (3- (3,4,5-trichlorophenyl) -4,4,4-trifluorobut-1-en-1-yl) phenyl) methanamine ( 0.2 g, 0.5 mmol in CH2Cl2 (5 mL) at 0 ° C were added TEA (0.141 mL, 1 mmol) and di-tert-butyl dicarbonate (0.163 mL, 0.75 mmol), and the reaction was stirred. for 4 h at ambient temperature The reaction mixture was diluted with CH2Cl2 The organic layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 10-20% EtOAc in hexane) provided the title compound as a white solid (0.147 g, 60%): 1H NMR (400 MHz, CDCl₃) δ 7.39 (m, 4H), 7.28 (m, 1H), 6.54 (d, J = 16.0 Hz, 1H), 6.34 (dd, J = 16.0, 8, 0 Hz, 1H), 4.97 (br s, 1H), 4.38 (d, J = 6.0 Hz, 2H), 4.10 (m, 1H), 1.53 (s, 9H); ESIMS m / z 526.09 ([MH] -); IR (thin layer) 3350, 1705, 1114, 808 cm-1.

[0543] Compound CC40 * not of the invention in Table 1 was prepared according to the procedures disclosed in Example 79.

Example 80 * not according to the invention: Preparation of (E) -2 - ((2-Chloro-4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-en-1-yl) benzyl) amino) methyl -2-oxoacetate (CC41)

[0544]

EP-2934142B1PL

<img file="PL2934142T3_D0226.tif" />

To a mixed solution of (E) - (2-chloro-4- (3- (3,4,5-trichlorophenyl) -4,4,4-trifluorobut-1-en-1-yl) phenyl) methanamine ( 0.2 g, 0.5 mmol) in CH2Cl2 (5 ml) at 0 ° C were added TEA (0.141 ml, 1 mmol) and methyl 2-chloro-2-oxoacetate (0.09 g, 0.75 mmol) , and the reaction mixture was stirred for 1 h at 0 ° C. The reaction mixture was diluted with CH2Cl2. The organic layer was washed with H 2 O and brine, dried over Na 2 SO 4, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 20% EtOAc in hexanes) provided the title compound as a solid (0.12 g, 50%): 1H NMR (400 MHz, CDCl₃) δ 7.48 (m, 1H). 7.43 (m, 3H), 7.38 (m, 1H), 7.23 (s, 1H), 6.55 (d, J = 16.0Hz, 1H), 6.36 (dd, J = 16.0, 8.0 Hz, 1H), 4.60 (d, J = 4.4 Hz, 2H), 4.18 (m, 1H), 3.85 (s, 3H); ESIMS m / z 512.22 ([MH]^-); IR (thin layer) 1740, 1701, 1114, 808 cm^-1.

Example 81 * not according to the invention: Preparation of (E) -N¹ - (2-Chloro-4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-en-1-yl) benzyl) -N²- (2,2,2-trifluoroethyl) oxalamide (CC42)

[0546]

<img file="PL2934142T3_D0227.tif" />

[0547] To a stirred solution of 2,2,2-trifluoroethylamine hydrochloride (0.1 g, 0.77 mmol) in CH2Cl2 (10 mL) was added trimethylaluminum (2 M toluene solution; 0.39 mL, 0.77 mmol) dropwise. ), and the reaction mixture was stirred at 25 ° C for 30 min. Solution of (E) -2 - ((2-chloro-4- (4,4,4-trifluoro-3 (3,4,5-trichlorophenyl) but-1-en-1-yl) benzyl) -2-oxoacetate methyl (0.2 g, 0.38 mmol) in CH 2 Cl 2 (5 mL) was added dropwise to the reaction mixture at 25 ° C. The reaction mixture was stirred at reflux for 18 h, cooled to 25 ° C, quenched with 0.5 N HCl solution (50 ml) and extracted with EtOAc (2 x 50 ml). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude compound was purified by flash chromatography (SiO2, 100-200 mesh; 20% -40% EtOAc in n-hexane) to afford the title compound (0.13 g, 60%): mp 161-163 ° C; 1H NMR (400MHz, DMSO-d₆) δ 9.45 (br s, 2H), 7.90 (s, 2H), 7.75 (s, 1H), 7.46 (s, 1H), 7.28 (s, 1H), 6, 93 (m, 1H), 6.75 (m, 1H), 4.80 (m, 1H), 4.40 (s, 2H), 3.90 (s, 2H); ESIMS m / z 578.96 ([MH]^-).

Example 82 * not according to the invention: Preparation of (E) -N- (2-Chloro-4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-en-1-yl) benzyl ) pyridin-2-amine (CC43)

[0548]

<img file="PL2934142T3_D0228.tif" />

5- (1-Bromo) was added to a stirred solution of N- (2-chloro-4-vinylbenzyl) pyridin-2-amine (0.3 g, 1.22 mmol) in 1,2-dichlorobenzene (5 ml). -2,2,2-trifluoroethyl) -1,2,3-trichlorobenzene (0.83 g, 2.44 mmol), CuCl (24 mg, 0.24 mmol) and 2,2-bipyridyl (76 mg, 0 , 48 mmol). The resulting reaction mixture was degassed with argon for 30 min, then stirred at 180 ° C for 24 h. After

After judging the reaction complete by TLC, the reaction mixture was cooled to ambient temperature and filtered, and the filtrate was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 100-200 mesh; 15% EtOAc in n-hexane) provided the title compound as an off-white solid (0.2 g, 35%): mp 140-142 ° C; 1 H NMR (400 MHz, CDCl₃) δ 8.11 (d, J = 4.0 Hz, 1H), 7.40 (m, 5H), 7.22 (m, 1H), 6.61 (m, 2H), 6.35 (m , 2H), 4.94 (br s, 1H), 4.61 (d, J = 6.4 Hz, 2H), 4.11 (m, 1H); ESIMS m / z 505.39 ([M + H] +).

Example 83 * not according to the invention: Preparation of (E) -N - ((3-Chloro-5- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) -but-1-en-1-yl) ) pyridin-2-yl) methyl) -3,3,3-trifluoropropanamide (CC44) cf₃

Ύ ί Ί T ^H.

AJ Ί Ά a

C1 ^ 0 γχτ₃

Custom duty

To a mixed solution of (E) - (3-chloro-5- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-en-1-yl) pyridin-2 -yl) methanamine (0.1 g, 0.2 mmol) in CH2Cl2 (5 mL) added 3,3,3-trifluoropropanoic acid (45 mg, 0.350 mmol), EDC^.HCl (67 mg, 0.350 mmol), HOBt^.H 2 O (71 mg, 0.467 mmol) and DIPEA (60.2 mg, 0.467 mmol), and the reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with CH 2 Cl 2 and washed with water. The combined CH2Cl2 layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; 15% EtOAc in petroleum ether) gave the title compound as a pale yellow liquid (30 mg, 35%): 1H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H ), 7.77 (s, 1H), 7.47 (br s, 1H), 7.40 (s, 2H), 6.58 (d, J = 16.0Hz, 1H), 6.45 ( dd, J = 16.0, 8.0 Hz, 1H), 4.68 (d, J = 4.0 Hz, 2H), 4.14 (m, 1H), 3.24 (q, J = 10 , 8 Hz, 2H); ESIMS m / z 536.88 ([MH]^-); IR (thin layer) 3320, 1674, 1114, 808.

[0552] The non-inventive compound * in Table 1 was prepared according to the procedures disclosed in Example 83.

Example 84 * not according to the invention: Preparation of (E) -3,3,3-Trifluoro-N- ((4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-en- 1-yl) naphthalen-1-yl) methyl) propanamide (CC46)

[0553]

CF₃C1.A 'Λ

Cl

To a stirred solution of (E) - (4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-en-1-yl) naphthalen-1-yl) methanamine (0 , 1 g, 0.22 mmol) in CH2Cl2 (8 mL) added 3,3,3-trifluoropropanoic acid (0.032 g, 0.24 mmol), HOBt^.H 2 O (52 mg, 0.33 mmol), EDC^.HCl (0.065 g, 0.33 mmol) and DIPEA (0.044 g, 0.45 mmol), and the resulting reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with water and extracted with EtOAc (3 x 30 mL). The combined EtOAc layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. Purification by flash column chromatography (SiO2 100-200 mesh; 15% EtOAc in n-hexane) provided the title compound as a gummy material (60 mg, 50%): mp 151-153 ° C; 1 H NMR (400 MHz, CDCl 3) δ 8.06 (m, 1H), 7.61 (m, 4H), 7.48 (s, 2H), 7.44 (d, J = 8.0 Hz, 1H ), 7.38 (m, 1H), 6.42 (m, 1H), 5.92 (br s, 1H), 4.92 (m, 2H), 4.24 (m, 1H), 3. 12 (m, 2H); ESIMS m / z 554.04 ([MH] -).

<img file="PL2934142T3_D0229.tif" />

EP-2934142B1PL

[0555] Compounds CC47-CC48 * not according to the invention in Table 1 were prepared according to the procedures disclosed in Example 84.

Example 85 * not according to the invention: Preparation of (E) -1-ethyl-3 - ((4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-en-1-yl) naphthalen-1-yl) methyl) urea (CC49)

[0556]

CF.

<img file="PL2934142T3_D0230.tif" />

To a stirred solution of (E) - (4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-en-1-yl) naphthalen-1-yl) methanamine (0 , 1 g, 0.22 mmol) in CH2Cl2 at 0 ° C were added TEA (0.064 mL, 0.44 mmol) and ethyl isocyanate (0.023 mL, 0.33 mmol), and the reaction mixture was stirred for 1 h at 0 ° C. C. The reaction mixture was diluted with CH2Cl2. The organic layer was washed with H 2 O and brine, dried over Na 2 SO 4, and concentrated under reduced pressure. Purification by column chromatography (SiO2 100-200 mesh; 30% EtOAc in hexanes) provided the title compound as a solid (0.07 g, 60%): mp 84-87 ° C; 1 H NMR (400 MHz, CDCl₃) δ 8.06 (m, 1H), 7.98 (m, 1H), 7.61 (m, 3H), 7.48 (s, 2H), 7.44 (d, J = 8.0Hz , 1H), 7.38 (m, 2H), 6.42 (m, 1H), 4.92 (s, 2H), 4.6 (br s, 1H), 4.24 (m, 1H), 3.21 (m, 2H), 1.2 (t, J = 4.6 Hz, 3H); ESIMS m / z 515.33 ([M + H] +).

Example 86 * not according to the invention: Preparation of (E) -N- (4- (4,4,4-Trifluoro-3- (3,4,5-trichlorophenyl) but-1-en-1-yl) phenyl) cyclopropanecarbohydrazide (CC50)

[0558]

<img file="PL2934142T3_D0231.tif" />

To a mixed solution of (E) - (4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-en-1-yl) phenyl) hydrazine (0.1 g, 0.3 mmol) in CH2Cl2 (10 mL) added DIPEA (65 mg, 0.51 mmol), HOBt.H2O (59 mg, 0.38 mmol), EDC^.HCl (73 mg, 0.38 mmol) and cyclopropanecarbonyl chloride (0.024 g, 0.28 mmol), and the reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was diluted with saturated aqueous NaHCO3 and extracted with CH2Cl2. The combined CH2Cl2 layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2; 5-25% EtOAc in petroleum ether) gave the title compound as a solid (65 mg, 55%): mp 138-140 ° C; 1 H NMR (400 MHz, CDCl 3) δ 9.81 (s, 1H), 7.90 (s, 1H), 7.84 (s, 2H), 7.34 (d, J = 8.4 Hz, 2H ), 6.65 (d, J = 15.6 Hz, 1H), 6.61 (m, 1H), 6.57 (s, 1H), 6.48 (dd, J = 15.6.8, 8 Hz, 1H), 4.74 (m, 1H), 1.64 (m, 1H), 0.75 (m, 4H); ESIMS m / z 461.32 ([MH]^-).

Compound CC51 * not of the invention in Table 1 was prepared according to the procedures disclosed in Example 86.

Example 87 * not according to the invention: Preparation of (E) - N- (4- (4,4,4-Trifluoro-3- (3,4,5-trichlorophenyl) but-1-en-1-yl) phenoxy) cyclopropanecarboxamide (CC52 )

[0561]

EP-2934142B1PL

<img file="PL2934142T3_D0232.tif" />

[0562] To a stirred solution of (E) - O - (4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-en-1-yl) phenyl) hydroxylamine (0 , 15 g, 0.38 mmol) in CH2Cl2 (5 mL) were added EDC.HCl (0.109 g, 0.569 mmol), HOBt.H2O (0.087 g, 0.569 mmol), DIPEA (0.097 g, 0.758 mmol) and cyclopropanecarboxylic acid ( 0.049 g, 0.569 mmol). The resulting reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with H 2 O and extracted with CHCl 3 (35 mL). The combined CHCl3 layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification by flash column chromatography (SiO2; 20% EtOAc in hexanes) provided the title compound as a brown liquid (0.06 g, 34%): 1 H NMR (400 MHz, CDCl₃) δ 7.40 (s, 2H), 7.18 (s, 1H), 7.08 (s, 1H), 6.85 (m, 1H), 6.45 (m, 1H), 6.65 (m, 1H), 6.20 (m, 1H), 5.55 (s, 1H), 4.08 (m, 1H), 1.90 (m, 1H), 1.30 1.10 (m , 4H); ESIMS m / z 464.87 ([MH] -).

Compound CC53 * not of the invention in Table 1 was prepared according to the procedures disclosed in Example 87.

Example 88 * not according to the invention: Preparation of (Z) -3,3,3-Trifluoro-N- (4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-en-1) -yl) benzyl) propanamide (CC54)

[0564]

<img file="PL2934142T3_D0233.tif" />

[0565] A borosilicate glass vial was filled with (E) -3,3,3-trifluoro-N- (4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-ene. -1-yl) benzyl) propanamide (133 mg, 0.269 mmol) and dimethylsulfoxide (DMSO; 10 mL). The mixture was placed 0.6 to 1 meter (m) from a set of eight 115 watt Sylvania FR48T12 / 350BL / VHO / 180 Fluorescent Tube Black Lights and four 115 watt Sylvania (daylight) F48T12 / D / VHO Straight T12 Fluorescent Tube Lights on 72 h. The mixture was concentrated under reduced pressure and purified by reverse phase chromatography to provide the title compound as a colorless oil (11mg, 8%): ¹H NMR (300 MHz, CDCl3) δ 7.28 (s, 2H), 7.25 (m, 2H), 7.10 (d, J = 8.0 Hz, 2H), 6.89 (d, J = 11.4 Hz, 1H), 6.07 (br s, 1H), 6.01 (m, 1H), 4.51 (d, J = 5.8 Hz, 2H), 4.34 (m, 1H), 3.12 (q, J = 7.5 Hz, 2H); 13 C NMR (101 MHz, CDCl₃) δ 162.44, 137.20, 135.38, 135.23, 134.82, 134.68, 131.71, 129.00, 128.80, 128.69, 128.10, 127.96, 122.63, 76.70, 47.33 (q, J = 28 Hz), 43.59, 42.12 (q, J = 30 Hz); ESIMS m / z 504 ([M + H] +).

[0566] Compounds DC46, AC93. The AC94 * not according to the invention in Table 1 was prepared according to the procedures disclosed in Example 88.

Example 89 * not according to the invention: Preparation of 1- (1-Bromo-2,2,2-trifluoroethyl) -3-chlorobenzene (DI2)

[0567]

<img file="PL2934142T3_D0234.tif" />

EP-2934142B1PL

[0568] The title compound was synthesized in two steps by 1- (3-chlorophenyl) -2,2,2-trifluoroethanol (DI1, prepared as in step 1, Method B in Example 1); isolated as a colorless viscous oil (1.5 g,

75%): ¹H NMR (400 MHz, CDCl₃) δ 7.50 (s, 1H), 7.42-7.35 (m, 3H), 5.02 (m, 1H), 2.65 (br s, 1H)) and Step in Example 1 and isolated (0.14 g, 22%): 1 H NMR (400 MHz, CDCl₃) δ 7.50 (br s, 1H), 7.42-7.35 (m,

3H), 5.07 (m, 1H).

[0569] The following compounds * not according to the invention were prepared according to the procedures disclosed in

Example 89. (1-Bromo-2,2,2-trifluoroethyl) benzene (DI4) [0570]

<img file="PL2934142T3_D0235.tif" />

2,2,2-Trifluoro-1-phenylethanol (DI 3) was isolated (10 g, 80%): 1H NMR (300 MHz, CDCl₃) δ 7.48 (m, 2H), 7.40 (m, 3H), 5.02 (m, 1H), 2.65 (d, J = 7.1 Hz, 1H). The title compound (DI4) was isolated as a liquid (8.0 g, 60%): 1 H NMR (400 MHz, CDCl₃) δ 7.50 (m, 2H), 7.40 (m, 3H), 5.00 (q, J = 7.5 Hz, 1H).

1- (1-Bromo-2,2,2-trifluoroethyl) -3,5-dimethylbenzene (DI2O)

[0572]

<img file="PL2934142T3_D0236.tif" />

1- (3,5-Dimethylphenyl) -2,2,2-trifluoroethanol (DI19) isolated as an off-white solid: 1H NMR (400MHz, CDCl₃) δ 7.05 (s, 2H), 7.02 (s, 1H), 4.95 (m, 1H), 2.32 (s, 6H); ESIMS mlz 204 ([M]^-). The title compound (DI2O) was isolated (3.0 g, 51%).

1- (1-Bromo-2,2,2-trifluoroethyl) -2,4-dichlorobenzene (DI22)

[0574]

<img file="PL2934142T3_D0237.tif" />

1- (2,4-Dichlorophenyl) -2,2,2-trifluoroethanol (DI21) is isolated as an off-white powder (5.3 g, 61%): mp 49-51 ° C; 1 H NMR (400 MHz, CDCl₃) δ 7.62-7.66 (d, 1H), 7.42-7.44 (d, 1H), 7.32-7.36 (d, 1H), 5.6 (m, 1H), 2.7 (s. 1H); ESIMS m / z 244 ([M] +). The title compound (DI22) was isolated (3.2 g, 50%): 1 H NMR (400 MHz, CDCl₃) δ 7.62-7.72 (m, 1H), 7.4-7.42 (m, 1H), 7.3-7.38 (m, 1H), 5.7-5.8 (m , 1H).

1- (1-Bromo-2,2,2-trifluoroethyl) -2,3-dichlorobenzene (DI24)

[0576]

<img file="PL2934142T3_D0238.tif" />

1- (2,3-Dichlorophenyl) -2,2,2-trifluoroethanol (DI23) was isolated as a pale yellow oil (5.2 g, 60%): 1H NMR (400MHz, CDCl₃) δ 7.62-7.64 (d, 1H), 7.52-7.54 (m, 1H), 7.29-7.33 (t, 1H), 5.6-5.76 (m , 1H), 2.7

100

EP-2934142B1PL (s, 1H); ESIMS m / z 243.9 ([M]⁺). The title compound (DI24) was isolated as an oil (8.7 g, 60%):¹H NMR (400 MHz, CDCl₃) δ 7.62-7.71 (m, 1H), 7.44-7.52 (m, 1H), 7.27-7.3 (s, 1H), 5.81-5.91 (m , 1H).

2- (1-Bromo-2,2,2-trifluoroethyl) -1,4-dichlorobenzene (DI26)

[0578]

<img file="PL2934142T3_D0239.tif" />

1- (2,5-Dichlorophenyl) -2,2,2-trifluoroethanol (DI 25) isolated as a yellow oil (4.1 g, 60%): 1H NMR (400MHz, CDCl₃) δ 7.68-7.7 (s, 1H), 7.3-7.37 (m, 2H), 5.51-5.6 (m, 1H), 2.7 (s, 1H); ESIMS mlz 244 ([M] +)). The title compound (DI26) was isolated (3.0 g, 60%): 1 H NMR (400 MHz, CDCl₃) δ 7.7-7.78 (m, 1H), 7.3-7.4 (m, 2H), 5.7-5.8 (m, 1H).

1- (1-Bromo-2,2,2-trifluoroethyl) -3,5-bis (trifluoromethyl) benzene (DI28) [0580]^F.3cf

[i] ii cf₃cf.

DI27 'DI28

1- (3,5-Bis (trifluoromethyl) phenyl) -2,2,2-trifluoroethanol (DI27) isolated (3.8 g, 60%): 1H NMR (400MHz, CDCl₃) δ 7.98 (m, 3H), 5.25 (m, 1H), 3.2 (br, 1H); ESIMS mlz 312.2 ([M] +). The title compound (DI28) was prepared and used as crude material.

1- (1-Bromo-2,2,2-trifluoroethyl) -2,3,5-trichlorobenzene (DI30)

[0582] cf₃^C.'Yl ⁰¹¹*

Y ^ ciY ^ ci

Clci

DI29DI30

2,2,2-Trifluoro-1- (2,3,5-trichlorophenyl) ethanol (DI29) was isolated as a white solid (4.0 g, 60%): mp 113-115 ° C; 1 H NMR (400 MHz, CDCl₃) δ 7.62 (d, 1H), 7.50 (d, 1H), 5.60-5.70 (m, 1H), 2.75 (s, 1H); ESIMS m / z 278.0 ([M +]). The title compound (DI30) was isolated (2.9 g, 60%): 1 H NMR (400 MHz, CDCl₃) δ 7.70 (d, 1H), 7.50 (d, 1H), 5.72-5.82 (m, 1H).

1- (1-Bromo-2,2,2-trifluoroethyl) -3-chloro-5- (trifluoromethyl) benzene (DI32)

[0584]

<img file="PL2934142T3_D0240.tif" />

1- (3-Chloro-5- (trifluoromethyl) phenyl) -2,2,2-trifluoroethanol (DI31) isolated as a pale yellow oil (2.0g, 50%): 1H NMR (400MHz, CDCl₃) δ 7.51 (m, 3H), 5.08 (m, 1H), 2.81 (s, 1H); ESIMS m / z 278.1 ([M]⁺). The title compound (DI32) isolated an oil (2.0 g, 40%): ESIMS mlz 342 ([M]⁺).

5- (1-Bromo-2,2,2-trifluoroethyl) -1,3-dichloro-2-methoxybenzene (DI34)

101

EP-2934142B1PL

[0586]

<img file="PL2934142T3_D0241.tif" />

1- (3,5-Dichloro-4-methoxyphenyl) -2,2,2-trifluoroethanol (DI33) is isolated as an off-white solid (0.8 g, 60%); mp 92-95 ° C: 1 H NMR (400 MHz, CDCl₃) δ 7.41 (s, 2H), 5.00 (m, 1H), 3.89 (s, 3H), 2.64 (m, 1H); ESIMS m / z 274 ([M]⁺). The title compound (DI34) was isolated as a colorless liquid (0.6 g, 57%).

Example 90 * not according to the invention: Preparation of 1- (1-Bromo-2,2,2-trifluoroethyl) -3,5-difluorobenzene (DI36) [0588]

<img file="PL2934142T3_D0242.tif" />

[0589] The title compound was synthesized in two steps by 1- (3,5-difluorophenyl) -2,2,2-trifluoroethanol (DI35, prepared as in step 1, Method A in Example 1; isolated as a colorless oil (0.2 g, 75%): 1 H NMR (400 MHz, CDCl₃) δ 7.05 (m, 2H), 6.88 (m, 1H), 5.06 (m, 1H), 2.66 (s, 1H); ESIMS m / z 212 ([M] +) and Step 2 in Example 1 and isolated (3.2 g, 50%); 1 H NMR (400 MHz, CDCl₃) δ 7.05 (m, 2H), 6.86 (m, 1H), 5.03 (q, J = 7.4 Hz, 1H).

[0590] The following compounds * not according to the invention were prepared according to the procedures disclosed in Example 90.

1- (1-Bromo-2,2,2-trifluoroethyl) -4-chlorobenzene (DI38)

[0591]

<img file="PL2934142T3_D0243.tif" />

1- (4-Chlorophenyl) -2,2,2-trifluoroethanol (DI37) isolated as a colorless oil (5.0 g, 99%): 1H NMR (400MHz, CDCl₃) δ 7.44-7.38 (m, 4H), 5.05 (m, 1H), 2.55 (s, 1H); ESIMS mlz 210 ([M] +). The title compound (DI38) was isolated (3.0 g, 46%): 1 H NMR (400 MHz, CDCl₃) δ 7.45 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 8.2 Hz, 2H), 5.10 (q, J = 7.2 Hz, 1H).

1- (1-Bromo-2,2,2-trifluoroethyl) -4-methoxybenzene (DI40)

[0593]

<img file="PL2934142T3_D0244.tif" />

2,2,2-Trifluoro-1- (4-methoxyphenyl) ethanol (DI39) was isolated as a pale yellow liquid: ¹H NMR (400 MHz, CDCl₃) δ 7.41 (d, J = 8.8 Hz, 2H), 6.95 (m, J = 8.8 Hz, 2H), 5.00 (m, 1H), 3.82 (s, 3H ), 2.44 (s. 1H); ESIMS m / z 206.1 ([M] +). The title compound (DI40) was isolated (3.8 g, 62%).

102

EP-2934142B1PL

1- (1-Bromo-2,2,2-trifluoroethyl) -4-fluorobenzene (DI42) [0595]

<img file="PL2934142T3_D0245.tif" />

2,2,2-Trifluoro-1- (4-fluorophenyl) ethanol (DI41) was isolated as a colorless oil (5 g, 99%): ¹H NMR (400 MHz, CDCl₃) δ 7.48-7.45 (m, 2H), 7.13-7.07 (m, 2H), 5.06 (m, 1H), 2.53 (s, 1H); ESIMS m / z 194 ([M] +). The title compound (DI42) was prepared and transferred as crude intermediate.

1- (1-Bromo-2,2,2-trifluoroethyl) -4-methylbenzene (DI44)

[0597]

<img file="PL2934142T3_D0246.tif" />

2,2,2-Trifluoro-1- (p-tolyl) ethanol (DI43) is isolated as a colorless oil (5.0 g, 99%): ¹H NMR (400 MHz, CDCl₃) δ 7.37 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 5.02 (m, 1H), 2.46 (m, 1H ). 2.37 (s. 3H); ESIMS m / z 190 ([M] +). The title compound (DI44) was isolated (3.0 g, 45%).

1- (1-Bromo-2,2,2-trifluoroethyl) -3-fluorobenzene (DI46)

[0599]

<img file="PL2934142T3_D0247.tif" />

[0600] 2,2,2-Trifluoro-1- (3-fluorophenyl) ethanol (DI45) was isolated as a colorless viscous oil (2.8 g, 93%): 1 H NMR (400 MHz, CDCl₃) δ 7.41 (m, 1H), 7.25 (m, 2H), 7.14 (m, 1H), 5.06 (m, 1H), 2.60 (s, 1H); ESIMS m / z 194 ([M]⁺). The title compound (DI46) was isolated (2.0 g, 61%).

1- (1-Bromo-2,2,2-trifluoroethyl) -2-fluorobenzene (DI48)

[0601]

<img file="PL2934142T3_D0248.tif" />

2,2,2-Trifluoro-1- (2-fluorophenyl) ethanol (DI47) was isolated as a colorless oil (2.5 g, 99%): ¹H NMR (400 MHz, CDCl₃) δ 7.40 (m, 1H), 7.43 (m, 1H), 7.24 (m, 1H), 7.13 (m, 1H), 5.42 (m, 1H), 2.65 (s. 1H); ESIMS mlz 194 ([M] +). The title compound (DI48) was isolated (2.0 g, 61%): 1 H NMR (400 MHz, CDCl₃) δ 7.61 (m, 1H), 7.40 (m, 1H), 7.23 (m, 1H), 7.10 (m, 1H), 5.40 (m, 1H); GCMS m / z 255 ([MH]^-).

Example 91 * not according to the invention: Preparation of 4- (1H-1,2,4-triazol-1-yl) benzaldehyde (DI5) [0603]

103

EP-2934142B1PL

<img file="PL2934142T3_D0249.tif" />

To a stirred solution of 4-fluorobenzaldehyde (10.0 g, 80.6 mmol) in DMF (150 ml) was added K2CO3 (13.3 g, 96.7 mmol) and 1,2,4-triazole (6, 67 g, 96.7 mmol) and the resulting reaction mixture was stirred at 120 ° C for 6 h. After completion of the reaction (by TLC), the reaction mixture was diluted with H 2 O and extracted with EtOAc (3 x 100 mL). The combined EtOAc layers were washed with H 2 O and brine, dried over Na 2 SO 4, and concentrated in vacuo to provide the title compound as a solid (9.0 g, 65%): mp 145-149 ° C: ¹H NMR (400 MHz, CDCl₃) δ 10.08 (s, 1H), 8.70 (s, 1H), 8.16 (s, 1H), 8.06 (d, J = 8.0 Hz, 2H), 7.92 (d , J = 8.0 Hz, 2H); ESIMS m / z 173.9 ([M + H] +).

[0605] The following compound * not according to the invention was prepared according to the procedures disclosed in Example 91.

5-Formyl-2- (1H-1,2,4-triazol-1-yl) benzonitrile (DI49)

[0606]

<img file="PL2934142T3_D0250.tif" />

[0607] The title compound was isolated (2.8 g, 60%); 1 H NMR (400 MHz, CDCl₃) δ 10.10 (s, 1H), 8.98 (s, 1H), 8.35 (s, 1H), 8.30 (d, 1H), 8.22 (s, 1H), 8.07 (d, 1H); IR (thin layer) 3433, 3120, 1702, 1599, 1510 cm^-1.

2-Chloro-4- (1H-1,2,4-triazol-1-yl) benzaldehyde (DI50) [0608]

<img file="PL2934142T3_D0251.tif" />

[0609] The title compound was isolated as an off-white solid (3.0 g, 40%): mp 149-151 ° C; 1 H NMR (400 MHz, CDCl₃) δ 10.05 (s, 1H), 8.74 (s, 1H), 8.17 (s, 1H), 8.10 (s, 1H), 7.90 (m, 2H); ESIMS m / z 208.10 ([M + H]⁺).

5-Methyl-4- (1H-1,2,4-triazol-1-yl) benzaldehyde (DI51)

[0610]

<img file="PL2934142T3_D0252.tif" />

[0611] The title compound was isolated as a white solid (0.5 g, 74%): mp 109-111 ° C; 1H NMR (400MHz, D6-DMSO) δ 10.06 (s, 1H), 9.00 (s, 1H), 8.30 (s, 1H), 7.99 (s, 1H), 7.92 (d, J = 9.2 Hz, 1H), 7.69 (d, J = 9.2 Hz, 1H), 2.30 (s, 3H); ESIMS m / z 188.13 ([M + H] +).

Example 92 * not according to the invention: Preparation of 5-Formyl-2- (3-nitro-1H-1,2,4-triazol-1-yl) benzonitrile (DI52) [0612]

104

EP-2934142B1PL

<img file="PL2934142T3_D0253.tif" />

[0613] To a stirred solution of 2-fluoro-5-formylbenzonitrile (0.5 g, 3.3 mmol) in DMF (25 mL) was added K2CO3 (0.68 g, 4.95 mmol) and 3-nitro-1. 2.4 triazole (0.45 g, 4.2 mmol) and the resulting reaction mixture was stirred at ambient temperature for 14 h. After completion of the reaction (TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined EtOAc layers were washed with water and brine then dried over Na2SO4 and concentrated in vacuo to provide the title compound as a pale yellow solid (0.36 g, 45%): mp 170-172 ° C; 1 H NMR (300 MHz, DMSO-d₆) δ 10.12 (s, 1H), 9.61 (s, 1H), 8.69 (s, 1H), 8.45 (d, J = 9.3 Hz, 1H), 8.23 ​​(d , J = 9.3 Hz, 1H); ESIMS m / z 242.3 ([MH] -); IR (thin layer) 2238, 1705, 1551, 1314 cm^-1.

Example 93 * not according to the invention: Preparation of 4- (3-Methyl-1H-1,2,4-triazol-1-yl) benzaldehyde (DI53) [0614]

<img file="PL2934142T3_D0254.tif" />

[0615] To a stirred solution of 4-fluorobenzaldehyde (5.0 g, 40.32 mmol) in DMF (50 mL), K2CO3 (3.34 g, 40.32 mmol) and 3-methyl-1,2,4 were added. -triazole (3.34 g, 40.32 mmol) and the resulting reaction mixture was stirred at ambient temperature for 4 h. After completion of the reaction (TLC), the reaction mixture was diluted with water and extracted with EtOAc (3 ×). The combined EtOAc layers were washed with water and brine then dried over Na2SO4 and concentrated in vacuo to provide the title compound as a white solid (4.1 g, 60%): mp 125-128 ° C; 1 H NMR (400 MHz, CDCl₃) δ 10.05 (s, 1H), 8.76 (s, 1H), 8.02 (d, 2H), 7.85 (d, 2H), 2.50 (s, 3H); ESIMS m / z 188.04 ([M + H] +).

[0616] The following compound * not according to the invention was prepared according to the procedures disclosed in Example 93.

4- (1H-1,2,4-Triazol-1-yl) -3- (trifluoromethyl) benzaldehyde (DI54)

[0617]

<img file="PL2934142T3_D0255.tif" />

[0618] The title compound was isolated as a white solid (1.05 g, 60%): mp 81-83 ° C; 1 H NMR (400 MHz, CDCl₃) δ 10.15 (s, 1H), 8.43 (s, 1H), 8.37 (s, 1H), 8.25 (d, J = 7.2 Hz, 1H), 8.18 (s , 1H), 7.79 (d, J = 7.2Hz, 1H); ESIMS m / z 241.0 ([M] +).

4- (3-Nitro-1H-1,2,4-triazol-1-yl) benzaldehyde (DI55)

[0619]

105

EP-2934142B1PL

<img file="PL2934142T3_D0256.tif" />

[0620] The title compound was isolated as a pale yellow solid (0.10 g, 23%): mp 159-161 ° C; ¹H NMR (400 MHz, CDCl₃) δ 10.10 (s, 1H), 8.89 (s, 1H), 8.15 (m, 2H), 8.00 (m, 2H); ESIMS m / z 217.11 ([MH] -).

3-Bromo-4- (1H-1,2,4-triazol-1-yl) benzaldehyde (DI56)

[0621]

<img file="PL2934142T3_D0257.tif" />

The title compound was isolated as a white solid (3.2 g, 51%): mp 126-128 ° C; 1 H NMR (400 MHz, CDCl₃) δ 10.04 (s, 1H), 8.69 (s, 1H), 8.27 (M, 1H, 8.18 (s, 1H) 7.99 (d, J = 9.2 Hz, 1H ), 7.76 (d, J = 9.2 Hz, 1H); ESIMS m / z 250.9 ([M] +).

5-Formyl-2- (3-methyl-1H-1,2,4-triazol-1-yl) benzonitrile (DI57)

[0623]

<img file="PL2934142T3_D0258.tif" />

The title compound was isolated as a white solid (0.13 g, 30%): mp 147-149 ° C; 1 H NMR (400 MHz, CDCl₃) δ 10.07 (s, 1H), 8.89 (s, 1H), 8.32 (d, J = 1.8 Hz, 1H), 8.24 (dd, J = 8.6, 1, 3 Hz, 1H), 8.06 (d, J = 8.6 Hz, 1H), 2.54 (s, 3H); ESIMS m / z 213.09 ([M + H] +); IR (thin layer) 2239, 1697 cm-1. 3-Nitro-4- (1H-1,2,4-triazol-1-yl) benzaldehyde (DI58)

[0625]

<img file="PL2934142T3_D0259.tif" />

[0626] The title compound was isolated as a pale yellow solid (3.0 g, 60%): mp 116-118 ° C; 1 H NMR (400 MHz, CDCl₃) δ 10.15 (s, 1H), 8.48 (s, 1H), 8.46 (s, 1H), 8.26 (d, J = 6.9 Hz, 1H), 8.16 (s , 1H), 7.83 (d, J = 6.9 Hz, 1H); ESIMS m / z 219.00 ([M + H]⁺).

Example 94 * not according to the invention: Preparation of 1- (4-vinylphenyl) -1H-1,2,4-triazole (DI59)

[0627]

<img file="PL2934142T3_D0260.tif" />

[0628] To a stirred solution of 4- [1,2,4] triazol-1-yl-benzaldehyde (9.0 g, 52 mmol) in 1,4-dioxane (100 mL), was added K2CO3 (10.76 g, 78 mmol) and methyltriphenylphosphonium bromide (22.2 g, 62.4 mmol) at ambient temperature. The resulting reaction mixture was heated to 70 ° C for 18 h. Po

106

After completion of the reaction (TLC), the reaction mixture was cooled to ambient temperature and filtered, and the resulting filtrate was concentrated under reduced pressure. Purification by flash chromatography (SiO2 100-200 mesh; 25-30% EtOAc in petroleum ether) gave the title compound as a white solid (5.6 g, 63%): ESIMS mlz 172.09 ([M + H] +) .

[0629] The following compound * not according to the invention was prepared according to the procedures disclosed in Example 94.

- (2-Methyl-4-vinylphenyl) -1H-1,2,4-triazole (DI60) [0630]

<img file="PL2934142T3_D0261.tif" />

[0631] The title compound was isolated as an off-white solid (1.5 g, 76%): ¹H NMR (400 MHz, CDCl₃) δ 8.25 (s, 1H), 8.11 (s, 1H), 7.35 (m, 2H), 7.27 (d, J = 8.7 Hz, 1H), 6.74 (m , 1H), 5.82 (d, J = 17.3 Hz, 1H), 5.36 (d, J = 10.0 Hz, 1H), 2.25 (s, 3H); ESIMS m / z 186.14 ([M + H]⁺).

2- (1H-1,2,4-Thriazol-1-yl) -5-vinylbenzonitrile (DI61)

[0632]

<img file="PL2934142T3_D0262.tif" />

[0633] The title compound was isolated as an off-white solid (1.40 g, 71%): mp 126-129 ° C; 1 H NMR (400 MHz, CDCl₃) δ 8.76 (s, 1H), 8.18 (s, 1H), 7.82-7.84 (m, 1H), 7.72-7.80 (m, 2H), 6.70- 6.80 (dd, J = 17.6, 10.8 Hz, 1H), 5.90-5.95 (d, J = 17.6 Hz, 1H), 5.50-5.70 (d, J = 10.8 Hz, 1H); ESIMS mlz 197.03 ([M + H] +).

Example 95 * not according to the invention: Preparation of 2- (3-Nitro-1H-1,2,4-triazol-1-yl) -5-vinylbenzonitrile (DI62)

[0634]

<img file="PL2934142T3_D0263.tif" />

[0635] To a stirred solution of 5-formyl-2- (3-nitro-1H-1,2,4-triazol-1-yl) benzonitrile (0.36 g, 1.49 mmol) in 1,4-dioxane (25 mL), K2CO3 (0.3 g, 2.2 mmol) and methyltriphenylphosphonium bromide (0.63 g, 1.79 mmol) were added. The resulting reaction mixture was heated to 100 ° C for 18 h. After completion of the reaction (TLC), the reaction mixture was cooled to ambient temperature and filtered, and the resulting filtrate was concentrated under reduced pressure. Purification by flash chromatography (SiO2 100-200 mesh; 25-30% EtOAc in petroleum ether) gave the title compound as a solid (0.25 g, 70%): mp 103-105 ° C; 1H NMR (400MHz, DMSO-d₆) δ 9.50 (s, 1H), 8.34 (m, 1H), 7.98 (d, J = 7.8 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H ), 6.87 (m, 1H), 6.20 (d, J = 15.7 Hz, 1H), 5.56 (d, J = 11.8 Hz, 1H); ESIMS m / z 240.27 ([MH]^-); IR (thin layer) 2240, 1514, 1312 cm^-1.

[0636] The following compound * not according to the invention was prepared according to the procedures disclosed in Example 95.

1- (3-Chloro-4-vinylphenyl) -1H-1,2,4-triazole (DI63)

107

EP-2934142B1PL

[0637]

<img file="PL2934142T3_D0264.tif" />

[0638] The title compound was isolated as an off-white solid (2.3 g, 80%): mp 134-137 ° C; ¹H NMR (400 MHz, CDCl₃) δ 8.56 (s, 1H), 8.11 (s, 1H), 7.76 (s, 1H), 7.70 (d, J = 9.0 Hz, 1H), 7.57 (d , J = 9.0 Hz, 1H), 7.10 (m, 1H), 5.80 (d, J = 17.2 Hz, 1H), 5.47 (d, J = 12.4 Hz, 1H ); ESIMS m / z 206.04 ([M + H] +.

3-Methyl-1- (4-vinylphenyl) -1H-1,2,4-triazole (DI64)

[0639]

<img file="PL2934142T3_D0265.tif" />

[0640] The title compound was isolated as a white solid (0.6 g, 60%): mp 109-111 ° C; 1 H NMR (400 MHz, CDCl₃) δ 8.42 (s, 1H), 7.40-7.60 (m, 4H), 6.70-7.00 (dd, J = 17.6, 10.8 Hz, 1H), 5, 80 (d, J = 17.6 Hz, 1H), 5.30 (d, J = 17.6 Hz, 1H), 2.50 (s, 3H); ESIMS m / z 186.20 ([M + H]⁺).

- (2- (Trifluoromethyl) -4-vinylphenyl) -1H-1,2,4-triazole (DI65)

[0641]

<img file="PL2934142T3_D0266.tif" />

[0642] The title compound was isolated as a colorless oil (0.6 g, 60%): ¹H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 8.14 (s, 1H), 7.84 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H ), 7.50 (d, J = 7.6 Hz, 1H), 6.70-6.90 (dd, J = 17.6, 10.8 Hz, 1H), 5.90-6.00 ( d, J = 17.6 Hz, 1H), 5.50-5.80 (d, J = 10.8 Hz, 1H); ESIMS mlz 240.16 ([M + H] +).

3-Nitro-1- (4-vinylphenyl) -1H-1,2,4-triazole (DI66)

[0643]

<img file="PL2934142T3_D0267.tif" />

The title compound was isolated as a pale yellow solid (61 mg, 20%): mp 137-139 ° C; 1 H NMR (400 MHz, CDCl₃) δ 8.60 (s, 1H), 7.68 (d, J = 7.7 Hz, 2H), 7.60 (d, J = 8.3 Hz, 2H), 6.77 (dd, J = 17.7, 10.8, 1H), 5.87 (d, J = 17.7 Hz, 1H), 5.42 (d, J = 10.8 Hz, 1H); ESIMS m / z 217.28 ([M + H] +).

1- (2-Bromo-4-vinylphenyl) -1H-1,2,4-triazole (DI67)

[0645]

<img file="PL2934142T3_D0268.tif" />

[0646] The title compound was isolated as a white solid (1.2 g, 40%): mp 75-77 ° C; ¹H NMR (400 MHz, CDCl₃) δ 8.48 (s, 1H), 8.12 (s, 1H), 7.75 (s, 1H) 7.42 (s, 2H), 6.70 (m, 1H), 5.83 ( d, J = 18Hz, 1H), 5.42 (d, J = 12Hz, 1H); ESIMS m / z 249.1 ([M] +).

2- (3-Methyl-1H-1,2,4-triazol-1-yl) -5-vinylbenzonitrile (DI68)

108

EP-2934142B1PL

[0647]

<img file="PL2934142T3_D0269.tif" />

[0648] The title compound was isolated as an off-white solid (0.6 g, 60%): mp 96-97 ° C; 1 H NMR (400 MHz, CDCl₃) δ 8.66 (s, 1H), 7.80 (s, 1H), 7.74 (m, 2H), 6.73 (dd, J = 17.6 Hz, 10.8 Hz, 1H), 5.88 (d, J = 17.6 Hz, 1H), 5.49 (d, J = 10.8 Hz, 1H), 2.52 (s, 3H); ESIMS m / z 211.10 ([M + H] +); IR (thin layer) 2229 cm^-1.

1- (2-Nitro-4-vinylphenyl) -1H-1,2,4-triazole (DI69)

[0649]

<img file="PL2934142T3_D0270.tif" />

[0650] The title compound was isolated as a yellow solid (1.78 g, 60%): mp 102-104 ° C; 1 H NMR (400 MHz, CDCl₃) δ 8.40 (s, 1H), 8.12 (s, 1H), 8.02 (s, 1H), 7.72-7.76 (d, J = 8.0 Hz, 1H), 7 , 52-7.56 (d, J = 17.6 Hz, 1H), 6.70-6.82 (dd, J = 17.6, 10.8 Hz, 1H), 5.85-6.00 (d, J = 17.6 Hz, 1H), 5.50-5.60 (d, J = 10.8, Hz, 1H); ESIMS m / z 217.0 ([M + H] +).

Example 96 * not according to the invention: Preparation of 3-Methyl-2- (1H-1,2,4-triazol-1-yl) -5-vinylbenzonitrile (DI70)

[0651]

<img file="PL2934142T3_D0271.tif" />

Step 1. 5-Bromo-2-fluoro-3-methylbenzaldehyde: To a stirred solution of diisopropylamine (4.01 g, 39.88 mmol) in THF (20 mL) was added n-butyl lithium (1.6 M in hexane ) (19.9 ml, 31.91 mmol) at -78 ° C slowly dropwise over a period of 10 min, the reaction mixture was stirred at -78 ° C for 30 min. A solution of 4-bromo-1-fluoro-2-methylbenzene (5.0 g, 26.6 mmol) in THF (30.0 mL) was added at -78 ° C, and the reaction mixture was stirred for 1 h at the same temperature. DMF (5.0 ml) was added and stirred at -78 ° C for another 30 min. The reaction was monitored by TLC; then the reaction mixture was quenched with 1 N HCl solution (aq) at 0 ° C. The aqueous layer was extracted with diethyl ether, washed with water and saturated brine. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure, the obtained crude compound was purified by flash column chromatography (SiO2 100-200 mesh; eluted with 5% ethyl acetate / petroleum ether) to afford the title compound as a white solid (3, 6 g, 64%); mp 48-50 ° C: 1 H NMR (400 MHz, CDCl₃) δ 8.33 (s, 1H), 8.22 (s, 1H), 7.67 (s, 1H), 7.60 (s, 1H), 6.75 (dd, J = 17.6, 10.8 Hz, 1H), 5.92 (dd, J = 17.6, 10.8 Hz, 1H), 5.52 (d, J = 17.6 Hz, 1H), 2.21 (s, 3H); ESIMS m / z 211.35 ([MH]^-).

Step 2. ((E) -5-bromo-2-fluoro-3-methylbenzaldehyde oxime: To a stirred solution of 5-bromo-2-fluoro-3-methylbenzaldehyde (3.5 g, 16.2 mmol) in ethanol ( 50.0 ml) sodium acetate (2.0 g, 24.3 mmol) and hydroxylamine hydrochloride (1.69 g, 24.3 mmol) were added at ambient temperature The reaction mixture was stirred at ambient temperature for 3 h. on a rotary evaporator to give a crude compound which was washed with water, filtered and dried in vacuo

109

Pressure to provide the title compound as a white solid: mp 126-127 ° C; ¹H NMR (400 MHz,

CDCl₃) δ 8.32 (s, 1H), 7.73 (d, J = 2.4 Hz, 1H), 7.51 (s, 1H), 7.34 (d, J = 2.4 Hz, 1H ). 2.25 (s, 3H); ESIMS m / z 232.10 ([M + H] +).

Step 3. 5-Bromo-2-fluoro-3-methylbenzonitrile: Mixed solution of (E) -5-bromo-2-fluoro-3-methylobenzonitrile oxime (0.5 g, 2.2 mmol) in acetic anhydride (5 0.0 ml) was heated to reflux for 18 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine and dried over Na2SO4 and concentrated in vacuo to give the crude compound as light brown gummy material (0.4 g, crude): ESIMS m / z 213.82 ([M + H]⁺).

Step 4. 5-Bromo-3-methyl-2- (1H-1,2,4-triazol-1-yl) benzonitrile (DI71): To a mixed solution of 5-bromo-2-fluoro-3-methylbenzonitrile (1.0 g, 47.716 mmol), in DMF (10.0 mL) added potassium carbonate (1.95 g, 14.14 mmol) followed by 1H-1,2,4-triazole (0.811 g, 9.433 mmol) ) at ambient temperature. The reaction mixture was heated to 140 ° C for 18 h. The reaction mixture was cooled to ambient temperature, diluted with water and extracted with ethyl acetate (2 x 100 ml). The combined ethyl acetate layers were washed with brine and dried over Na2SO4 and concentrated under reduced pressure, the obtained crude compound was purified by flash column chromatography (SiO2 100-200 mesh; eluted with 30% ethyl acetate / petroleum ether) to afford the title compound as a pink solid (0.6 g, 49%): ¹H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 8.23 ​​(s, 1H), 7.91 (d, J = 2.4 Hz, 2H), 2.21 (s, 3H ), ESIMS m / z 262.57 ([M + H]⁺); IR (thin layer) 2231, 554 cm^-1.

Step 5. 3-Methyl-2- (1H-1,2,4-triazol-1-yl) -5-vinylbenzonitrile (DI70): A mixture of 5-bromo-3-methyl-2- (1H-1,2 , 4-triazol-1-yl) benzonitrile (0.6 g, 2.3 mmol), potassium carbonate (0.95 g, 6.87 mmol), vinylboronic acid anhydride (0.82 g, 3.43 mmol) and triphenylphosphine (0.13 g, 0.114 mmol) in toluene (20.0 ml) was stirred and degassed with argon for 30 min. The reaction mixture was heated to reflux for 18 h. The reaction mixture was cooled to ambient temperature, diluted with water and extracted with ethyl acetate (2 x 100 ml). The combined ethyl acetate layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude compound which was purified by flash column chromatography (SiO2 100-200 mesh; eluted with 30% ethyl acetate / petroleum ether) to afford the title compound as a pink solid (0.25 g, 52%): 1 H NMR (400 MHz, CDCl₃) δ 8.33 (s, 1H), 8.22 (s, 1H), 7.67 (s, 1H), 7.60 (s, 1H), 6.75 (dd, J = 17.6, 10.8 Hz, 1H), 5.92 (d, J = 17.6, 1H), 5.52 (d, J = 10.8 Hz, 1H), 2.21 (s, 3H); ESIMS m / z 211.35 ([M + H] +); IR (thin layer) 2236, 1511 cm^-1.

The following compound * not according to the invention was prepared according to the procedures disclosed in Steps 4 and 5 of Example 96.

- (2-Fluoro-4-vinylphenyl) -1H-1,2,4-triazole (DI72)

[0658]

<img file="PL2934142T3_D0272.tif" />

1- (4-Bromo-2-fluorophenyl) -1H-1,2,4-triazole (DI73) was isolated as a pale yellow solid (3.0 g, 75%): mp 113-116 ° C; 1 H NMR (400 MHz, CDCl₃) δ 8.69 (s, 1H), 8.13 (m, 2H), 7.50 (m, 1H), 7.21 (m, 1H); ESIMS m / z 241.93 ([M] +). The title compound (DI72) was isolated as a yellow solid (1.0 g,

110

EP-2934142B1PL

71%): mp 67-70 ° C; 1 H NMR (400 MHz, CDCl₃) δ 8.67 (s, 1H), 8.13 (s, 1H), 7.94 (m, 1H), 7.41 (m, 1H),

7.24 (s, 1H), 6.75 (dd, J = 17.6, 10.8 Hz, 1H), 5.81 (d, J = 17.6 Hz, 1H), 5.37 (d , J = 10.8 Hz, 1H); ESIMS m / z 190.00 ([M + H] +).

Example 119 * not according to the invention: Preparation of 1- (1- (4-Vinylphenyl) -1H-1,2,4-triazol-5-yl) ethanone (DI78)

[0660]

<img file="PL2934142T3_D0273.tif" />

[0661] To a stirred solution of 1- (4-vinyl-phenyl) -1 H- [1,2,4] triazole (1 g, 5.8 mmol) in 25 mL of THF, n-BuLi (0.37 g , 5.8 mmol) at -78 ° C and stirred for 30 min. Thereto was added N-methoxy-N-methylacetamide in THF (0.66 g, 6.4 mmol) and the resulting reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was quenched with saturated aqueous NH4Cl solution and extracted with EtOAc (3 x50 mL). The combined EtOAc layers were washed with brine and dried over sodium sulfate and concentrated in vacuo. The crude compound was purified by flash chromatography (SiO2, 100-200 mesh, 40% EtOAc in petroleum ether) to afford the title compound as an off-white solid (280 mg, 23%): mp 97-98 ° C; 1 H NMR (400 MHz, CDCl 3) δ 8.10 (s, 1H), 7.50 (d, 2H), 7.38 (d, 2H), 6.68 (dd, 1H), 5.85 (d , 1H), 5.38 (d, 1H), 2.75 (s, 3H); ESIMS m / z 214.14 ([M + H] +).

Example 120 * not according to the invention: Preparation of Cyclopropyl- (1- (4-vinylphenyl) -1H-1,2,4-triazol-5-yl) methanone (DI79)

[0662]

<img file="PL2934142T3_D0274.tif" />

[0663] To a mixed solution of 1- (4-vinyl-phenyl) -1H- [1,2,4] triazole (1 g, 5.8 mmol) in 25 mL of THF, n-BuLi (0.37 g , 5.8 mmol) at -78 ° C and stirred for 30 min. Thereto was added N-methoxy-N-methylcyclopropoxide in THF (0.82 g, 6.4 mmol) and the resulting reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was quenched with saturated aqueous NH4Cl solution and extracted with EtOAc (3 x25 mL). The combined EtOAc layers were washed with brine and dried over sodium sulfate and concentrated in vacuo. The crude compound was purified by flash chromatography (SiO2, 100-200 mesh, 40% EtOAc in petroleum ether) to afford the title compound as an off-white solid (420 mg, 30%): mp 90-91 ° C; 1 H NMR (400 MHz, CDCl 3) δ 8.12 (s, 1H), 7.50 (d, J = 7.8 Hz, 2H), 7.38 (d, J = 7.8 Hz, 2H), 6.75 (dd, J = 16.3, 10.7 Hz, 1H), 5.81 (d, J = 16.3 Hz, 1H), 5.35 (d, J = 10.7 Hz, 1H ), 3.22 (m, 1H), 1.27 (m, 2H), 1.18 (m, 2H); ESIMS m / z 240.18 ([M + H]⁺); IR (thin layer) 2922, 1630 cm^-1.

Example 121 * not according to the invention: Preparation of 5- (Methylthio) -1- (4-vinylphenyl) -1H-1,2,4-triazole (DI80)

[0664]

<img file="PL2934142T3_D0275.tif" />

111

EP-2934142B1PL

[0665] To a stirred solution of 1- (4-vinyl-phenyl) -1 H- [1,2,4] triazole (1 g, 5.8 mmol) in 50 mL of THF, n-BuLi (0.41 g , 6.4 mmol) at -78 ° C and stirred for 30 min. Thereto, dimethyldisulfide in THF (0.6 g, 6.43 mmol) was added and the resulting reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was quenched with saturated aqueous NH4Cl solution and extracted with EtOAc (3 x 25 mL). The combined EtOAc layers were washed with brine and dried over sodium sulfate and concentrated in vacuo. The crude compound was purified by flash chromatography (SiO2, 100-200 mesh, 40% EtOAc in petroleum ether) to afford the title compound as an off-white solid (0.6 g, 48%): mp 68-70 ° C; 1 H NMR (400 MHz, CDCl₃) δ 7.96 (s, 1H), 7.05 (m, 4H), 6.75 (dd, J = 16.4, 10.7 Hz, 1H), 5.81 (d, J = 16, 4 Hz, 1H), 5.35 (d, J = 10.7 Hz, 1H), 2.73 (s, 3H); ESIMS m / z 218.09 ([M + H] +).

Example 122 * not according to the invention: Preparation of 5-Methyl-1- (4-vinylphenyl) -1H-1,2,4-triazole (DI81)

[0666]

<img file="PL2934142T3_D0276.tif" />

[0667] To a mixed solution of 1- (4-vinyl-phenyl) -1H- [1,2,4] triazole (0.5 g, 2.9 mmol) in 10 mL of THF, n-BuLi (0, 22 g, 3.5 mmol) at -78 ° C and stirred for 30 min. Thereto was added methyl iodide in THF (0.50 g, 3.5 mmol) and the resulting reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was quenched with saturated aqueous NH4Cl solution and extracted with EtOAc (3 x 25 mL). The combined EtOAc layers were washed with brine and dried over sodium sulfate and concentrated in vacuo. The crude compound was purified by flash chromatography (SiO2, 100-200 mesh, 40% EtOAc in petroleum ether) to afford the title compound as a pale brown liquid (250 mg, 46%): 1 H NMR (400 MHz, CDCl₃) δ 7.93 (s, 1H), 7.55 (d, J = 9 Hz, 2H), 7.42 (d, J = 9 Hz, 2H), 6.76 (dd, J = 18.11 Hz, 1H), 5.83 (d, J = 18 Hz, 1H), 5.38 (d, J = 11 Hz, 1H), 2.55 (s, 3H); ESIMS m / z 186.13 ([M + H]⁺); IR (thin layer) 1517, 1386, 1182, 847 cm^-1.

Example 97 * not according to the invention: Preparation of (E) -1- (4- (3- (3,5-Dichlorophenyl) -4,4,4-trifluorobut-1-en-1-yl) phenyl) -1 H-1, 2,4-triazole (DC1)

[0668]

<img file="PL2934142T3_D0277.tif" />

To a stirred solution of 1- (1-bromo-2,2,2-trifluoro-ethyl) -3,5-dichloro-benzene (2.0 g, 6.51 mmol) in 1,2-dichlorobenzene (25 ml), 1- (4-vinyl-phenyl) -1H- [1,2,4] triazole (2.22 g, 13.0 mmol), CuCl (64 mg, 0.65 mmol) and 2, 2-bipyridyl (0.2 g, 1.3 mmol). The resulting reaction mixture was degassed with argon for 30 min, then stirred at 180 ° C for 24 h. After completion of the reaction (TLC), the reaction mixture was cooled to ambient temperature and filtered, and the filtrate was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 100-200 mesh; 25-30% EtOAc in petroleum ether) gave the title compound as an off-white solid (0.8 g, 32%): mp 93-97 ° C; 1 H NMR (300 MHz, CDCl₃) δ 8.56 (s, 1H), 8.11 (s, 1H), 7.68 (d, J = 8.4

112

EP-2934142B1PL

Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.38 (t, J = 1.8 Hz, 1H), 7.29 (s, 2H), 6.62 ( d, J = 15.6 Hz, 1H), 6.42 (dd,

J = 15.6,8.2 Hz, 1H), 4.15 (m, 1H); ESIMS m / z 398.05 ([M + H] +).

Compounds DC2-DC37, DC44, DC45, DC47-49, DC50, DC51, DC54, DC58, DC60, DC62, and DC63DC67 * not according to the invention in Table 1 were prepared according to the procedures disclosed in Example

97.

Example 98 * not according to the invention: Preparation of (E) -2- (3-Nitro-1H-1,2,4-triazol-1-yl) -5- (4,4,4trifluoro-3- (3,4 , 5-trichlorophenyl) but-1-en-1-yl) benzonitrile (DC40) [0671]

<img file="PL2934142T3_D0278.tif" />

To a stirred solution of 2- (3-nitro-1H-1,2,4-triazol-1-yl) -5-vinylbenzonitrile (0.9 g, 3.7 mmol) in 1,2-dichlorobenzene ( 10 ml) 5- (1-bromo-2,2,2-trifluoroethyl) -1,2,3-trichlorobenzene (2.5 g, 7.5 mmol), CuCl (73 mg, 0.74 mmol) was added and 2,2-bipyridyl (0.23 g, 1.49 mmol) and the resulting reaction mixture was degassed with argon for 30 min, then stirred at 180 ° C for 14 h. After completion of the reaction (TLC), the reaction mixture was cooled to ambient temperature and filtered, and the filtrate was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 100-200 mesh, 25-30% EtOAc in petroleum ether) gave the title compound as an off-white solid (0.9 g, 50%): mp 70-73 ° C; 1 H NMR (300 MHz, CDCl₃) δ 8.86 (s, 1H), 7.88 (m, 3H), 7.44 (s, 2H), 6.67 (d, J = 16.0 Hz, 1H), 6.56 (dd , J = 16.0, 7.6 Hz, 1H), 4.19 (m, 1H); ESIMS m / z 436.11 ([M-2H]^-).

Example 99 * not according to the invention: Preparation of (E) -2- (3-Amino-1H-1,2,4-triazol-1-yl) -5- (4,4,4trifluoro-3- (3,4 , 5-trichlorophenyl) but-1-en-1-yl) benzonitrile (DC41)

[0673]

<img file="PL2934142T3_D0279.tif" />

To a stirred solution of (E) -2- (3-nitro-1H-1,2,4-triazol-1-yl) -5- (4,4,4-trifluoro-3- (3,4, 5-trichlorophenyl) but-1-enyl) benzonitrile (0.6 g, 1.2 mmol) in MeOH (10 mL), zinc dust (0.39 g, 5.98 mmol) and saturated aqueous NH4Cl solution (5 ml) and the resulting reaction mixture was stirred at ambient temperature for 2 h. After completion of the reaction (TLC), the reaction mass was concentrated under reduced pressure. Reaction mass was diluted with CH2Cl2, filtered through a celite pad, and the resulting filtrate was concentrated under reduced pressure to provide the title compound as a solid (0.5 g, 89%): mp 72-75 ° C; 1 H NMR (300 MHz, DMSO-d₆) δ 8.72 (s, 1H), 8.26 (s, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.91 (s, 2H), 7.77 (d , J = 8.4 Hz, 1H), 6.42 (dd, J = 15.6, 9.2 Hz, 1H), 6.83 (d, J = 15.6 Hz, 1H), 5.87 (s, 2H); 4.89 (m, 1H); ESIMS m / z 469.95 ([MH] -).

Compound DC38 * not of the invention in Table 1 was prepared according to the procedures disclosed in Example 99. Also, DC55 * not of the invention in Table 1 was prepared from DC54 according to the procedures disclosed in Example 99 except that ammonium formate instead of ammonium chloride.

113

EP-2934142B1PL

Example 100 * not according to the invention: Preparation of (E) -N- (1- (2-Cyano-4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-ene- 1-yl) phenyl) -1H-1,2,4-triazol-3-yl) -N- (cyclopropanecarbonyl) cyclopropanecarboxamide (DC42)

[0676]

<img file="PL2934142T3_D0280.tif" />

To a mixed solution of (E) -2- (3-amino-1H-1,2,4-triazol-1-yl) -5- (4,4,4-trifluoro-3- (3,4 , 5-trichlorophenyl) but-1-enyl) benzonitrile (0.1 g, 0.21 mmol) in CH₂Cl₂ at ambient temperature, cyclopropylcarbonyl chloride (0.045 g, 0.42 mmol) was added and the reaction mixture was stirred for 2 h at ambient temperature. The reaction mixture was diluted with CH2Cl2 and washed with water and brine and dried over Na2SO4. Concentration under reduced pressure and purification by preparative HPLC gave the title compound as a solid (0.09 g, 79%): mp 104-107 ° C; 1 H NMR (300 MHz, CDCl 3) δ 8.78 (s, 2H), 7.83 (s, 1H), 7.80 (m, 2H), 7.42 (s, 2H), 6.65 (d , J = 16.4 Hz, 1H), 6.51 (dd, J = 7.6, 8.0 Hz, 1H), 4.17 (m, 1H), 2.16 (m, 2H), 1 . 25 (m, 4H), 1.00 (m, 4H); ESIMS m / z 609.98 ([M + H] +); IR (thin layer) 2234, 1714, 1114, 807 cm^-1.

Example 101 * not according to the invention: Preparation of (E) -N- (1- (2-Cyano-4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-en-1-) yl) phenyl) -1H-1,2,4-triazol-3-yl) cyclopropanecarboxamide (DC43) [0678]

<img file="PL2934142T3_D0281.tif" />

To a mixed solution of (E) -2- (3-amino-1H-1,2,4-triazol-1-yl) -5- (4,4,4-trifluoro-3- (3,4, 5-trichlorophenyl) but-1-enyl) benzonitrile (0.15 g, 0.31 mmol) in CH2Cl2 at 0 ° C, TEA (0.1 g, 1 mmol) and cyclopropylcarbonyl chloride (0.04 g, 0.38 mmol) and the reaction mixture was stirred for 1 h at 0 ° C. The reaction mixture was diluted with CH2Cl2 and washed with water and brine and dried over Na2SO4. Concentration under reduced pressure and purification by column chromatography (SiO2, 100-200 mesh) gave the title compound as a solid (66 mg, 34%): mp 109-112 ° C; 1 H NMR (300 MHz, DMSO-d₆) δ 10.94 (br s, 1H), 8.36 (s, 1H), 8.08 (m, J = 8.4 Hz, 1H), 7.91 (s, 2H), 7.84 ( d, J = 8.4 Hz, 1H), 7.13 (dd, J = 15.6, 9.2 Hz, 1H), 6.87 (d, J = 15.6 Hz, 1H), 4, 92 (m, 1H), 1.99 (br s, 1H), 0.82 (s, 4H); ESIMS m / z 540.04 ([M + H] +); IR (thin layer) 3233, 2233, 1699, 1114, 807cm^-1.

Compound DC39 * not of the invention in Table 1 was prepared according to the procedures disclosed in Example 101.

Example 102 * not according to the invention: Preparation of 1- (4- (1H-1,2,4-Triazol-1-yl) phenyl) ethanone (DI74)

[0681]

<img file="PL2934142T3_D0282.tif" />

114

EP-2934142B1PL

[0682] To a stirred solution of 4-bromoacetophenone (10 g, 50 mmol) in DMF (100 ml), 1,2,4 triazole (5 g, 75 mmol), Cs2CO3 (32.6 g, 100.5 mmol) and CuI (1.4 g, 10.1 mmol) and the resulting reaction mixture was refluxed for 48 h. After completion of the reaction (by TLC), the reaction mixture was cooled to ambient temperature and diluted with water (200 mL) and extracted with EtOAc. The combined organic layers were washed with brine and dried over Na2SO4 and concentrated under reduced pressure. Purification by washing with diethyl ether gave the title compound as a solid (5 g, 96%): ¹H NMR (400 MHz, CDCl 3) δ 8.71 (s, 1H), 8.16, (s, 1H), 8.13 (d, J = 8.6 Hz, 2H), 7.83 (d, J = 8.6 Hz, 2H), 2.66 (s, 3H); ESIMS m / z 186.02 ([MH] -).

Example 103 * not according to the invention: Preparation of 1- (4- (1H-1,2,4-Triazol-1-yl) phenyl) -3- (3,5-dichlorophenyl) -4,4,4-trifluorobutan-1- onu (DI75)

[0683]

<img file="PL2934142T3_D0283.tif" />

Step 1. 1- (4- (1- (Trimethylsilyloxy) vinyl) phenyl) -1H-1,2,4-triazole (DI76) To a mixed solution of 1- (4- (1H-1,2, 4-triazol-1-yl) phenyl) ethanone (4.5 g, 24.0 mmol) in CH2Cl2 at 0 ° C, added TEA (3.7 g, 36.1 mmol) and trimethylsilyl triflate (8 g, 36 mmol) and the resulting reaction mixture was stirred for 1 h. The reaction mixture was quenched with a mixture of saturated aqueous sodium bicarbonate solution and ether. Ether layer separated, washed with brine, dried over Na2SO4 and concentrated in vacuo to give the title compound (5.5 g) which was taken directly to the next step.

Step 2. 1- (4- (1H-1,2,4-triazol-1-yl) phenyl) -3- (3,5-dichlorophenyl) -4,4,4-trifluorobutan-1- on (DI75): Mixed solution of 1- (4- (1- (trimethylsilyloxy) vinyl) phenyl) -1H-1,2,4-triazole (6 g, 23 mmol) and 1- (1-bromo-2,2,2 -trifluoro-ethyl) -3,5-dichlorobenzene (7.1 g, 34.7 mmol) in 1,2-dichlorobenzene (30 ml) was deaerated with argon. CuCl (0.23 g, 2.31 mmol) and 2,2-bipyridyl (0.73 g, 4.63 mmol) were added to the above reaction mixture and the resulting reaction mixture was heated to 180 ° C for 18 h. After completion of the reaction (by TLC), the reaction mixture was absorbed onto silica gel and purified by column chromatography (SiO2; 10% EtOAc in petroleum ether) to provide the title compound as a solid (3 g, 31%): 1H NMR (400MHz, CDCl3) δ 8.67 (s, 1H), 8.15 (s, 1H), 8.10 (d, J = 8.3 Hz, 2H), 7.82 (d, J = 8.3 Hz, 2H), 7.33 (m, 1H), 7.30 (m, 2H), 4.20 (m, 1H), 3.63 (m, 2H); ESIMS m / z 412. 14 ([MH] -).

Example 104 * not according to the invention: Preparation of 2- (4- (1H-1,2,4-triazol-1-yl) phenyl) -4- (3,5-dichlorophenyl) -5,5,5-trifluoropentan-2- olu (DI77)

[0686]

<img file="PL2934142T3_D0284.tif" />

[0687] To a solution of 1- (4- (1H-1,2,4-triazol-1-yl) phenyl) -3- (3,5-dichlorophenyl) -4,4,4-trifluorobutan-1-one ( 300 mg, 0.726 mmol) in THF cooled to 0 ° C, methylmagnesium bromide (450 mg, 5 mmol) was added dropwise. The reaction was stirred for 3 h at 0 ° C, then the reaction mixture was quenched with saturated aqueous NH 4 Cl solution and extracted with ethyl acetate. Combined EtOAc layers

115

Washed with water and brine, dried over NapSO4 and concentrated in vacuo. Purification by column chromatography (SiO2, 100-200 mesh; 20% -25% EtOAc in petroleum ether) gave the title compound as a solid (100 mg, 32%): 1 H NMR (400 MHz, CDCl 3) δ two diastereoisomers 8.58 (s, 1H, minor), 8.48 (s, 1H, major), 8.13 (s, 1H, minor), 8.09 (s, 1H, major), 7.70 (d, J = 9.0 Hz, 2H, minor), 7.53 (d, J = 9.0 Hz, 2H, minor), 7.40 (d, J = 9 , 0 Hz, 2H, major), 7.31 (m, 1H, minor), 7.27 (d, J = 9.0 Hz, 2H, major), 7.20 (m, 2H, minor), 7 . 01 (m, 1H, major), 6.75 (m, 2H, major), 350 (m, 1H), 2.50 (m, 2H), 1.56 (s, 3H, major), 1, 54 (s, 3H, minor); ESIMS m / z 430.05 ([M + H] +).

Example 105 * not according to the invention: Preparation of (E) -1- (4- (4- (3,5-Dichlorophenyl) -5,5,5-trifluoropent-2-en-2-yl) phenyl) -1H-1, 2,4-triazole (DC68)

[0688]

<img file="PL2934142T3_D0285.tif" />

[0689] To a solution of 2- (4- (1H-1,2,4-triazol-1-yl) phenyl) -4- (3,5-dichlorophenyl) -5,5,5-trifluoropentan-2-ol (100 mg, 0.233 mmol) in toluene, a catalytic amount of p-toluenesulfonic acid (PTSA) was added and the water was removed by azeotropic distillation over 12 h. The reaction mixture was cooled to ambient temperature and dissolved in ethyl acetate. The solution was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4 and concentrated in vacuo. Purification by column chromatography (SiO2, 100-200 mesh; 20% -25% EtOAc in petroleum ether) gave the title compound as a solid (30 mg, 31%).

Example 123 * not according to the invention: Preparation of (E) -5- (3- (3,5-Dichlorophenyl) -4,4,4-trifluorobut-1 -en-1-yl) -2- (1H-1,2, 4-triazol-1-yl) benzaldehyde (DC52)

[0690]

<img file="PL2934142T3_D0286.tif" />

[0691] To a mixed solution of (E) -5- (3- (3,5-dichlorophenyl) -4,4,4-trifluorobut-1-en-1-yl) -2- (1H-1,2, 4-triazol-1-yl) benzonitrile (0.3 g, 0.71 mmol) in toluene (10 ml) was added dropwise at -78 ° C diisobutylaluminum hydride (DIBAL-H, 1.0 M solution in toluene; 0.85 ml), and the reaction mixture was stirred at -78 ° C for 20 min. The reaction mixture was quenched by adding 1 N HCl solution, then the aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (SiO2; 50% EtOAc / petroleum ether) to afford the title compound as yellow oil.

Compound DC53 * not of the invention in Table 1 was prepared according to the procedures disclosed in Example 123.

Example 124 * not according to the invention: Preparation of (E) -5- (3- (3,5-Dichlorophenyl) -4,4,4-trifluorobut-1-en-1-yl) -N-methyl-2- (1H- 1,2,4-triazol-1-yl) aniline (DC57)

[0693]

116

EP-2934142B1PL

<img file="PL2934142T3_D0287.tif" />

To a mixed solution of (E) -5- (3- (3,5-dichlorophenyl) -4,4,4-trifluorobut-1-en-1-yl) -2- (1H-1,2, 4-triazol-1-yl) aniline (0.3 g, 0.7 mmol) in CH2Cl2 (10 mL) was added TEA (0.155 mL, 1.09 mmol) and methyl iodide (0.124 g, 0.873 mmol). The reaction was stirred at ambient temperature for 18 h. The CH2Cl2 layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The crude compound was purified by flash column chromatography (SiO2; 50% EtOAc / petroleum ether) to afford the title compound as a yellow semi-solid (0.07 g, 70%).

Example 125 * not according to the invention: Preparation of Acid (E) -5- (3- (3,5-dichlorophenyl) -4,4,4-trifluorobut-1-en-1-yl) -2- (1H-1,2 , 4-triazol-1-yl) benzoic acid (DC61)

[0695]

<img file="PL2934142T3_D0288.tif" />

[0696] Solution of (E) -5- (3- (3,5-dichlorophenyl) -4,4,4-trifluorobut-1-en-1-yl) -2- (1H-1,2,4- Ethyl triazol-1-yl) benzoate (0.2 g, 0.4 mmol) in 6 N HCl (10 mL) was stirred at 100 ° C for 18 h. The reaction was cooled to ambient temperature causing a white solid to crash out. The precipitate was filtered off to provide the title compound as a white solid (0.12 g, 60%).

Example 126 * not according to the invention: Preparation of (Z) -5 - ((E) -3- (3,5-Dichlorophenyl) -4,4,4-trifluorobut-1-en-1-yl) -N-hydroxy-2- (1H-1,2,4-triazol-1-yl) benzimidamide (DC59)

[0697]

<img file="PL2934142T3_D0289.tif" />

Solution of (E) -5- (3- (3,5-dichlorophenyl) -4,4,4-trifluorobut-1-en-1-yl) -2- (1H-1,2,4- triazol-1-yl) benzonitrile (0.3 g, 0.71 mmol), sodium acetate (0.087 g, 1.065 mmol), and hydroxylammonium chloride (0.072 g, 1.065 mmol) in 9: 1 ethanol / water (10 mL) stirred at 70 ° C for 8 h. The reaction was cooled to ambient temperature, and the ethanol was evaporated. The residue was dissolved in water and extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to provide the title compound as an off-white solid.

Example 127 * not according to the invention: Preparation of (E) -1- (4- (3- (3,5-Dichlorophenyl) -4,4,4-trifluoro-3-methoxybut-1-en-1-yl) phenyl) -1 H-1,2,4-triazole (DC70) [0699]

<img file="PL2934142T3_D0290.tif" />

Step 1. (E) -3- (4- (1H-1,2,4-triazol-1-yl) phenyl) -1- (3,5-dichlorophenyl) prop-2-en-1 -one: To a solution of 1- (3,5-dichlorophenyl) ethanone (0.5 g, 2.6 mmol) in ethanol (20 ml) was added 4- (1H-1,2,4-triazol-1117)

EP-2 934142B1PL yl) benzaldehyde (0.46 g, 2.65 mmol) and the reaction was cooled to 0 ° C. Then sodium hydroxide (0.22 g, 5.29 mmol) in water (10 ml) was added and the stirred reaction was allowed to proceed for 2 h at 0 ° C.

The reaction was extracted with EtOAc and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to afford the title compound (0.149 g, 17%): ESIMS m / z 430.05 ([M + H] +)

344,08

Step 2. (E) -4- (4- (1H-1,2,4-triazol-1-yl) phenyl) -2- (3,5-dichlorophenyl) -1,1,1- trifluorobut-3-en-2ol (DC69): For solution of (E) -3- (4- (1H-1,2,4-triazol-1-yl) phenyl) -1- (3,5-dichlorophenyl) prop-2-en-1-one (1 g, 3 mmol) in THF (150 ml) was added trifluoromethyltrimethylsilane (0.517 g, 3.644 mmol) and tetra-n-butylammonium fluoride (TBAF) (1.0 M, 1 ml) in at 0 ° C. The reaction was slowly warmed to ambient temperature and allowed to stir for 2 h. The reaction was then cooled to 0 ° C and 5 M HCl was added and the reaction was stirred for an additional 4 h at ambient temperature. The reaction was extracted with CH2Cl2 and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (SiO2; 25% EtOAc / hexane) to provide the title compound as an off-white solid (0.3 g, 25%).

Step 3. (E) -1- (4- (3- (3,5-Dichlorophenyl) -4,4,4-trifluoro-3-methoxybut-1-en-1-yl) phenyl) -1 H1,2,4-triazole (DC70): For a solution of (E) -4- (4- (1H-1,2,4-triazol-1-yl) phenyl) -2- (3,5-dichlorophenyl) -1,1,1-trifluorobut-3-en-2-ol (0.15 g, 0.36 mmol) in THF (5 ml) added NaH (60%, 10 mg, 0.44 mmol) at 0 ° C . The reaction was allowed to stir at 0 ° C for 30 min, then methyl iodide (61 mg, 0.44 mmol) was slowly added and the reaction was warmed to ambient temperature and allowed to stir for 4 h. The reaction was quenched with aq. NH4Cl and extracted with CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to provide the title compound as an off-white solid (55mg, 35%).

Example F1: Preparation of (E) -2- (2-bromo-4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-en-1-yl) benzoyl) -N- ethyl-1-methylhydrazinecarboxamide (F1)

[0703]

<img file="PL2934142T3_D0291.tif" />

[0704] It was anticipated that (E) -2-bromo-4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-en-1-yl) benzoic acid could be reacted with N-ethyl-1-methylhydrazinecarboxamide in the presence of N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (EDC-HCl) and DMAP in 1,2-dichloroethane (DCE) to give the title molecule (Org. Lett. 2004, 6 , 929-931).

Example 128: Preparation of (E) -2- (2-Bromo-4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-en-1-yl) benzoyl) -N - (2,2,2-trifluoroethyl) hydrazinecarboxamide (F7) cf₃

YY XX sa ^^ YNN CF, Cl o ^HH

Step 1. tert-Butyl 2 - ((2,2,2-trifluoroethyl) carbamoyl) hydrazinecarboxylate: To a stirred solution of butyl tert-hydroxy carboxylate (1.0 g, 8 mmol) in anhydrous benzene (10, 0

118

Ml) 1,1,1-trifluoro-2-isocyananoethane (1.06 g, 8 mmol) was added via syringe to form a gelatin-like mixture. Then, anhydrous THF was added to give a clear solution which was stirred for 10 minutes then the reaction mixture was evaporated to give the title compound as a white solid (1.62 g, 79%):¹H NMR (400 MHz, CDCl3) δ 6.63 (s, 1H), 6.40 (d, j = 2.2 Hz, 1H), 5.84 (s, 1H), 3.88 (qd, j = 9.0, 6.6 Hz, 2H), 1.48 (s, 9H); ¹⁹F NMR (376 MHz, CDCl 3)? 73.2. This material was used without further purification.

Step 2. N- (2,2,2-Trifluoroethyl) Hydrazinecarboxamide Hydrochloride: To a mixed solution of tert-butyl 2 - ((2,2,2-trifluoroethyl) carbamoyl) hydrazinecarboxylate (1.62g, 6.30 mmol) in dry dioxane (10.0 mL) was added HCl (4 M in dioxane, 2-3 mL). The reaction mixture was stirred at ambient temperature for 18 hours and then refluxed for 2-3 hours. Thereafter, the reaction mixture was allowed to cool to ambient temperature and then evaporated to afford the title compound as a white solid (1.33 g, 109%): ¹H NMR (400 MHz, DMSO-re6) δ 10.12 (s, 3H), 9.25 (s, 1H), 7.72 (t, j = 6.5 Hz, 1H), 3.91 (qd , j = 9.7, 6.5 Hz, 2H); ¹⁹F NMR (376 MHz, DMSO-re 6) δ -71.41; ESIMS m / z 156 ([MH]^-). This material was used without further purification.

Step 3. (E -2- (2-bromo-4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-en-1-yl) benzoyl) N- (2,2,2-trifluoroethyl) hydrazinecarboxamide: For a solution containing (E) -2-bromo-4 (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1) acid en-1-yl) benzoic acid (120 mg, 0.246 mmol), 1,2-dichloroethane (DCE) (5 ml) were successively added EDCl2 HCl (70.6 mg, 0.368 mmol), N- (2,2,2-trifluoroethyl) hydrochloride hydrazinecarboxamide (52.3 mg, 0.270 mmol) and DMAP (63.0 mg, 0.516 mmol). The reaction mixture was stirred at ambient temperature for 18 hours. Then, the reaction mixture was diluted with CH2Cl2, washed with 0.1N HCl, and successively with aqueous NaHCO3, dried (MgSO4), filtered and evaporated to dryness. The crude product was purified by flash column chromatography to afford the title compound as a glassy oil (40mg, 26%):¹H NMR (400 MHz, CDCl 3) δ 8.12 (s, 1H), 7.65 (s, 1H), 7.60 (d, j = 8.0 Hz, 1H), 7.51 (d, one = 6.4 Hz, 1H), 7.40 (s, 3H), 6.54 (d, j = 15.8 Hz, 1H), 6.42 (dd, j = 16.0, 7.7 Hz , 1H), 5.95 (s, 1H), 4.10 (s, 1H), 3.91 (m, 2H); ¹⁹F NMR (376 MHz, CDCl 3)? -68.56, -73.02; ESIMS m / z 627.9 ([M + H] +).

Example 129: Preparation of (E) -1-isopropyl-2- (4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-enyl) -2- (trifluoromethyl) benzoyl) -N- (2,2,2-trifluoroethyl) hydrazinecarboxamide (FA3) [0709]

<img file="PL2934142T3_D0292.tif" />

[0710] To a stirred solution of 2- (trifluoromethyl) -4 - [(E) -4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-enyl] benzoic acid (300 mg, 0.63 mmol) in DMF (2 ml) at ambient temperature, added DIPEA (0.32 ml, 1.88 mmol), 1- [bis (dimethylamino) methylene] -1H-1.2 3-oxide hexafluorophosphate , 3-triazolo [4,5-b] pyridinium (HATU) (263 mg, 0.69 mmol) and 1-amino-1-isopropyl-3- (2,2,2-trifluoroethyl) urea hydrochloride (178 mg, 0.75 mmol) and the reaction mixture was stirred for 4 hours. Water was added to the reaction mixture and it was extracted with EtOAc. The organic layer was washed with brine then water, dried (Na2SO4), filtered and concentrated. The residue was purified by a method

119

On silica column chromatography, eluting with 20% EtOAc in petroleum ether, the title compound was obtained as a brown gum (135mg, 29%).

Example 130 * not according to the invention: Preparation of 1-isopropyl-N- (2,2,2 trifluoroethyl) hydrazinecarboxamide hydrochloride: [0711]

HCI H₂N

ABOUT

Step 1. Tert-butyl 2-isopropyl-2- (2,2,2-trifluoroethylcarbamoyl) hydrazine carboxylate: To a solution of triphosgene (298 mg, 1 mmol) in CH2Cl2 (8 mL) at -40 ° C was added 2. 2,2-trifluoroethanamine (284 mg, 2.87 mmol), TEA (0.8 mL, 5.74 mmol)) in CH2Cl2 (6 mL) and the reaction mixture was stirred for 30 minutes. Then tert-butyl N (isopropylamino) carbamate (JOC, 2013, 78, 3541-3552) (500 mg, 2.87 mmol) in CH2Cl2 (4 mL) was added to the reaction mixture at -40 ° C and stirred at ambient temperature for night. Subsequently, water was added to the reaction mixture and extracted with CH2Cl2. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated to provide the title compound as an off-white solid (580 mg, crude): mp 90-94 ° C;¹H NMR (400 MHz, DMSO-re 6) δ 8.70 (bs, 1H), 6.81 (t, J = 6.3, 1H), 3.89-3.80 (m, 2H), 3. 11 - 3.08 (m, 1H), 1.40 (s, 9H), 0.97 (d, j = 6.0 Hz, 6H); ESIMS m / z 241.9 ([M-tert-Butyl] +).

[0713] The following compounds * not according to the invention were prepared according to the procedures disclosed in Step 1 of Example 130.

Benzyl-2-methyl-2- (2,2,2-trifluoroethylcarbamoyl) hydrazinecarboxylate

[0714]

<img file="PL2934142T3_D0293.tif" />

[0715] The title compound is isolated as a colorless gum (8.0 g, 20%): ¹H NMR (300 MHz, DMSO-d6) δ 9.45 (s, 1H), 7.41 (m, 6H), 5.11 (s, 2H), 3.85-3.73 (m, 2H) . 2.95 (s, 3H); IR (thin layer) 3332, 2960, 1735, 1161.742 cm^-1.

Benzyl - ((2,2-difluoroethyl) carbamoyl) -2-methylhydrazinecarboxylate [0716]

<img file="PL2934142T3_D0294.tif" />

[0717] The title compound is isolated as a brown solid: mp 79-82 ° C; ¹H NMR (300 MHz, DMSOre6) δ 9.39 (bs, 1H), 7.38 - 7.35 (m, 5H), 6.10 - 5.75 (m, 1H), 5.72 (bs, 1H), 5.10 (s, 2H), 3.41-3.36 (m, 2H), 2.94 (s, 3H).

Benzyl 2-methyl-2 - ((3,3,3-trifluoropropyl) carbamoyl) hydrazinecarboxylate

[0718]

120

EP-2934142B1PL

<img file="PL2934142T3_D0295.tif" />

[0719] The title compound is isolated as a brown solid: ¹H NMR (300 MHz, DMSO-re6) δ 9.46 (bs, 1H), 7.37 - 7.30 (m, 5H), 5.10 (s, 2H), 4.50 (bs, 1H) , 3.31 - 3.19 (m, 2H), 2.92 (s, 3H), 2.38 - 2.33 (m, 2H); ESIMS m / z 320.3 ([M + H] +); IR (thin layer) 3415, 1647, 1267, 1143, 742, 514 cm^-1.

Step 2. 1-Isopropyl-N- (2,2,2-trifluoroethyl) hydrazinecarboxamide hydrochloride

[0720] HCl (4 M in dioxane, 10 ml) and the reaction mixture was stirred at ambient temperature for 2 hours. Volatiles were evaporated and the residue washed with pentane to afford the title compound as a pale yellow solid. (360 mg, crude):¹H NMR (300 MHz, DMSO-re 6) δ 11.2 (bs, 2H), 9.81 (s, 1H), 6.98 (t, j = 6.3 Hz, 1H), 3.90 3. 80 (m, 2H), 3.07-3.03 (m, 1H), 1.18 (d, j = 6.6 Hz, 6H); ¹³C NMR (300 MHz, DMSO-re 6) 157.06, 126.90, 52.25, 45.33, 17.49; ¹⁹F NMR (300 MHz, DMSO-re 6)? - 71.52; ESIMS m / z 200.0 ([M-HCl]⁺).

Example 131: Preparation of 1-methyl-N- (2,2,2-trifluoroethyl) hydrazinecarboxamide hydrochloride:

[0721]

ABOUT

HCl H₂N._nAND_n^ Ih ³[0722] To a stirred solution of benzyl N- (2,2,2-trifluoroethylcarbamoylamino) carbamate (8.0 g, 27.47 mmol) in MeOH (80 mL) was added Pd-C (10%, 0.88 g, 8.24 mmol) and the reaction mixture was stirred under a hydrogen atmosphere (30 psi) at ambient temperature for 12 hours. Then, the reaction mixture was filtered through Celite® and washed with MeOH. The filtrate was concentrated and the residue was dissolved in 1,4-dioxane (20 ml) and HCl (4M in 1,4-dioxane, 10 ml) was added with stirring. After stirring at ambient temperature for 3 hours, the volatiles were evaporated in vacuo and the residue was washed with EtOAc. The precipitated solid was dried in vacuo to give the title compound as a white solid (3 g, 50%):¹H NMR (300 MHz, DMSO-re6) δ 9.88 (bs, 2H), 7.99 (bs, 1H), 3.94-3.82 (m, 2H), 3.12 (s, 3H); ¹⁹F NMR (300 MHz, DMSO-re 6) 8711.11; ESIMS m / z 171.2 ([M-HCl]⁺); IR (thin layer) 3243, 1679, 1565, 1157, 648 cm^-1.

[0723] The following compounds * not of the invention were prepared according to the procedures disclosed in Example 131 without further treatment with HCl.

N- (2,2-Difluoroethyl) -1-methylhydrazinecarboxamide [0724]

O ^ 'N ^ N ^ CHFz

IH ²

[0725] The title compound is isolated as a pale yellow solid: mp 81-84 ° C; ¹H NMR (300 MHz, DMSO-re6) δ 7.00 (t, j = 6.3 Hz, 1H), 6.14 - 5.74 (m, 1H), 4.52 (bs, 2H), 3 , 46 - 3.32 (m, 2H); 2.95 (s, 3H); EIMS m / z 153.2 ([M] +).

1-Methyl-N- (3,3,3-trifluoropropyl) hydrazinecarboxamide

121

EP-2934142B1PL

[0726]

<img file="PL2934142T3_D0296.tif" />

[0727] The title compound was isolated as a yellow semisolid: ¹H NMR (300 MHz, DMSO-ree) δ 6.93 (bs, 1H), 4.40 (bs, 2H), 3.25 - 3.02 (m, 2H), 2.91 (s, 3H) , 2.87 - 2.56 (m, 2H); EIMS m / z 185.2 ([M] +); IR (thin layer) 3409, 1652, 1530, 1144, 763, 552 cm^-1.

Example 132 * not according to the invention: Preparation of 3,5-dibromo-4-chlorobenzaldehyde [0728] ^Br^^ b ^^CH0TT

Br

Step 1. Methyl 4-Amino-3,5-dibromobenzoate: Conc. H2SO4 (1.35 mL, 25.48 mmol) was added dropwise to a stirred solution of 4-amino-3,5-dibromobenzoic acid (5.0 g, 16.99 mmol) in MeOH (50 mL) at ambient temperature followed by the reaction mixture was stirred at 80 ° C for 8 h. The reaction mixture was allowed to cool to ambient temperature, the volatiles were evaporated and ice water was added to the residue which was then extracted with EtOAc. The organic layer was washed with an aqueous NaHCO3 solution followed by brine and water. The solution was then dried (Na2SO4), filtered and concentrated to provide the title compound as an off-white solid (5.0 g, 95%):¹H NMR (300 MHz, DMSO-d5) δ 7.91 (s, 2H), 6.20 (bs, 2H), 3.78 (s, 3H); ESIMS m / z 307.0 ([M] +); IR (thin layer) 3312, 2953, 1726, 595 cm^-1.

[0730] Step 2. Methyl 3,5-Dibromo-4-chlorobenzoate: CuCl2 (2.82 g, 21.0 mmol) in MeCN (30 mL) was stirred at 80 ° C for 30 min. Then tert-butyl nitrite (2.7 ml, 23 mmol) was added dropwise to this mixture at the same temperature, and the mixture was stirred for another 10 min. Methyl 4-amino-3,5-dibromobenzoate (5.0 g, 16 mmol) in MeCN (30 mL) was added dropwise to the reaction mixture, followed by stirring at 80 ° C for 30 min. The reaction mixture was allowed to cool to ambient temperature and an aqueous ammonia solution (20 ml) was added to the reaction mixture and extracted with petroleum ether. The organic layer was washed with brine then water, dried (Na2SO4), filtered and concentrated to provide the title compound as an off-white solid (4.5 g, 84%). 1 H NMR (300 MHz, DMSO-d6) δ 8.21 (s, 2H), 3.94 (s, 3H); ESIMS m / z 326 ([M] +); IR (thin layer) 1732.746 cm^-1.

Step 3. (3,5-Dibromo-4-chlorophenyl) methanol: NaBH4 (1.53 g, 40.65 mmol) was added portionwise to a stirred solution of methyl 3,5-dibromo-4-chlorobenzoate (4.45 g, 13.6 mmol) in MeOH (50 mL) at 0 ° C. The reaction mixture was then stirred at ambient temperature for 8 h. The volatiles were evaporated and the residue was diluted with CH2Cl2 and washed with brine then water. The organic layer was dried (Na2SO4), filtered and concentrated to give the title compound as an off-white solid (3.3 g, 80%): 1H NMR (300 MHz, DMSO-d6) δ 7.71 (s, 2H), 5. 49 (bs, 1H), 4.48 (d, J = 4.5 Hz, 2H); ESIMS m / z 297.9 ([M] +); IR (thin layer) 3460, 747, 534 cm^-1.

Step 4. 3,5-Dibromo-4-chlorobenzaldehyde: Pyridinium chlorochromate (PCC, 3.44 g, 15.9 mmol) was added in one portion to a stirred solution of (3,5-dibromo-4-chlorophenyl) methanol (3.2 g, 11.0

122

EP-2934142B1PL mmol) in CHCl3 (40 ml) at ambient temperature and the reaction mixture was stirred overnight.

The reaction mixture was filtered through Celite®, the Celite® pad was washed with CHCl3 and the filtrate concentrated to provide the title compound as an off-white solid (2.0 g, 62%): mp 110-113 ° C; 1H NMR (300

MHz, DMSO-d6) δ 9.93 (s, 1H), 8.27 (s, 2H); ESIMS m / z 297.0 ([M] +).

Example 133 * not according to the invention: Preparation of 4-Bromo-3,5-dichlorobenzaldehyde

[0733]

<img file="PL2934142T3_D0297.tif" />

Step 1. Methyl 4-Amino-3,5-dichlorobenzoate: Conc. H 2 SO 4 (2.5 mL, 97.04 mmol) was added dropwise to a stirred solution of 4-amino-3,5-dichlorobenzoic acid (10.0 g, 48.54 mmol) in MeOH (150 mL) at 0 ° C. then the reaction mixture was stirred at 80 ° C for 8 h. Volatiles were evaporated; ice water was added to the residue which was then extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to provide the title compound as a white solid (7.5 g, 70%): 1H NMR (300 MHz, DMSO-d6) δ 8.05 ( s. 2H); 3.96 (s, 3H); ESIMS m / z 282 ([M] +); IR (KBr): 1733,762,514 cm^-1.

Step 2. Methyl 4-Bromo-3,5-dichlorobenzoate: CuBr2 (7.5 g, 34.08 mmol) in MeCN (50 mL) was stirred at 80 ° C for 30 min. To this solution was added tert-butyl nitrite (6.5 ml, 54.55 mmol) dropwise at the same temperature, and the mixture was stirred for another 10 min. Methyl 4-amino-3,5-dichlorobenzoate in MeCN (30 ml) was added dropwise to the reaction mixture, which was then stirred at 80 ° C for 30 min. The reaction mixture was allowed to cool to ambient temperature. Aqueous ammonia solution (20 ml) was added and extraction was carried out with petroleum ether. The organic layer was washed with brine then water, dried (Na2SO4), filtered and concentrated to provide the title compound as an off-white solid (7.5 g, 77%):¹H NMR (300 MHz, DMSO-d6) δ 8.02 (s, 2H), 3.94 (s, 3H); ESIMS m / z 282 ([M]⁺); IR (thin layer) 1733, 762, 514 cm^-1.

Step 3. (4-Bromo-3,5-dichlorophenyl) methanol: DIBAL-H (1M in toluene, 66 mL, and 66.0 mmol) was added dropwise to a stirred solution of 4-bromo-3,5-dichlorobenzoate methyl (7.5 g, 26.0 mmol) in THF (50 mL) at -78 ° C. The reaction mixture was allowed to warm to ambient temperature and was stirred for 6 h. The reaction mixture was poured into ice water and extracted with CH2Cl2. The organic layer was washed with brine then water, dried (Na2SO4), filtered and concentrated to give a mixture of (4-bromo-3,5-dichlorophenyl) methanol and 4-bromo-3,5-dichlorobenzaldehyde (6.0 g) as an off-white solid that was taken to the next step without purification.

Step 4. 4-Bromo-3,5-dichlorobenzaldehyde: PCC (7.5 g, 35.16 mmol) was added in one portion to a stirred solution containing a mixture of (4-bromo-3,5-dichlorophenyl) methanol and 4-bromo-3,5-dichlorobenzaldehyde (6.0 g) in CHCl3 (40 ml) at ambient temperature and the reaction mixture was stirred overnight. The reaction mixture was filtered through celite. The celite layer was washed with CHCl3. The filtrate was concentrated to provide the title compound as an off-white solid (3.5 g, 67%): mp 125-128 ° C; 1 H NMR (300 MHz, DMSO-d₆) δ 9.96 (s, 1H), 8.10 (s, 2H); ESIMS m / z252 ([M] +).

123

EP-2934142B1PL

Example 134 * not according to the invention: Preparation of (E) - N- (2-Aminoethyl) -2-bromo-4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-enyl) benzamide

[0738]

<img file="PL2934142T3_D0298.tif" />

Step 1. tert- (E) -2- (2-Bromo-4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-enyl) benzamido) ethylcarbamate butyl: PyBOP (420 mg, 0.82 mmol) and DIPEA (0.410 mL, 2.46 mmol) were added to the stirred solution of (E) -2-bromo-4- (4,4,4-trifluoro-3- ( 3,4,5-trichlorophenyl) but-1-phenyl) benzoic acid (400 mg, 0.82 mmol) and tert-butyl 2-aminoethylcarbamate (130 mg, 0.82 mmol) in CH2Cl2 (10 mL) and the reaction mixture was stirred at ambient temperature for 18 h. Water was added to the reaction mixture, followed by extraction with CH2Cl2 (25 mL). The organic layer was washed with 2N HCl followed by saturated aqueous NaHCO3 solution and brine. The organic layer was dried (Na2SO4), filtered, concentrated and the residue was purified by column chromatography on silica (100-200 mesh) eluting with 40% EtOAc in petroleum ether to afford the title compound as a tan solid (200mg, 39%):¹1 H NMR (400 MHz, DMSO-d₆) δ 8.38 (t, J = 5.2 Hz, 1H), 7.91 - 7.89 (m, 3H), 7.58 (d, J = 6.8 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H), 6.99 (dd, J = 15.6, 9.2 Hz, 1H), 6.84 (t, J = 6.0 Hz, 1H), 6 . 76 (t, J = 15.6 Hz, 1H), 4.84 - 4.80 (m, 1H), 3.24 - 3.20 (m, 2H), 3.11- 3.08 (m , 2H), 1.30 (s, 9H); ESIMS m / z 628.80 ([M + H] +); IR (thin layer) 3365, 1701, 1167, 699, 555 cm^-1.

Step 2. (E) -N- (2-Aminoethyl) -2-bromo-4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-enyl) Benzamide: TFA (0.5 ml) was added to the stirred solution of (E) -2- (2-bromo-4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-enyl) benzamido) tert-butyl ethyl carbamate (200 mg, 0.31 mmol) in CH2Cl2 (10 mL) at 0 ° C and then the reaction mixture was stirred at ambient temperature for 18 h. Volatiles were evaporated under reduced pressure; Water was added to the residue, and the mixture was extracted with CH2Cl2. The organic layer was washed with brine, dried (Na2SO4), filtered, concentrated and the residue was purified by column chromatography on silica (100-200 mesh) eluting with 1-5% MeOH in CH2Cl2 to give the title compound as a tan solid (50mg, 31% ): 1 H NMR (400 MHz, DMSO-d₆) δ 8.56 (bs, 1H), 7.70 (bs, 2H), 7.94 - 7.91 (m, 3H), 7.62 -7.59 (m, 1H), 7.50 ( d, J = 7.6 Hz, 1H), 7.00 (dd, J = 15.6, 9.2 Hz, 1H), 6.77 [0741] (d, J = 15.6 Hz, 1H) , 4.84 - 4.81 (m, 1H), 3.46-3.41 (m, 2H), 2.95 - 2.92 (m, 2H); ESIMS m / z 528.72 ([M + H] +); IR (thin layer) 3435, 1671, 1113, 722, 555 cm^-1.

Example 135: Preparation of (E) - N- (2-aminoethyl) -4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-en-yl) -2- ( trifluoromethyl) benzamide (FA10)

[0742]

<img file="PL2934142T3_D0299.tif" />

To solution of (E) - N-2-aminoethyl) -4- (4,4,4-trifluoro-3- (3,4,5-trichlorophenyl) but-1-en-1-yl) -2 (trifluoromethyl) benzamide (0.2 g, 0.385 mmol) in CH2CL (4 ml) under nitrogen atmosphere, triphosgene (228 mg, 0.770 mmol) and triethylamine (0.445 ml, 3.19 mmol) were added and cooled in an ice bath. Then, the mixture was stirred at ambient temperature for 1.5 hours before it was treated with 2.2.2124

Trifluoroethanamine (0.248 mL, 3.01 mmol). After stirring for 18 hours at ambient temperature, the mixture was partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc. The combined organic phases were concentrated in vacuo and the resulting crude oil was purified by silica column chromatography eluting with EtOAc and hexanes - affording the title compound as a viscous yellow / green oil (50 mg, 20%).

[0744] The following predicted molecules can be made according to the procedures disclosed in Predictive Example F1:

[0744] The following prophetic molecules can be made according to the procedures disclosed in Prophetic Example F1:

<td>Relationship number</td><td>Structure</td>

<td>F1</td><td>cf₃^CI\ zA&gt; / VYY /^BrAnd I CI ^ Y ^ nn Cl OI ^H.</td>

<td>F2</td><td>cf₃^c\ XzxY^withv-^ErAJ AAA a VNN Cl OI ^H.</td>

<td>F3</td><td>cf₃Br O। ^H.</td>

<td>F4</td><td>cf₃Cl OI ^H.</td>

<td>F5</td><td>cf₃aj (Za a □ Y 'NN Custom duty ^{1 H.}</td>

<td>F6</td><td>CF, AJ YEARS a CI ^ Y ^ NN Custom duty . ^H.</td>

<td>F7</td><td>cf₃TW- Custom duty ^HH</td>

<td>F8</td><td>cf₃Custom duty ^HH</td>

125

EP-2934142B1PL

<td>Relationship number</td><td>Structure</td>

<td>F9</td><td>cf₃TM- Br 0</td>

<td>F10</td><td>cf₃Custom duty ^HH</td>

<td>F11</td><td>cf₃you Fr ^HH</td>

<td>F12</td><td>cf₃you Fr ^hh</td>

<td>F13</td><td>cf₃Μγ ^_ΝΑ_Ν^ 0Ε3 you o ^hh</td>

<td>F14</td><td>cf₃Custom duty ^HH</td>

<td>F15</td><td>cf₃Br 0</td>

<td>F 16</td><td>cf₃Custom duty ^HH</td>

<td>F17</td><td>cf₃Cl ^^ L0y^N'_NT ^ CF3 Custom duty ^HH</td>

<td>F18</td><td>cf₃you Fr ^hh</td>

<td>F19</td><td>cf₃XX Thai j CI ^ Y] ^HNCl 0 L._nX₀H.</td>

126

EP-2934142B1PL

<td>Relationship number</td><td>Structure</td>

<td>F20</td><td>CF₃XX XXr j^F. ^ fi] ^HNCl 0 L._nAND₀H.</td>

<td>F21</td><td>cf₃ΥΧΧΧΐ J χ T hn Br 0 L._nAND₀H.</td>

<td>F22</td><td>cf₃χγ uCn j ci ^ Y ^ γ η hn You 0 L._nAND₀H.</td>

<td>F23</td><td>CF₃Ck / ^ X XXn j Cl ^ f ^ Π] ^HNYou 0 l_NAND₀H.</td>

<td>F24</td><td>CF₃Xyi uCn j ci ^ f ^ Y i ^HNYou 0 l_NAND₀H.</td>

<td>F25</td><td>cf₃those ^BrX XXn j ci ^ Y ^ Y η hn C '0 Ik AND</td>

<td>F26</td><td>cf₃ΧΧΐΧΐ j^F. T. ^HNYou 0 L._nAND₀AND</td>

<td>F27</td><td>cf₃XX XXn j γ ^ ^ Y Ί HN Br 0 L._nAND_qAND</td>

<td>F28</td><td>- \ About PLN ^x zxz \ Y ° lY? ° \ &lt;^ Ao oo</td>

127

EP-2934142B1PL

<td>Relationship number</td><td>Structure</td>

<td>F29</td><td>CF₃YOU XXn j ci ^ Y ^ Y i ^HNCl 0 L._nAND₀AND</td>

<td>F30</td><td>cf₃YY j CI ^ Y ^ γ η HN^{Cl 0} Vo AND</td>

<td>F31</td><td>cf₃Cl ^Brtt iXn j CI ^ YI ^HNCl 0 L._NAND_S.H.</td>

<td>F32</td><td>cf₃Cl ^Brχτ UU j^F. ^ TI ^HNYou 0 H.</td>

<td>F33</td><td>cf₃U τχ bj Y ^ ΥΠ HN Br 0 H.</td>

<td>F34</td><td>cf₃Ck / A / \ AvAZ XT uCn j ci ^ yi ^HNYou 0 L._nAND_sH.</td>

<td>F35</td><td>cf₃CI \ ^ YAa / a ^ ci AJ XXn j ci ^ Y ^ hn ci 0 Y_sH.</td>

<td>F36</td><td>cf₃υπΧκ j CI ^ Y ^ Y] ^HNCl 0 Y_sH.</td>

<td>F37</td><td>cf₃cIyYtyt ω IJ UJ A ClY ^ ^ γ NN ^ Cl 0 ^{1 H.}</td>

128

EP-2934142B1PL

<img file="PL2934142T3_D0300.tif" />

[0745] The following anticipated molecules can be prepared according to the procedures disclosed in this application:

<img file="PL2934142T3_D0301.tif" />

<td>Relationship number</td><td>R1</td><td>R2</td><td>R3</td><td>R4</td><td>R6</td><td>R8</td><td>R10</td><td>R11a</td><td>X5</td><td>R11 b</td>

<td>F41</td><td>F.</td><td>F.</td><td>F.</td><td>H.</td><td>CF₃</td><td>H.</td><td>Br</td><td>ch₃</td><td> 0</td><td>CH₂CH₃</td>

<td>F42</td><td>F.</td><td>F.</td><td>F.</td><td>H.</td><td>cf₃</td><td>H.</td><td>Cl</td><td>ch₃</td><td> 0</td><td>ch₂ch₃</td>

<td>F43</td><td>F.</td><td>F.</td><td>F.</td><td>H.</td><td>cf₃</td><td>H.</td><td>CF₃</td><td>ch₃</td><td> 0</td><td>ch₂ch₃</td>

<td>F44</td><td>F.</td><td>F.</td><td>F.</td><td>H.</td><td>cf₃</td><td>H.</td><td>ch₃</td><td>ch₃</td><td> 0</td><td>ch₂ch₃</td>

<td>F45</td><td>F.</td><td>F.</td><td>F.</td><td>H.</td><td>cf₃</td><td>H.</td><td>Br</td><td>ch₃</td><td>S.</td><td>ch₂ch₃</td>

<td>F46</td><td>F.</td><td>F.</td><td>F.</td><td>H.</td><td>cf₃</td><td>H.</td><td>Cl</td><td>ch₃</td><td>S.</td><td>ch₂ch₃</td>

<td>F47</td><td>F.</td><td>F.</td><td>F.</td><td>H.</td><td>cf₃</td><td>H.</td><td>CF₃</td><td>ch₃</td><td>S.</td><td>ch₂ch₃</td>

<td>F48</td><td>F.</td><td>F.</td><td>F.</td><td>H.</td><td>cf₃</td><td>H.</td><td>ch₃</td><td>ch₃</td><td>S.</td><td>ch₂ch₃</td>

<td>F49</td><td>F.</td><td>F.</td><td>F.</td><td>H.</td><td>cf₃</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>ch₂ch₃</td>

<td>F50</td><td>F.</td><td>F.</td><td>F.</td><td>H.</td><td>cf₃</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>ch₂ch₃</td>

<td>F51</td><td>F.</td><td>F.</td><td>F.</td><td>H.</td><td>cf₃</td><td>H.</td><td>cf₃</td><td>H.</td><td> 0</td><td>ch₂ch₃</td>

<td>F52</td><td>F.</td><td>F.</td><td>F.</td><td>H.</td><td>cf₃</td><td>H.</td><td>ch₃</td><td>H.</td><td> 0</td><td>ch₂ch₃</td>

<td>F53</td><td>F.</td><td>F.</td><td>F.</td><td>H.</td><td>cf₃</td><td>H.</td><td>Br</td><td>H.</td><td>s</td><td>ch₂ch₃</td>

129

EP-2934142B1PL

<td>Relationship number</td><td>R1</td><td>R2</td><td>R3</td><td>R4</td><td>R6</td><td>R8</td><td>R10</td><td>R11a</td><td>X5</td><td>R11b</td>

<td>F54</td><td>F.</td><td>F.</td><td>F.</td><td>H.</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F55</td><td>F.</td><td>F.</td><td>F.</td><td>H.</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F56</td><td>F.</td><td>F.</td><td>F.</td><td>H.</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F57</td><td>F.</td><td>F.</td><td>F.</td><td>H.</td><td>CFs</td><td>CFs</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F58</td><td>F.</td><td>F.</td><td>F.</td><td>H.</td><td>CFs</td><td>CFs</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F59</td><td>F.</td><td>F.</td><td>F.</td><td>H.</td><td>CFs</td><td>CFs</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F60</td><td>F.</td><td>F.</td><td>F.</td><td>H.</td><td>CFs</td><td>CFs</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F61</td><td>F.</td><td>F.</td><td>F.</td><td>H.</td><td>CF2CF3</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F62</td><td>F.</td><td>F.</td><td>F.</td><td>H.</td><td>CF2CF3</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F63</td><td>F.</td><td>F.</td><td>F.</td><td>H.</td><td>CF2CF3</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F64</td><td>F.</td><td>F.</td><td>F.</td><td>H.</td><td>CF2CF3</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F65</td><td>F.</td><td>F.</td><td>F.</td><td>H.</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F66</td><td>F.</td><td>F.</td><td>F.</td><td>H.</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F67</td><td>F.</td><td>F.</td><td>F.</td><td>H.</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F68</td><td>F.</td><td>F.</td><td>F.</td><td>H.</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F69</td><td>F.</td><td>F.</td><td>F.</td><td>H.</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F70</td><td>F.</td><td>F.</td><td>F.</td><td>H.</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F71</td><td>F.</td><td>F.</td><td>F.</td><td>H.</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F72</td><td>F.</td><td>F.</td><td>F.</td><td>H.</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F73</td><td>Cl</td><td>Cl</td><td>H.</td><td>Cl</td><td>CFs</td><td>H.</td><td>Br</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F74</td><td>Cl</td><td>Cl</td><td>H.</td><td>Cl</td><td>CFs</td><td>H.</td><td>Cl</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F75</td><td>Cl</td><td>Cl</td><td>H.</td><td>Cl</td><td>CFs</td><td>H.</td><td>CFs</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F76</td><td>Cl</td><td>Cl</td><td>H.</td><td>Cl</td><td>CFs</td><td>H.</td><td>CHs</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F77</td><td>Cl</td><td>Cl</td><td>H.</td><td>Cl</td><td>CFs</td><td>H.</td><td>Br</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F78</td><td>Cl</td><td>Cl</td><td>H.</td><td>Cl</td><td>CFs</td><td>H.</td><td>Cl</td><td>CHs</td><td>s</td><td>CH2CH3</td>

<td>F79</td><td>Cl</td><td>Cl</td><td>H.</td><td>Cl</td><td>CFs</td><td>H.</td><td>CFs</td><td>CHs</td><td>s</td><td>CH2CH3</td>

<td>F80</td><td>Cl</td><td>Cl</td><td>H.</td><td>Cl</td><td>CFs</td><td>H.</td><td>CHs</td><td>CHs</td><td>s</td><td>CH2CH3</td>

<td>F81</td><td>Cl</td><td>Cl</td><td>H.</td><td>Cl</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F82</td><td>Cl</td><td>Cl</td><td>H.</td><td>Cl</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F83</td><td>Cl</td><td>Cl</td><td>H.</td><td>Cl</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CH3</td>

130

EP-2934142B1PL

<td>Relationship number</td><td>R1</td><td>R2</td><td>R3</td><td>R4</td><td>R6</td><td>R8</td><td>R10</td><td>R11a</td><td>X5</td><td>R11b</td>

<td>F84</td><td>Cl</td><td>Cl</td><td>H.</td><td>Cl</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F85</td><td>Cl</td><td>Cl</td><td>H.</td><td>Cl</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F86</td><td>Cl</td><td>Cl</td><td>H.</td><td>Cl</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F87</td><td>Cl</td><td>Cl</td><td>H.</td><td>Cl</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F88</td><td>Cl</td><td>Cl</td><td>H.</td><td>Cl</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F89</td><td>Cl</td><td>Cl</td><td>H.</td><td>Cl</td><td>CFs</td><td>CFs</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F90</td><td>Cl</td><td>Cl</td><td>H.</td><td>Cl</td><td>CFs</td><td>CFs</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F91</td><td>Cl</td><td>Cl</td><td>H.</td><td>Cl</td><td>CFs</td><td>CFs</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F92</td><td>Cl</td><td>Cl</td><td>H.</td><td>Cl</td><td>CFs</td><td>CFs</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F93</td><td>Cl</td><td>Cl</td><td>H.</td><td>Cl</td><td>CF2CF3</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F94</td><td>Cl</td><td>Cl</td><td>H.</td><td>Cl</td><td>CF2CF3</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F95</td><td>Cl</td><td>Cl</td><td>H.</td><td>Cl</td><td>CF2CF3</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F96</td><td>Cl</td><td>Cl</td><td>H.</td><td>Cl</td><td>CF2CF3</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F97</td><td>Cl</td><td>Cl</td><td>H.</td><td>Cl</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F98</td><td>Cl</td><td>Cl</td><td>H.</td><td>Cl</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F99</td><td>Cl</td><td>Cl</td><td>H.</td><td>Cl</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F100</td><td>Cl</td><td>Cl</td><td>H.</td><td>Cl</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F101</td><td>Cl</td><td>Cl</td><td>H.</td><td>Cl</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F102</td><td>Cl</td><td>Cl</td><td>H.</td><td>Cl</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F103</td><td>Cl</td><td>Cl</td><td>H.</td><td>Cl</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F104</td><td>Cl</td><td>Cl</td><td>H.</td><td>Cl</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F105</td><td>H.</td><td>H.</td><td>H.</td><td>OCFS</td><td>CFs</td><td>H.</td><td>Br</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F106</td><td>H.</td><td>H.</td><td>H.</td><td>0CF3</td><td>CFs</td><td>H.</td><td>Cl</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F107</td><td>H.</td><td>H.</td><td>H.</td><td>0CF3</td><td>CFs</td><td>H.</td><td>CFs</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F108</td><td>H.</td><td>H.</td><td>H.</td><td>0CF3</td><td>CFs</td><td>H.</td><td>CHs</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F109</td><td>H.</td><td>H.</td><td>H.</td><td>0CF3</td><td>CFs</td><td>H.</td><td>Br</td><td>CHs</td><td>s</td><td>CH2CH3</td>

<td>F110</td><td>H.</td><td>H.</td><td>H.</td><td>0CF3</td><td>CFs</td><td>H.</td><td>Cl</td><td>CHs</td><td>s</td><td>CH2CH3</td>

<td>F111</td><td>H.</td><td>H.</td><td>H.</td><td>0CF3</td><td>CFs</td><td>H.</td><td>CFs</td><td>CHs</td><td>s</td><td>CH2CH3</td>

<td>F112</td><td>H.</td><td>H.</td><td>H.</td><td>0CF3</td><td>CFs</td><td>H.</td><td>CHs</td><td>CHs</td><td>s</td><td>CH2CH3</td>

<td>F113</td><td>H.</td><td>H.</td><td>H.</td><td>0CF3</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CH3</td>

131

EP-2934142B1PL

<td>Relationship number</td><td>R1</td><td>R2</td><td>R3</td><td>R4</td><td>R6</td><td>R8</td><td>R10</td><td>R11a</td><td>X5</td><td>R11b</td>

<td>F114</td><td>H.</td><td>H.</td><td>H.</td><td>OCFs</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F115</td><td>H.</td><td>H.</td><td>H.</td><td>OCFs</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F116</td><td>H.</td><td>H.</td><td>H.</td><td>OCFs</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F117</td><td>H.</td><td>H.</td><td>H.</td><td>OCFs</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F118</td><td>H.</td><td>H.</td><td>H.</td><td>OCFs</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F119</td><td>H.</td><td>H.</td><td>H.</td><td>OCFs</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F120</td><td>H.</td><td>H.</td><td>H.</td><td>OCFs</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F121</td><td>H.</td><td>H.</td><td>H.</td><td>OCFs</td><td>CFs</td><td>CFs</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F122</td><td>H.</td><td>H.</td><td>H.</td><td>OCFs</td><td>CFs</td><td>CFs</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F123</td><td>H.</td><td>H.</td><td>H.</td><td>OCFs</td><td>CFs</td><td>CFs</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F124</td><td>H.</td><td>H.</td><td>H.</td><td>OCFs</td><td>CFs</td><td>CFs</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F125</td><td>H.</td><td>H.</td><td>H.</td><td>OCFs</td><td>CF2CF3</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F126</td><td>H.</td><td>H.</td><td>H.</td><td>OCFs</td><td>CF2CF3</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F127</td><td>H.</td><td>H.</td><td>H.</td><td>OCFs</td><td>CF2CF3</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F128</td><td>H.</td><td>H.</td><td>H.</td><td>OCFs</td><td>CF2CF3</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F129</td><td>H.</td><td>H.</td><td>H.</td><td>OCFs</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F130</td><td>H.</td><td>H.</td><td>H.</td><td>OCFs</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F131</td><td>H.</td><td>H.</td><td>H.</td><td>OCFs</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F132</td><td>H.</td><td>H.</td><td>H.</td><td>OCFs</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F133</td><td>H.</td><td>H.</td><td>H.</td><td>OCFs</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F134</td><td>H.</td><td>H.</td><td>H.</td><td>OCFs</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F135</td><td>H.</td><td>H.</td><td>H.</td><td>OCFs</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F136</td><td>H.</td><td>H.</td><td>H.</td><td>OCFs</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F137</td><td>H.</td><td>F.</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>Br</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F138</td><td>H.</td><td>F.</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>Cl</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F139</td><td>H.</td><td>F.</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>CFs</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F140</td><td>H.</td><td>F.</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>CHs</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F141</td><td>H.</td><td>F.</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>Br</td><td>CHs</td><td>s</td><td>CH2CH3</td>

<td>F142</td><td>H.</td><td>F.</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>Cl</td><td>CHs</td><td>s</td><td>CH2CH3</td>

<td>F143</td><td>H.</td><td>F.</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>CFs</td><td>CHs</td><td>s</td><td>CH2CH3</td>

132

EP-2934142B1PL

<td>Relationship number</td><td>R1</td><td>R2</td><td>R3</td><td>R4</td><td>R6</td><td>R8</td><td>R10</td><td>R11a</td><td>X5</td><td>R11b</td>

<td>F144</td><td>H.</td><td>F.</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>CHs</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F145</td><td>H.</td><td>F.</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F146</td><td>H.</td><td>F.</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F147</td><td>H.</td><td>F.</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F148</td><td>H.</td><td>F.</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F149</td><td>H.</td><td>F.</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F150</td><td>H.</td><td>F.</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F151</td><td>H.</td><td>F.</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F152</td><td>H.</td><td>F.</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F153</td><td>H.</td><td>F.</td><td>H.</td><td>Br</td><td>CFs</td><td>CFs</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F154</td><td>H.</td><td>F.</td><td>H.</td><td>Br</td><td>CFs</td><td>CFs</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F155</td><td>H.</td><td>F.</td><td>H.</td><td>Br</td><td>CFs</td><td>CFs</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F156</td><td>H.</td><td>F.</td><td>H.</td><td>Br</td><td>CFs</td><td>CFs</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F157</td><td>H.</td><td>F.</td><td>H.</td><td>Br</td><td>CF2CF3</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F158</td><td>H.</td><td>F.</td><td>H.</td><td>Br</td><td>CF2CF3</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F159</td><td>H.</td><td>F.</td><td>H.</td><td>Br</td><td>CF2CF3</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F160</td><td>H.</td><td>F.</td><td>H.</td><td>Br</td><td>CF2CF3</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F161</td><td>H.</td><td>F.</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F162</td><td>H.</td><td>F.</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F163</td><td>H.</td><td>F.</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F164</td><td>H.</td><td>F.</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F165</td><td>H.</td><td>F.</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F166</td><td>H.</td><td>F.</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F167</td><td>H.</td><td>F.</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F168</td><td>H.</td><td>F.</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td>s</td><td>CH2CF3</td>

<td>F169</td><td>H.</td><td>CHs</td><td>Cl</td><td>H.</td><td>CFs</td><td>H.</td><td>Br</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F170</td><td>H.</td><td>CHs</td><td>Cl</td><td>H.</td><td>CFs</td><td>H.</td><td>Cl</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F171</td><td>H.</td><td>CHs</td><td>Cl</td><td>H.</td><td>CFs</td><td>H.</td><td>CFs</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F172</td><td>H.</td><td>CHs</td><td>Cl</td><td>H.</td><td>CFs</td><td>H.</td><td>CHs</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F173</td><td>H.</td><td>CHs</td><td>Cl</td><td>H.</td><td>CFs</td><td>H.</td><td>Br</td><td>CHs</td><td>s</td><td>CH2CH3</td>

133

EP-2934142B1PL

<td>Relationship number</td><td>R1</td><td>R2</td><td>R3</td><td>R4</td><td>R6</td><td>R8</td><td>R10</td><td>R11a</td><td>X5</td><td>R11b</td>

<td>F174</td><td>H.</td><td>CHs</td><td>Cl</td><td>H.</td><td>CFs</td><td>H.</td><td>Cl</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F175</td><td>H.</td><td>CHs</td><td>Cl</td><td>H.</td><td>CFs</td><td>H.</td><td>CFs</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F176</td><td>H.</td><td>CHs</td><td>Cl</td><td>H.</td><td>CFs</td><td>H.</td><td>CHs</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F177</td><td>H.</td><td>CHs</td><td>Cl</td><td>H.</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F178</td><td>H.</td><td>CHs</td><td>Cl</td><td>H.</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F179</td><td>H.</td><td>CHs</td><td>Cl</td><td>H.</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F180</td><td>H.</td><td>CHs</td><td>Cl</td><td>H.</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F181</td><td>H.</td><td>CHs</td><td>Cl</td><td>H.</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F182</td><td>H.</td><td>CHs</td><td>Cl</td><td>H.</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F183</td><td>H.</td><td>CHs</td><td>Cl</td><td>H.</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F184</td><td>H.</td><td>CHs</td><td>Cl</td><td>H.</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F185</td><td>H.</td><td>CHs</td><td>Cl</td><td>H.</td><td>CFs</td><td>CFs</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F186</td><td>H.</td><td>CHs</td><td>Cl</td><td>H.</td><td>CFs</td><td>CFs</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F187</td><td>H.</td><td>CHs</td><td>Cl</td><td>H.</td><td>CFs</td><td>CFs</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F188</td><td>H.</td><td>CHs</td><td>Cl</td><td>H.</td><td>CFs</td><td>CFs</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F189</td><td>H.</td><td>CHs</td><td>Cl</td><td>H.</td><td>CF2CF3</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F190</td><td>H.</td><td>CHs</td><td>Cl</td><td>H.</td><td>CF2CF3</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F191</td><td>H.</td><td>CHs</td><td>Cl</td><td>H.</td><td>CF2CF3</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F192</td><td>H.</td><td>CHs</td><td>Cl</td><td>H.</td><td>CF2CF3</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F193</td><td>H.</td><td>CHs</td><td>Cl</td><td>H.</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F194</td><td>H.</td><td>CHs</td><td>Cl</td><td>H.</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F195</td><td>H.</td><td>CHs</td><td>Cl</td><td>H.</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F196</td><td>H.</td><td>CHs</td><td>Cl</td><td>H.</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F197</td><td>H.</td><td>CHs</td><td>Cl</td><td>H.</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F198</td><td>H.</td><td>CHs</td><td>Cl</td><td>H.</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td>s</td><td>CH2CF3</td>

<td>F199</td><td>H.</td><td>CHs</td><td>Cl</td><td>H.</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td>s</td><td>CH2CF3</td>

<td>F200</td><td>H.</td><td>CHs</td><td>Cl</td><td>H.</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td>s</td><td>CH2CF3</td>

<td>F201</td><td>H.</td><td>Cl</td><td>CHs</td><td>H.</td><td>CFs</td><td>H.</td><td>Br</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F202</td><td>H.</td><td>Cl</td><td>CHs</td><td>H.</td><td>CFs</td><td>H.</td><td>Cl</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F203</td><td>H.</td><td>Cl</td><td>CHs</td><td>H.</td><td>CFs</td><td>H.</td><td>CFs</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

134

EP-2934142B1PL

<td>Relationship number</td><td>R1</td><td>R2</td><td>R3</td><td>R4</td><td>R6</td><td>R8</td><td>R10</td><td>R11a</td><td>X5</td><td>R11b</td>

<td>F204</td><td>H.</td><td>Cl</td><td>CHs</td><td>H.</td><td>CFs</td><td>H.</td><td>CHs</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F205</td><td>H.</td><td>Cl</td><td>CHs</td><td>H.</td><td>CFs</td><td>H.</td><td>Br</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F206</td><td>H.</td><td>Cl</td><td>CHs</td><td>H.</td><td>CFs</td><td>H.</td><td>Cl</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F207</td><td>H.</td><td>Cl</td><td>CHs</td><td>H.</td><td>CFs</td><td>H.</td><td>CFs</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F208</td><td>H.</td><td>Cl</td><td>CHs</td><td>H.</td><td>CFs</td><td>H.</td><td>CHs</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F209</td><td>H.</td><td>Cl</td><td>CHs</td><td>H.</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F210</td><td>H.</td><td>Cl</td><td>CHs</td><td>H.</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F211</td><td>H.</td><td>Cl</td><td>CHs</td><td>H.</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F212</td><td>H.</td><td>Cl</td><td>CHs</td><td>H.</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F213</td><td>H.</td><td>Cl</td><td>CHs</td><td>H.</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F214</td><td>H.</td><td>Cl</td><td>CHs</td><td>H.</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F215</td><td>H.</td><td>Cl</td><td>CHs</td><td>H.</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F216</td><td>H.</td><td>Cl</td><td>CHs</td><td>H.</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F217</td><td>H.</td><td>Cl</td><td>CHs</td><td>H.</td><td>CFs</td><td>CFs</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F218</td><td>H.</td><td>Cl</td><td>CHs</td><td>H.</td><td>CFs</td><td>CFs</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F219</td><td>H.</td><td>Cl</td><td>CHs</td><td>H.</td><td>CFs</td><td>CFs</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F220</td><td>H.</td><td>Cl</td><td>CHs</td><td>H.</td><td>CFs</td><td>CFs</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F221</td><td>H.</td><td>Cl</td><td>CHs</td><td>H.</td><td>CF2CF3</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F222</td><td>H.</td><td>Cl</td><td>CHs</td><td>H.</td><td>CF2CF3</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F223</td><td>H.</td><td>Cl</td><td>CHs</td><td>H.</td><td>CF2CF3</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F224</td><td>H.</td><td>Cl</td><td>CHs</td><td>H.</td><td>CF2CF3</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F225</td><td>H.</td><td>Cl</td><td>CHs</td><td>H.</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F226</td><td>H.</td><td>Cl</td><td>CHs</td><td>H.</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F227</td><td>H.</td><td>Cl</td><td>CHs</td><td>H.</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F228</td><td>H.</td><td>Cl</td><td>CHs</td><td>H.</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F229</td><td>H.</td><td>Cl</td><td>CHs</td><td>H.</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td>s</td><td>CH2CF3</td>

<td>F230</td><td>H.</td><td>Cl</td><td>CHs</td><td>H.</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td>s</td><td>CH2CF3</td>

<td>F231</td><td>H.</td><td>Cl</td><td>CHs</td><td>H.</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td>s</td><td>CH2CF3</td>

<td>F232</td><td>H.</td><td>Cl</td><td>CHs</td><td>H.</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td>s</td><td>CH2CF3</td>

<td>F233</td><td>H.</td><td>CHs</td><td>F.</td><td>CHs</td><td>CFs</td><td>H.</td><td>Br</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

135

EP-2934142B1PL

<td>Relationship number</td><td>R1</td><td>R2</td><td>R3</td><td>R4</td><td>R6</td><td>R8</td><td>R10</td><td>R11a</td><td>X5</td><td>R11b</td>

<td>F234</td><td>H.</td><td>CHs</td><td>F.</td><td>CHs</td><td>CFs</td><td>H.</td><td>Cl</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F235</td><td>H.</td><td>CHs</td><td>F.</td><td>CHs</td><td>CFs</td><td>H.</td><td>CFs</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F236</td><td>H.</td><td>CHs</td><td>F.</td><td>CHs</td><td>CFs</td><td>H.</td><td>CHs</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F237</td><td>H.</td><td>CHs</td><td>F.</td><td>CHs</td><td>CFs</td><td>H.</td><td>Br</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F238</td><td>H.</td><td>CHs</td><td>F.</td><td>CHs</td><td>CFs</td><td>H.</td><td>Cl</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F239</td><td>H.</td><td>CHs</td><td>F.</td><td>CHs</td><td>CFs</td><td>H.</td><td>CFs</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F240</td><td>H.</td><td>CHs</td><td>F.</td><td>CHs</td><td>CFs</td><td>H.</td><td>CHs</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F241</td><td>H.</td><td>CHs</td><td>F.</td><td>CHs</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F242</td><td>H.</td><td>CHs</td><td>F.</td><td>CHs</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F243</td><td>H.</td><td>CHs</td><td>F.</td><td>CHs</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F244</td><td>H.</td><td>CHs</td><td>F.</td><td>CHs</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F245</td><td>H.</td><td>CHs</td><td>F.</td><td>CHs</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F246</td><td>H.</td><td>CHs</td><td>F.</td><td>CHs</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F247</td><td>H.</td><td>CHs</td><td>F.</td><td>CHs</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F248</td><td>H.</td><td>CHs</td><td>F.</td><td>CHs</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F249</td><td>H.</td><td>CHs</td><td>F.</td><td>CHs</td><td>CFs</td><td>CFs</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F250</td><td>H.</td><td>CHs</td><td>F.</td><td>CHs</td><td>CFs</td><td>CFs</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F251</td><td>H.</td><td>CHs</td><td>F.</td><td>CHs</td><td>CFs</td><td>CFs</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F252</td><td>H.</td><td>CHs</td><td>F.</td><td>CHs</td><td>CFs</td><td>CFs</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F253</td><td>H.</td><td>CHs</td><td>F.</td><td>CHs</td><td>CF2CF3</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F254</td><td>H.</td><td>CHs</td><td>F.</td><td>CHs</td><td>CF2CF3</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F255</td><td>H.</td><td>CHs</td><td>F.</td><td>CHs</td><td>CF2CF3</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F256</td><td>H.</td><td>CHs</td><td>F.</td><td>CHs</td><td>CF2CF3</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F257</td><td>H.</td><td>CHs</td><td>F.</td><td>CHs</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F258</td><td>H.</td><td>CHs</td><td>F.</td><td>CHs</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F259</td><td>H.</td><td>CHs</td><td>F.</td><td>CHs</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F260</td><td>H.</td><td>CHs</td><td>F.</td><td>CHs</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F261</td><td>H.</td><td>CHs</td><td>F.</td><td>CHs</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td>s</td><td>CH2CF3</td>

<td>F262</td><td>H.</td><td>CHs</td><td>F.</td><td>CHs</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td>s</td><td>CH2CF3</td>

<td>F263</td><td>H.</td><td>CHs</td><td>F.</td><td>CHs</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td>s</td><td>CH2CF3</td>

136

EP-2934142B1PL

<td>Relationship number</td><td>R1</td><td>R2</td><td>R3</td><td>R4</td><td>R6</td><td>R8</td><td>R10</td><td>R11a</td><td>X5</td><td>R11b</td>

<td>F264</td><td>H.</td><td>CHs</td><td>F.</td><td>CHs</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F265</td><td>H.</td><td>Cl</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>Br</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F266</td><td>H.</td><td>Cl</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>Cl</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F267</td><td>H.</td><td>Cl</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>CFs</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F268</td><td>H.</td><td>Cl</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>CHs</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F269</td><td>H.</td><td>Cl</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>Br</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F270</td><td>H.</td><td>Cl</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>Cl</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F271</td><td>H.</td><td>Cl</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>CFs</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F272</td><td>H.</td><td>Cl</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>CHs</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F273</td><td>H.</td><td>Cl</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F274</td><td>H.</td><td>Cl</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F275</td><td>H.</td><td>Cl</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F276</td><td>H.</td><td>Cl</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F277</td><td>H.</td><td>Cl</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F278</td><td>H.</td><td>Cl</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F279</td><td>H.</td><td>Cl</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F280</td><td>H.</td><td>Cl</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F281</td><td>H.</td><td>Cl</td><td>H.</td><td>Br</td><td>CFs</td><td>CFs</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F282</td><td>H.</td><td>Cl</td><td>H.</td><td>Br</td><td>CFs</td><td>CFs</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F283</td><td>H.</td><td>Cl</td><td>H.</td><td>Br</td><td>CFs</td><td>CFs</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F284</td><td>H.</td><td>Cl</td><td>H.</td><td>Br</td><td>CFs</td><td>CFs</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F285</td><td>H.</td><td>Cl</td><td>H.</td><td>Br</td><td>CF2CF3</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F286</td><td>H.</td><td>Cl</td><td>H.</td><td>Br</td><td>CF2CF3</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F287</td><td>H.</td><td>Cl</td><td>H.</td><td>Br</td><td>CF2CF3</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F288</td><td>H.</td><td>Cl</td><td>H.</td><td>Br</td><td>CF2CF3</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F289</td><td>H.</td><td>Cl</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F290</td><td>H.</td><td>Cl</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F291</td><td>H.</td><td>Cl</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F292</td><td>H.</td><td>Cl</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F293</td><td>H.</td><td>Cl</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td>s</td><td>CH2CF3</td>

137

EP-2934142B1PL

<td>Relationship number</td><td>R1</td><td>R2</td><td>R3</td><td>R4</td><td>R6</td><td>R8</td><td>R10</td><td>R11a</td><td>X5</td><td>R11b</td>

<td>F294</td><td>H.</td><td>Cl</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F295</td><td>H.</td><td>Cl</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F296</td><td>H.</td><td>Cl</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F297</td><td>H.</td><td>H.</td><td>Br</td><td>Br</td><td>CFs</td><td>H.</td><td>Br</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F298</td><td>H.</td><td>H.</td><td>Br</td><td>Br</td><td>CFs</td><td>H.</td><td>Cl</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F299</td><td>H.</td><td>H.</td><td>Br</td><td>Br</td><td>CFs</td><td>H.</td><td>CFs</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F300</td><td>H.</td><td>H.</td><td>Br</td><td>Br</td><td>CFs</td><td>H.</td><td>CHs</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F301</td><td>H.</td><td>H.</td><td>Br</td><td>Br</td><td>CFs</td><td>H.</td><td>Br</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F302</td><td>H.</td><td>H.</td><td>Br</td><td>Br</td><td>CFs</td><td>H.</td><td>Cl</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F303</td><td>H.</td><td>H.</td><td>Br</td><td>Br</td><td>CFs</td><td>H.</td><td>CFs</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F304</td><td>H.</td><td>H.</td><td>Br</td><td>Br</td><td>CFs</td><td>H.</td><td>CHs</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F305</td><td>H.</td><td>H.</td><td>Br</td><td>Br</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F306</td><td>H.</td><td>H.</td><td>Br</td><td>Br</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F307</td><td>H.</td><td>H.</td><td>Br</td><td>Br</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F308</td><td>H.</td><td>H.</td><td>Br</td><td>Br</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F309</td><td>H.</td><td>H.</td><td>Br</td><td>Br</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F310</td><td>H.</td><td>H.</td><td>Br</td><td>Br</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F311</td><td>H.</td><td>H.</td><td>Br</td><td>Br</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F312</td><td>H.</td><td>H.</td><td>Br</td><td>Br</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F313</td><td>H.</td><td>H.</td><td>Br</td><td>Br</td><td>CFs</td><td>CFs</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F314</td><td>H.</td><td>H.</td><td>Br</td><td>Br</td><td>CFs</td><td>CFs</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F315</td><td>H.</td><td>H.</td><td>Br</td><td>Br</td><td>CFs</td><td>CFs</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F316</td><td>H.</td><td>H.</td><td>Br</td><td>Br</td><td>CFs</td><td>CFs</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F317</td><td>H.</td><td>H.</td><td>Br</td><td>Br</td><td>CF2CF3</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F318</td><td>H.</td><td>H.</td><td>Br</td><td>Br</td><td>CF2CF3</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F319</td><td>H.</td><td>H.</td><td>Br</td><td>Br</td><td>CF2CF3</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F320</td><td>H.</td><td>H.</td><td>Br</td><td>Br</td><td>CF2CF3</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F321</td><td>H.</td><td>H.</td><td>Br</td><td>Br</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F322</td><td>H.</td><td>H.</td><td>Br</td><td>Br</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F323</td><td>H.</td><td>H.</td><td>Br</td><td>Br</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

138

EP-2934142B1PL

<td>Relationship number</td><td>R1</td><td>R2</td><td>R3</td><td>R4</td><td>R6</td><td>R8</td><td>R10</td><td>R11a</td><td>X5</td><td>R11b</td>

<td>F324</td><td>H.</td><td>H.</td><td>Br</td><td>Br</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F325</td><td>H.</td><td>H.</td><td>Br</td><td>Br</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F326</td><td>H.</td><td>H.</td><td>Br</td><td>Br</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F327</td><td>H.</td><td>H.</td><td>Br</td><td>Br</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F328</td><td>H.</td><td>H.</td><td>Br</td><td>Br</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F329</td><td>H.</td><td>H.</td><td>Cl</td><td>N0₂</td><td>CFs</td><td>H.</td><td>Br</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F330</td><td>H.</td><td>H.</td><td>Cl</td><td>NO2</td><td>CFs</td><td>H.</td><td>Cl</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F331</td><td>H.</td><td>H.</td><td>Cl</td><td>NO2</td><td>CFs</td><td>H.</td><td>CFs</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F332</td><td>H.</td><td>H.</td><td>Cl</td><td>NO2</td><td>CFs</td><td>H.</td><td>CHs</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F333</td><td>H.</td><td>H.</td><td>Cl</td><td>NO2</td><td>CFs</td><td>H.</td><td>Br</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F334</td><td>H.</td><td>H.</td><td>Cl</td><td>NO2</td><td>CFs</td><td>H.</td><td>Cl</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F335</td><td>H.</td><td>H.</td><td>Cl</td><td>NO2</td><td>CFs</td><td>H.</td><td>CFs</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F336</td><td>H.</td><td>H.</td><td>Cl</td><td>NO2</td><td>CFs</td><td>H.</td><td>CHs</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F337</td><td>H.</td><td>H.</td><td>Cl</td><td>NO2</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F338</td><td>H.</td><td>H.</td><td>Cl</td><td>NO2</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F339</td><td>H.</td><td>H.</td><td>Cl</td><td>NO2</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F340</td><td>H.</td><td>H.</td><td>Cl</td><td>NO2</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F341</td><td>H.</td><td>H.</td><td>Cl</td><td>NO2</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F342</td><td>H.</td><td>H.</td><td>Cl</td><td>NO2</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F343</td><td>H.</td><td>H.</td><td>Cl</td><td>NO2</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F344</td><td>H.</td><td>H.</td><td>Cl</td><td>NO2</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F345</td><td>H.</td><td>H.</td><td>Cl</td><td>NO2</td><td>CFs</td><td>CFs</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F346</td><td>H.</td><td>H.</td><td>Cl</td><td>NO2</td><td>CFs</td><td>CFs</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F347</td><td>H.</td><td>H.</td><td>Cl</td><td>NO2</td><td>CFs</td><td>CFs</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F348</td><td>H.</td><td>H.</td><td>Cl</td><td>NO2</td><td>CFs</td><td>CFs</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F349</td><td>H.</td><td>H.</td><td>Cl</td><td>NO2</td><td>CF2CF3</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F350</td><td>H.</td><td>H.</td><td>Cl</td><td>NO2</td><td>CF2CF3</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F351</td><td>H.</td><td>H.</td><td>Cl</td><td>NO2</td><td>CF2CF3</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F352</td><td>H.</td><td>H.</td><td>Cl</td><td>NO2</td><td>CF2CF3</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F353</td><td>H.</td><td>H.</td><td>Cl</td><td>NO2</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

139

EP-2934142B1PL

<td>Relationship number</td><td>R1</td><td>R2</td><td>R3</td><td>R4</td><td>R6</td><td>R8</td><td>R10</td><td>R11a</td><td>X5</td><td>R11b</td>

<td>F354</td><td>H.</td><td>H.</td><td>Cl</td><td>NO2</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F355</td><td>H.</td><td>H.</td><td>Cl</td><td>NO2</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F356</td><td>H.</td><td>H.</td><td>Cl</td><td>NO2</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F357</td><td>H.</td><td>H.</td><td>Cl</td><td>NO2</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F358</td><td>H.</td><td>H.</td><td>Cl</td><td>NO2</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F359</td><td>H.</td><td>H.</td><td>Cl</td><td>NO2</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F360</td><td>H.</td><td>H.</td><td>Cl</td><td>NO2</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F361</td><td>H.</td><td>H.</td><td>F.</td><td>CN</td><td>CFs</td><td>H.</td><td>Br</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F362</td><td>H.</td><td>H.</td><td>F.</td><td>CN</td><td>CFs</td><td>H.</td><td>Cl</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F363</td><td>H.</td><td>H.</td><td>F.</td><td>CN</td><td>CFs</td><td>H.</td><td>CFs</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F364</td><td>H.</td><td>H.</td><td>F.</td><td>CN</td><td>CFs</td><td>H.</td><td>CHs</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F365</td><td>H.</td><td>H.</td><td>F.</td><td>CN</td><td>CFs</td><td>H.</td><td>Br</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F366</td><td>H.</td><td>H.</td><td>F.</td><td>CN</td><td>CFs</td><td>H.</td><td>Cl</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F367</td><td>H.</td><td>H.</td><td>F.</td><td>CN</td><td>CFs</td><td>H.</td><td>CFs</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F368</td><td>H.</td><td>H.</td><td>F.</td><td>CN</td><td>CFs</td><td>H.</td><td>CHs</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F369</td><td>H.</td><td>H.</td><td>F.</td><td>CN</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F370</td><td>H.</td><td>H.</td><td>F.</td><td>CN</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F371</td><td>H.</td><td>H.</td><td>F.</td><td>CN</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F372</td><td>H.</td><td>H.</td><td>F.</td><td>CN</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F373</td><td>H.</td><td>H.</td><td>F.</td><td>CN</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F374</td><td>H.</td><td>H.</td><td>F.</td><td>CN</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F375</td><td>H.</td><td>H.</td><td>F.</td><td>CN</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F376</td><td>H.</td><td>H.</td><td>F.</td><td>CN</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F377</td><td>H.</td><td>H.</td><td>F.</td><td>CN</td><td>CFs</td><td>CFs</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F378</td><td>H.</td><td>H.</td><td>F.</td><td>CN</td><td>CFs</td><td>CFs</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F379</td><td>H.</td><td>H.</td><td>F.</td><td>CN</td><td>CFs</td><td>CFs</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F380</td><td>H.</td><td>H.</td><td>F.</td><td>CN</td><td>CFs</td><td>CFs</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F381</td><td>H.</td><td>H.</td><td>F.</td><td>CN</td><td>CF2CF3</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F382</td><td>H.</td><td>H.</td><td>F.</td><td>CN</td><td>CF2CF3</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F383</td><td>H.</td><td>H.</td><td>F.</td><td>CN</td><td>CF2CF3</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

140

EP-2934142B1PL

<td>Relationship number</td><td>R1</td><td>R2</td><td>R3</td><td>R4</td><td>R6</td><td>R8</td><td>R10</td><td>R11a</td><td>X5</td><td>R11b</td>

<td>F384</td><td>H.</td><td>H.</td><td>F.</td><td>CN</td><td>CF2CF3</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F385</td><td>H.</td><td>H.</td><td>F.</td><td>CN</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F386</td><td>H.</td><td>H.</td><td>F.</td><td>CN</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F387</td><td>H.</td><td>H.</td><td>F.</td><td>CN</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F388</td><td>H.</td><td>H.</td><td>F.</td><td>CN</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F389</td><td>H.</td><td>H.</td><td>F.</td><td>CN</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F390</td><td>H.</td><td>H.</td><td>F.</td><td>CN</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F391</td><td>H.</td><td>H.</td><td>F.</td><td>CN</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F392</td><td>H.</td><td>H.</td><td>F.</td><td>CN</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F393</td><td>H.</td><td>Cl</td><td>OCFs</td><td>Cl</td><td>CFs</td><td>H.</td><td>Br</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F394</td><td>H.</td><td>Cl</td><td>OCFs</td><td>Cl</td><td>CFs</td><td>H.</td><td>Cl</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F395</td><td>H.</td><td>Cl</td><td>OCFs</td><td>Cl</td><td>CFs</td><td>H.</td><td>CFs</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F396</td><td>H.</td><td>Cl</td><td>OCFs</td><td>Cl</td><td>CFs</td><td>H.</td><td>CHs</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F397</td><td>H.</td><td>Cl</td><td>OCFs</td><td>Cl</td><td>CFs</td><td>H.</td><td>Br</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F398</td><td>H.</td><td>Cl</td><td>OCFs</td><td>Cl</td><td>CFs</td><td>H.</td><td>Cl</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F399</td><td>H.</td><td>Cl</td><td>OCFs</td><td>Cl</td><td>CFs</td><td>H.</td><td>CFs</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F400</td><td>H.</td><td>Cl</td><td>OCFs</td><td>Cl</td><td>CFs</td><td>H.</td><td>CHs</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F401</td><td>H.</td><td>Cl</td><td>OCFs</td><td>Cl</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F402</td><td>H.</td><td>Cl</td><td>OCFs</td><td>Cl</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F403</td><td>H.</td><td>Cl</td><td>OCFs</td><td>Cl</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F404</td><td>H.</td><td>Cl</td><td>OCFs</td><td>Cl</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F405</td><td>H.</td><td>Cl</td><td>OCFs</td><td>Cl</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F406</td><td>H.</td><td>Cl</td><td>OCFs</td><td>Cl</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F407</td><td>H.</td><td>Cl</td><td>OCFs</td><td>Cl</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F408</td><td>H.</td><td>Cl</td><td>OCFs</td><td>Cl</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F409</td><td>H.</td><td>Cl</td><td>OCFs</td><td>Cl</td><td>CFs</td><td>CFs</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F410</td><td>H.</td><td>Cl</td><td>OCFs</td><td>Cl</td><td>CFs</td><td>CFs</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F411</td><td>H.</td><td>Cl</td><td>OCFs</td><td>Cl</td><td>CFs</td><td>CFs</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F412</td><td>H.</td><td>Cl</td><td>OCFs</td><td>Cl</td><td>CFs</td><td>CFs</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F413</td><td>H.</td><td>Cl</td><td>OCFs</td><td>Cl</td><td>CF2CF3</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

141

EP-2934142B1PL

<td>Relationship number</td><td>R1</td><td>R2</td><td>R3</td><td>R4</td><td>R6</td><td>R8</td><td>R10</td><td>R11a</td><td>X5</td><td>R11b</td>

<td>F414</td><td>H.</td><td>Cl</td><td>OCFS</td><td>Cl</td><td>CF2CF3</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F415</td><td>H.</td><td>Cl</td><td>0CF3</td><td>Cl</td><td>CF2CF3</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F416</td><td>H.</td><td>Cl</td><td>0CF3</td><td>Cl</td><td>CF2CF3</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F417</td><td>H.</td><td>Cl</td><td>0CF3</td><td>Cl</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F418</td><td>H.</td><td>Cl</td><td>0CF3</td><td>Cl</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F419</td><td>H.</td><td>Cl</td><td>0CF3</td><td>Cl</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F420</td><td>H.</td><td>Cl</td><td>0CF3</td><td>Cl</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F421</td><td>H.</td><td>Cl</td><td>0CF3</td><td>Cl</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F422</td><td>H.</td><td>Cl</td><td>0CF3</td><td>Cl</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F423</td><td>H.</td><td>Cl</td><td>0CF3</td><td>Cl</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F424</td><td>H.</td><td>Cl</td><td>0CF3</td><td>Cl</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F425</td><td>H.</td><td>Cl</td><td>CN</td><td>Cl</td><td>CFs</td><td>H.</td><td>Br</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F426</td><td>H.</td><td>Cl</td><td>CN</td><td>Cl</td><td>CFs</td><td>H.</td><td>Cl</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F427</td><td>H.</td><td>Cl</td><td>CN</td><td>Cl</td><td>CFs</td><td>H.</td><td>CFs</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F428</td><td>H.</td><td>Cl</td><td>CN</td><td>Cl</td><td>CFs</td><td>H.</td><td>CHs</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F429</td><td>H.</td><td>Cl</td><td>CN</td><td>Cl</td><td>CFs</td><td>H.</td><td>Br</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F430</td><td>H.</td><td>Cl</td><td>CN</td><td>Cl</td><td>CFs</td><td>H.</td><td>Cl</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F431</td><td>H.</td><td>Cl</td><td>CN</td><td>Cl</td><td>CFs</td><td>H.</td><td>CFs</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F432</td><td>H.</td><td>Cl</td><td>CN</td><td>Cl</td><td>CFs</td><td>H.</td><td>CHs</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F433</td><td>H.</td><td>Cl</td><td>CN</td><td>Cl</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F434</td><td>H.</td><td>Cl</td><td>CN</td><td>Cl</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F435</td><td>H.</td><td>Cl</td><td>CN</td><td>Cl</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F436</td><td>H.</td><td>Cl</td><td>CN</td><td>Cl</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F437</td><td>H.</td><td>Cl</td><td>CN</td><td>Cl</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F438</td><td>H.</td><td>Cl</td><td>CN</td><td>Cl</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F439</td><td>H.</td><td>Cl</td><td>CN</td><td>Cl</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F440</td><td>H.</td><td>Cl</td><td>CN</td><td>Cl</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td>s</td><td>CH2CH3</td>

<td>F441</td><td>H.</td><td>Cl</td><td>CN</td><td>Cl</td><td>CFs</td><td>CFs</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F442</td><td>H.</td><td>Cl</td><td>CN</td><td>Cl</td><td>CFs</td><td>CFs</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F443</td><td>H.</td><td>Cl</td><td>CN</td><td>Cl</td><td>CFs</td><td>CFs</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

142

EP-2934142B1PL

<td>Relationship number</td><td>R1</td><td>R2</td><td>R3</td><td>R4</td><td>R6</td><td>R8</td><td>R10</td><td>R11a</td><td>X5</td><td>R11b</td>

<td>F444</td><td>H.</td><td>Cl</td><td>CN</td><td>Cl</td><td>CFs</td><td>CFs</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F445</td><td>H.</td><td>Cl</td><td>CN</td><td>Cl</td><td>CF2CF3</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F446</td><td>H.</td><td>Cl</td><td>CN</td><td>Cl</td><td>CF2CF3</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F447</td><td>H.</td><td>Cl</td><td>CN</td><td>Cl</td><td>CF2CF3</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F448</td><td>H.</td><td>Cl</td><td>CN</td><td>Cl</td><td>CF2CF3</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F449</td><td>H.</td><td>Cl</td><td>CN</td><td>Cl</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F450</td><td>H.</td><td>Cl</td><td>CN</td><td>Cl</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F451</td><td>H.</td><td>Cl</td><td>CN</td><td>Cl</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F452</td><td>H.</td><td>Cl</td><td>CN</td><td>Cl</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F453</td><td>H.</td><td>Cl</td><td>CN</td><td>Cl</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F454</td><td>H.</td><td>Cl</td><td>CN</td><td>Cl</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F455</td><td>H.</td><td>Cl</td><td>CN</td><td>Cl</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F456</td><td>H.</td><td>Cl</td><td>CN</td><td>Cl</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F457</td><td>H.</td><td>CHs</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>Br</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F458</td><td>H.</td><td>CHs</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>Cl</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F459</td><td>H.</td><td>CHs</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>CFs</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F460</td><td>H.</td><td>CHs</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>CHs</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F461</td><td>H.</td><td>CHs</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>Br</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F462</td><td>H.</td><td>CHs</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>Cl</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F463</td><td>H.</td><td>CHs</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>CFs</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F464</td><td>H.</td><td>CHs</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>CHs</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F465</td><td>H.</td><td>CHs</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F466</td><td>H.</td><td>CHs</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F467</td><td>H.</td><td>CHs</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F468</td><td>H.</td><td>CHs</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F469</td><td>H.</td><td>CHs</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td>s</td><td>CH2CH3</td>

<td>F470</td><td>H.</td><td>CHs</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td>s</td><td>CH2CH3</td>

<td>F471</td><td>H.</td><td>CHs</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td>s</td><td>CH2CH3</td>

<td>F472</td><td>H.</td><td>CHs</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td>s</td><td>CH2CH3</td>

<td>F473</td><td>H.</td><td>CHs</td><td>H.</td><td>Br</td><td>CFs</td><td>CFs</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

143

EP-2934142B1PL

<td>Relationship number</td><td>R1</td><td>R2</td><td>R3</td><td>R4</td><td>R6</td><td>R8</td><td>R10</td><td>R11a</td><td>X5</td><td>R11b</td>

<td>F474</td><td>H.</td><td>CHs</td><td>H.</td><td>Br</td><td>CFs</td><td>CFs</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F475</td><td>H.</td><td>CHs</td><td>H.</td><td>Br</td><td>CFs</td><td>CFs</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F476</td><td>H.</td><td>CHs</td><td>H.</td><td>Br</td><td>CFs</td><td>CFs</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F477</td><td>H.</td><td>CHs</td><td>H.</td><td>Br</td><td>CF2CF3</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F478</td><td>H.</td><td>CHs</td><td>H.</td><td>Br</td><td>CF2CF3</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F479</td><td>H.</td><td>CHs</td><td>H.</td><td>Br</td><td>CF2CF3</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F480</td><td>H.</td><td>CHs</td><td>H.</td><td>Br</td><td>CF2CF3</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F481</td><td>H.</td><td>CHs</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F482</td><td>H.</td><td>CHs</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F483</td><td>H.</td><td>CHs</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F484</td><td>H.</td><td>CHs</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F485</td><td>H.</td><td>CHs</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F486</td><td>H.</td><td>CHs</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F487</td><td>H.</td><td>CHs</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F488</td><td>H.</td><td>CHs</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F489</td><td>H.</td><td>H.</td><td>F.</td><td>CHs</td><td>CFs</td><td>H.</td><td>Br</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F490</td><td>H.</td><td>H.</td><td>F.</td><td>CHs</td><td>CFs</td><td>H.</td><td>Cl</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F491</td><td>H.</td><td>H.</td><td>F.</td><td>CHs</td><td>CFs</td><td>H.</td><td>CFs</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F492</td><td>H.</td><td>H.</td><td>F.</td><td>CHs</td><td>CFs</td><td>H.</td><td>CHs</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F493</td><td>H.</td><td>H.</td><td>F.</td><td>CHs</td><td>CFs</td><td>H.</td><td>Br</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F494</td><td>H.</td><td>H.</td><td>F.</td><td>CHs</td><td>CFs</td><td>H.</td><td>Cl</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F495</td><td>H.</td><td>H.</td><td>F.</td><td>CHs</td><td>CFs</td><td>H.</td><td>CFs</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F496</td><td>H.</td><td>H.</td><td>F.</td><td>CHs</td><td>CFs</td><td>H.</td><td>CHs</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F497</td><td>H.</td><td>H.</td><td>F.</td><td>CHs</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F498</td><td>H.</td><td>H.</td><td>F.</td><td>CHs</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F499</td><td>H.</td><td>H.</td><td>F.</td><td>CHs</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F500</td><td>H.</td><td>H.</td><td>F.</td><td>CHs</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F501</td><td>H.</td><td>H.</td><td>F.</td><td>CHs</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td>s</td><td>CH2CH3</td>

<td>F502</td><td>H.</td><td>H.</td><td>F.</td><td>CHs</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td>s</td><td>CH2CH3</td>

<td>F503</td><td>H.</td><td>H.</td><td>F.</td><td>CHs</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td>s</td><td>CH2CH3</td>

144

EP-2934142B1PL

<td>Relationship number</td><td>R1</td><td>R2</td><td>R3</td><td>R4</td><td>R6</td><td>R8</td><td>R10</td><td>R11a</td><td>X5</td><td>R11b</td>

<td>F504</td><td>H.</td><td>H.</td><td>F.</td><td>CHs</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F505</td><td>H.</td><td>H.</td><td>F.</td><td>CHs</td><td>CFs</td><td>CFs</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F506</td><td>H.</td><td>H.</td><td>F.</td><td>CHs</td><td>CFs</td><td>CFs</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F507</td><td>H.</td><td>H.</td><td>F.</td><td>CHs</td><td>CFs</td><td>CFs</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F508</td><td>H.</td><td>H.</td><td>F.</td><td>CHs</td><td>CFs</td><td>CFs</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F509</td><td>H.</td><td>H.</td><td>F.</td><td>CHs</td><td>CF2CF3</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F510</td><td>H.</td><td>H.</td><td>F.</td><td>CHs</td><td>CF2CF3</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F511</td><td>H.</td><td>H.</td><td>F.</td><td>CHs</td><td>CF2CF3</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F512</td><td>H.</td><td>H.</td><td>F.</td><td>CHs</td><td>CF2CF3</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F513</td><td>H.</td><td>H.</td><td>F.</td><td>CHs</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F514</td><td>H.</td><td>H.</td><td>F.</td><td>CHs</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F515</td><td>H.</td><td>H.</td><td>F.</td><td>CHs</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F516</td><td>H.</td><td>H.</td><td>F.</td><td>CHs</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F517</td><td>H.</td><td>H.</td><td>F.</td><td>CHs</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F518</td><td>H.</td><td>H.</td><td>F.</td><td>CHs</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F519</td><td>H.</td><td>H.</td><td>F.</td><td>CHs</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F520</td><td>H.</td><td>H.</td><td>F.</td><td>CHs</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F521</td><td>H.</td><td>H.</td><td>F.</td><td>Cl</td><td>CFs</td><td>H.</td><td>Br</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F522</td><td>H.</td><td>H.</td><td>F.</td><td>Cl</td><td>CFs</td><td>H.</td><td>Cl</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F523</td><td>H.</td><td>H.</td><td>F.</td><td>Cl</td><td>CFs</td><td>H.</td><td>CFs</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F524</td><td>H.</td><td>H.</td><td>F.</td><td>Cl</td><td>CFs</td><td>H.</td><td>CHs</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F525</td><td>H.</td><td>H.</td><td>F.</td><td>Cl</td><td>CFs</td><td>H.</td><td>Br</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F526</td><td>H.</td><td>H.</td><td>F.</td><td>Cl</td><td>CFs</td><td>H.</td><td>Cl</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F527</td><td>H.</td><td>H.</td><td>F.</td><td>Cl</td><td>CFs</td><td>H.</td><td>CFs</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F528</td><td>H.</td><td>H.</td><td>F.</td><td>Cl</td><td>CFs</td><td>H.</td><td>CHs</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F529</td><td>H.</td><td>H.</td><td>F.</td><td>Cl</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F530</td><td>H.</td><td>H.</td><td>F.</td><td>Cl</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F531</td><td>H.</td><td>H.</td><td>F.</td><td>Cl</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F532</td><td>H.</td><td>H.</td><td>F.</td><td>Cl</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F533</td><td>H.</td><td>H.</td><td>F.</td><td>Cl</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td>s</td><td>CH2CH3</td>

145

EP-2934142B1PL

<td>Relationship number</td><td>R1</td><td>R2</td><td>R3</td><td>R4</td><td>R6</td><td>R8</td><td>R10</td><td>R11a</td><td>X5</td><td>R11b</td>

<td>F534</td><td>H.</td><td>H.</td><td>F.</td><td>Cl</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F535</td><td>H.</td><td>H.</td><td>F.</td><td>Cl</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F536</td><td>H.</td><td>H.</td><td>F.</td><td>Cl</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F537</td><td>H.</td><td>H.</td><td>F.</td><td>Cl</td><td>CFs</td><td>CFs</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F538</td><td>H.</td><td>H.</td><td>F.</td><td>Cl</td><td>CFs</td><td>CFs</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F539</td><td>H.</td><td>H.</td><td>F.</td><td>Cl</td><td>CFs</td><td>CFs</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F540</td><td>H.</td><td>H.</td><td>F.</td><td>Cl</td><td>CFs</td><td>CFs</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F541</td><td>H.</td><td>H.</td><td>F.</td><td>Cl</td><td>CF2CF3</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F542</td><td>H.</td><td>H.</td><td>F.</td><td>Cl</td><td>CF2CF3</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F543</td><td>H.</td><td>H.</td><td>F.</td><td>Cl</td><td>CF2CF3</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F544</td><td>H.</td><td>H.</td><td>F.</td><td>Cl</td><td>CF2CF3</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F545</td><td>H.</td><td>H.</td><td>F.</td><td>Cl</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F546</td><td>H.</td><td>H.</td><td>F.</td><td>Cl</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F547</td><td>H.</td><td>H.</td><td>F.</td><td>Cl</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F548</td><td>H.</td><td>H.</td><td>F.</td><td>Cl</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F549</td><td>H.</td><td>H.</td><td>F.</td><td>Cl</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F550</td><td>H.</td><td>H.</td><td>F.</td><td>Cl</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F551</td><td>H.</td><td>H.</td><td>F.</td><td>Cl</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F552</td><td>H.</td><td>H.</td><td>F.</td><td>Cl</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F553</td><td>H.</td><td>F.</td><td>F.</td><td>F.</td><td>CFs</td><td>H.</td><td>Br</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F554</td><td>H.</td><td>F.</td><td>F.</td><td>F.</td><td>CFs</td><td>H.</td><td>Cl</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F555</td><td>H.</td><td>F.</td><td>F.</td><td>F.</td><td>CFs</td><td>H.</td><td>CFs</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F556</td><td>H.</td><td>F.</td><td>F.</td><td>F.</td><td>CFs</td><td>H.</td><td>CHs</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F557</td><td>H.</td><td>F.</td><td>F.</td><td>F.</td><td>CFs</td><td>H.</td><td>Br</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F558</td><td>H.</td><td>F.</td><td>F.</td><td>F.</td><td>CFs</td><td>H.</td><td>Cl</td><td>CHs</td><td>s</td><td>CH2CH3</td>

<td>F559</td><td>H.</td><td>F.</td><td>F.</td><td>F.</td><td>CFs</td><td>H.</td><td>CFs</td><td>CHs</td><td>s</td><td>CH2CH3</td>

<td>F560</td><td>H.</td><td>F.</td><td>F.</td><td>F.</td><td>CFs</td><td>H.</td><td>CHs</td><td>CHs</td><td>s</td><td>CH2CH3</td>

<td>F561</td><td>H.</td><td>F.</td><td>F.</td><td>F.</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F562</td><td>H.</td><td>F.</td><td>F.</td><td>F.</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F563</td><td>H.</td><td>F.</td><td>F.</td><td>F.</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CH3</td>

146

EP-2934142B1PL

<td>Relationship number</td><td>R1</td><td>R2</td><td>R3</td><td>R4</td><td>R6</td><td>R8</td><td>R10</td><td>R11a</td><td>X5</td><td>R11b</td>

<td>F564</td><td>H.</td><td>F.</td><td>F.</td><td>F.</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F565</td><td>H.</td><td>F.</td><td>F.</td><td>F.</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F566</td><td>H.</td><td>F.</td><td>F.</td><td>F.</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F567</td><td>H.</td><td>F.</td><td>F.</td><td>F.</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F568</td><td>H.</td><td>F.</td><td>F.</td><td>F.</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F569</td><td>H.</td><td>F.</td><td>F.</td><td>F.</td><td>CFs</td><td>CFs</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F570</td><td>H.</td><td>F.</td><td>F.</td><td>F.</td><td>CFs</td><td>CFs</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F571</td><td>H.</td><td>F.</td><td>F.</td><td>F.</td><td>CFs</td><td>CFs</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F572</td><td>H.</td><td>F.</td><td>F.</td><td>F.</td><td>CFs</td><td>CFs</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F573</td><td>H.</td><td>F.</td><td>F.</td><td>F.</td><td>CF2CF3</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F574</td><td>H.</td><td>F.</td><td>F.</td><td>F.</td><td>CF2CF3</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F575</td><td>H.</td><td>F.</td><td>F.</td><td>F.</td><td>CF2CF3</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F576</td><td>H.</td><td>F.</td><td>F.</td><td>F.</td><td>CF2CF3</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F577</td><td>H.</td><td>F.</td><td>F.</td><td>F.</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F578</td><td>H.</td><td>F.</td><td>F.</td><td>F.</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F579</td><td>H.</td><td>F.</td><td>F.</td><td>F.</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F580</td><td>H.</td><td>F.</td><td>F.</td><td>F.</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F581</td><td>H.</td><td>F.</td><td>F.</td><td>F.</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F582</td><td>H.</td><td>F.</td><td>F.</td><td>F.</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F583</td><td>H.</td><td>F.</td><td>F.</td><td>F.</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F584</td><td>H.</td><td>F.</td><td>F.</td><td>F.</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F585</td><td>H.</td><td>CFs</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>Br</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F586</td><td>H.</td><td>CFs</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>Cl</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F587</td><td>H.</td><td>CFs</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>CFs</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F588</td><td>H.</td><td>CFs</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>CHs</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F589</td><td>H.</td><td>CFs</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>Br</td><td>CHs</td><td>s</td><td>CH2CH3</td>

<td>F590</td><td>H.</td><td>CFs</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>Cl</td><td>CHs</td><td>s</td><td>CH2CH3</td>

<td>F591</td><td>H.</td><td>CFs</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>CFs</td><td>CHs</td><td>s</td><td>CH2CH3</td>

<td>F592</td><td>H.</td><td>CFs</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>CHs</td><td>CHs</td><td>s</td><td>CH2CH3</td>

<td>F593</td><td>H.</td><td>CFs</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CH3</td>

147

EP-2934142B1PL

<td>Relationship number</td><td>R1</td><td>R2</td><td>R3</td><td>R4</td><td>R6</td><td>R8</td><td>R10</td><td>R11a</td><td>X5</td><td>R11b</td>

<td>F594</td><td>H.</td><td>CFs</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F595</td><td>H.</td><td>CFs</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F596</td><td>H.</td><td>CFs</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F597</td><td>H.</td><td>CFs</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F598</td><td>H.</td><td>CFs</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F599</td><td>H.</td><td>CFs</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F600</td><td>H.</td><td>CFs</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F601</td><td>H.</td><td>CFs</td><td>H.</td><td>CFs</td><td>CFs</td><td>CFs</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F602</td><td>H.</td><td>CFs</td><td>H.</td><td>CFs</td><td>CFs</td><td>CFs</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F603</td><td>H.</td><td>CFs</td><td>H.</td><td>CFs</td><td>CFs</td><td>CFs</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F604</td><td>H.</td><td>CFs</td><td>H.</td><td>CFs</td><td>CFs</td><td>CFs</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F605</td><td>H.</td><td>CFs</td><td>H.</td><td>CFs</td><td>CF2CF3</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F606</td><td>H.</td><td>CFs</td><td>H.</td><td>CFs</td><td>CF2CF3</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F607</td><td>H.</td><td>CFs</td><td>H.</td><td>CFs</td><td>CF2CF3</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F608</td><td>H.</td><td>CFs</td><td>H.</td><td>CFs</td><td>CF2CF3</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F609</td><td>H.</td><td>CFs</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F610</td><td>H.</td><td>CFs</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F611</td><td>H.</td><td>CFs</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F612</td><td>H.</td><td>CFs</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F613</td><td>H.</td><td>CFs</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F614</td><td>H.</td><td>CFs</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F615</td><td>H.</td><td>CFs</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F616</td><td>H.</td><td>CFs</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F617</td><td>H.</td><td>F.</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>Br</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F618</td><td>H.</td><td>F.</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>Cl</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F619</td><td>H.</td><td>F.</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>CFs</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F620</td><td>H.</td><td>F.</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>CHs</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F621</td><td>H.</td><td>F.</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>Br</td><td>CHs</td><td>s</td><td>CH2CH3</td>

<td>F622</td><td>H.</td><td>F.</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>Cl</td><td>CHs</td><td>s</td><td>CH2CH3</td>

<td>F623</td><td>H.</td><td>F.</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>CFs</td><td>CHs</td><td>s</td><td>CH2CH3</td>

148

EP-2934142B1PL

<td>Relationship number</td><td>R1</td><td>R2</td><td>R3</td><td>R4</td><td>R6</td><td>R8</td><td>R10</td><td>R11a</td><td>X5</td><td>R11b</td>

<td>F624</td><td>H.</td><td>F.</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>CHs</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F625</td><td>H.</td><td>F.</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F626</td><td>H.</td><td>F.</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F627</td><td>H.</td><td>F.</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F628</td><td>H.</td><td>F.</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F629</td><td>H.</td><td>F.</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F630</td><td>H.</td><td>F.</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F631</td><td>H.</td><td>F.</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F632</td><td>H.</td><td>F.</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F633</td><td>H.</td><td>F.</td><td>H.</td><td>CFs</td><td>CFs</td><td>CFs</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F634</td><td>H.</td><td>F.</td><td>H.</td><td>CFs</td><td>CFs</td><td>CFs</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F635</td><td>H.</td><td>F.</td><td>H.</td><td>CFs</td><td>CFs</td><td>CFs</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F636</td><td>H.</td><td>F.</td><td>H.</td><td>CFs</td><td>CFs</td><td>CFs</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F637</td><td>H.</td><td>F.</td><td>H.</td><td>CFs</td><td>CF2CF3</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F638</td><td>H.</td><td>F.</td><td>H.</td><td>CFs</td><td>CF2CF3</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F639</td><td>H.</td><td>F.</td><td>H.</td><td>CFs</td><td>CF2CF3</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F640</td><td>H.</td><td>F.</td><td>H.</td><td>CFs</td><td>CF2CF3</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F641</td><td>H.</td><td>F.</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F642</td><td>H.</td><td>F.</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F643</td><td>H.</td><td>F.</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F644</td><td>H.</td><td>F.</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F645</td><td>H.</td><td>F.</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F646</td><td>H.</td><td>F.</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F647</td><td>H.</td><td>F.</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F648</td><td>H.</td><td>F.</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td>s</td><td>CH2CF3</td>

<td>F649</td><td>H.</td><td>Cl</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>Br</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F650</td><td>H.</td><td>Cl</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>Cl</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F651</td><td>H.</td><td>Cl</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>CFs</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F652</td><td>H.</td><td>Cl</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>CHs</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F653</td><td>H.</td><td>Cl</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>Br</td><td>CHs</td><td>s</td><td>CH2CH3</td>

149

EP-2934142B1PL

<td>Relationship number</td><td>R1</td><td>R2</td><td>R3</td><td>R4</td><td>R6</td><td>R8</td><td>R10</td><td>R11a</td><td>X5</td><td>R11b</td>

<td>F654</td><td>H.</td><td>Cl</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>Cl</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F655</td><td>H.</td><td>Cl</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>CFs</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F656</td><td>H.</td><td>Cl</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>CHs</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F657</td><td>H.</td><td>Cl</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F658</td><td>H.</td><td>Cl</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F659</td><td>H.</td><td>Cl</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F660</td><td>H.</td><td>Cl</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F661</td><td>H.</td><td>Cl</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F662</td><td>H.</td><td>Cl</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F663</td><td>H.</td><td>Cl</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F664</td><td>H.</td><td>Cl</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F665</td><td>H.</td><td>Cl</td><td>H.</td><td>CFs</td><td>CFs</td><td>CFs</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F666</td><td>H.</td><td>Cl</td><td>H.</td><td>CFs</td><td>CFs</td><td>CFs</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F667</td><td>H.</td><td>Cl</td><td>H.</td><td>CFs</td><td>CFs</td><td>CFs</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F668</td><td>H.</td><td>Cl</td><td>H.</td><td>CFs</td><td>CFs</td><td>CFs</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F669</td><td>H.</td><td>Cl</td><td>H.</td><td>CFs</td><td>CF2CF3</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F670</td><td>H.</td><td>Cl</td><td>H.</td><td>CFs</td><td>CF2CF3</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F671</td><td>H.</td><td>Cl</td><td>H.</td><td>CFs</td><td>CF2CF3</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F672</td><td>H.</td><td>Cl</td><td>H.</td><td>CFs</td><td>CF2CF3</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F673</td><td>H.</td><td>Cl</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F674</td><td>H.</td><td>Cl</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F675</td><td>H.</td><td>Cl</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F676</td><td>H.</td><td>Cl</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F677</td><td>H.</td><td>Cl</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F678</td><td>H.</td><td>Cl</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td>s</td><td>CH2CF3</td>

<td>F679</td><td>H.</td><td>Cl</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td>s</td><td>CH2CF3</td>

<td>F680</td><td>H.</td><td>Cl</td><td>H.</td><td>CFs</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td>s</td><td>CH2CF3</td>

<td>F681</td><td>H.</td><td>H.</td><td>F.</td><td>CFs</td><td>CFs</td><td>H.</td><td>Br</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F682</td><td>H.</td><td>H.</td><td>F.</td><td>CFs</td><td>CFs</td><td>H.</td><td>Cl</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F683</td><td>H.</td><td>H.</td><td>F.</td><td>CFs</td><td>CFs</td><td>H.</td><td>CFs</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

150

EP-2934142B1PL

<td>Relationship number</td><td>R1</td><td>R2</td><td>R3</td><td>R4</td><td>R6</td><td>R8</td><td>R10</td><td>R11a</td><td>X5</td><td>R11b</td>

<td>F684</td><td>H.</td><td>H.</td><td>F.</td><td>CFs</td><td>CFs</td><td>H.</td><td>CHs</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F685</td><td>H.</td><td>H.</td><td>F.</td><td>CFs</td><td>CFs</td><td>H.</td><td>Br</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F686</td><td>H.</td><td>H.</td><td>F.</td><td>CFs</td><td>CFs</td><td>H.</td><td>Cl</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F687</td><td>H.</td><td>H.</td><td>F.</td><td>CFs</td><td>CFs</td><td>H.</td><td>CFs</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F688</td><td>H.</td><td>H.</td><td>F.</td><td>CFs</td><td>CFs</td><td>H.</td><td>CHs</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F689</td><td>H.</td><td>H.</td><td>F.</td><td>CFs</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F690</td><td>H.</td><td>H.</td><td>F.</td><td>CFs</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F691</td><td>H.</td><td>H.</td><td>F.</td><td>CFs</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F692</td><td>H.</td><td>H.</td><td>F.</td><td>CFs</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F693</td><td>H.</td><td>H.</td><td>F.</td><td>CFs</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F694</td><td>H.</td><td>H.</td><td>F.</td><td>CFs</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F695</td><td>H.</td><td>H.</td><td>F.</td><td>CFs</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F696</td><td>H.</td><td>H.</td><td>F.</td><td>CFs</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F697</td><td>H.</td><td>H.</td><td>F.</td><td>CFs</td><td>CFs</td><td>CFs</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F698</td><td>H.</td><td>H.</td><td>F.</td><td>CFs</td><td>CFs</td><td>CFs</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F699</td><td>H.</td><td>H.</td><td>F.</td><td>CFs</td><td>CFs</td><td>CFs</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F700</td><td>H.</td><td>H.</td><td>F.</td><td>CFs</td><td>CFs</td><td>CFs</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F701</td><td>H.</td><td>H.</td><td>F.</td><td>CFs</td><td>CF2CF3</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F702</td><td>H.</td><td>H.</td><td>F.</td><td>CFs</td><td>CF2CF3</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F703</td><td>H.</td><td>H.</td><td>F.</td><td>CFs</td><td>CF2CF3</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F704</td><td>H.</td><td>H.</td><td>F.</td><td>CFs</td><td>CF2CF3</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F705</td><td>H.</td><td>H.</td><td>F.</td><td>CFs</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F706</td><td>H.</td><td>H.</td><td>F.</td><td>CFs</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F707</td><td>H.</td><td>H.</td><td>F.</td><td>CFs</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F708</td><td>H.</td><td>H.</td><td>F.</td><td>CFs</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F709</td><td>H.</td><td>H.</td><td>F.</td><td>CFs</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td>s</td><td>CH2CF3</td>

<td>F710</td><td>H.</td><td>H.</td><td>F.</td><td>CFs</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td>s</td><td>CH2CF3</td>

<td>F711</td><td>H.</td><td>H.</td><td>F.</td><td>CFs</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td>s</td><td>CH2CF3</td>

<td>F712</td><td>H.</td><td>H.</td><td>F.</td><td>CFs</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td>s</td><td>CH2CF3</td>

<td>F713</td><td>H.</td><td>Cl</td><td>Cl</td><td>Cl</td><td>CFs</td><td>H.</td><td>Br</td><td>CHs</td><td>s</td><td>CH2CH3</td>

151

EP-2934142B1PL

<td>Relationship number</td><td>R1</td><td>R2</td><td>R3</td><td>R4</td><td>R6</td><td>R8</td><td>R10</td><td>R11a</td><td>X5</td><td>R11b</td>

<td>F714</td><td>H.</td><td>Cl</td><td>Cl</td><td>Cl</td><td>CFs</td><td>H.</td><td>Cl</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F715</td><td>H.</td><td>Cl</td><td>Cl</td><td>Cl</td><td>CFs</td><td>H.</td><td>CFs</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F716</td><td>H.</td><td>Cl</td><td>Cl</td><td>Cl</td><td>CFs</td><td>H.</td><td>CHs</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F717</td><td>H.</td><td>Cl</td><td>Cl</td><td>Cl</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F718</td><td>H.</td><td>Cl</td><td>Cl</td><td>Cl</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F719</td><td>H.</td><td>Cl</td><td>Cl</td><td>Cl</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F720</td><td>H.</td><td>Cl</td><td>Cl</td><td>Cl</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F721</td><td>H.</td><td>Cl</td><td>Cl</td><td>Cl</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F722</td><td>H.</td><td>Cl</td><td>Cl</td><td>Cl</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F723</td><td>H.</td><td>Cl</td><td>Cl</td><td>Cl</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F724</td><td>H.</td><td>Cl</td><td>Cl</td><td>Cl</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F725</td><td>H.</td><td>Cl</td><td>Cl</td><td>Cl</td><td>CFs</td><td>CFs</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F726</td><td>H.</td><td>Cl</td><td>Cl</td><td>Cl</td><td>CFs</td><td>CFs</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F727</td><td>H.</td><td>Cl</td><td>Cl</td><td>Cl</td><td>CFs</td><td>CFs</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F728</td><td>H.</td><td>Cl</td><td>Cl</td><td>Cl</td><td>CFs</td><td>CFs</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F729</td><td>H.</td><td>Cl</td><td>Cl</td><td>Cl</td><td>CF2CF3</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F730</td><td>H.</td><td>Cl</td><td>Cl</td><td>Cl</td><td>CF2CF3</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F731</td><td>H.</td><td>Cl</td><td>Cl</td><td>Cl</td><td>CF2CF3</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F732</td><td>H.</td><td>Cl</td><td>Cl</td><td>Cl</td><td>CF2CF3</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F733</td><td>H.</td><td>Cl</td><td>H.</td><td>Cl</td><td>CFs</td><td>H.</td><td>Br</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F734</td><td>H.</td><td>Cl</td><td>H.</td><td>Cl</td><td>CFs</td><td>H.</td><td>Cl</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F735</td><td>H.</td><td>Cl</td><td>H.</td><td>Cl</td><td>CFs</td><td>H.</td><td>CFs</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F736</td><td>H.</td><td>Cl</td><td>H.</td><td>Cl</td><td>CFs</td><td>H.</td><td>CHs</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F737</td><td>H.</td><td>Cl</td><td>H.</td><td>Cl</td><td>CFs</td><td>H.</td><td>Br</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F738</td><td>H.</td><td>Cl</td><td>H.</td><td>Cl</td><td>CFs</td><td>H.</td><td>Cl</td><td>CHs</td><td>s</td><td>CH2CH3</td>

<td>F739</td><td>H.</td><td>Cl</td><td>H.</td><td>Cl</td><td>CFs</td><td>H.</td><td>CFs</td><td>CHs</td><td>s</td><td>CH2CH3</td>

<td>F740</td><td>H.</td><td>Cl</td><td>H.</td><td>Cl</td><td>CFs</td><td>H.</td><td>CHs</td><td>CHs</td><td>s</td><td>CH2CH3</td>

<td>F741</td><td>H.</td><td>Cl</td><td>H.</td><td>Cl</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F742</td><td>H.</td><td>Cl</td><td>H.</td><td>Cl</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F743</td><td>H.</td><td>Cl</td><td>H.</td><td>Cl</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CH3</td>

152

EP-2934142B1PL

<td>Relationship number</td><td>R1</td><td>R2</td><td>R3</td><td>R4</td><td>R6</td><td>R8</td><td>R10</td><td>R11a</td><td>X5</td><td>R11b</td>

<td>F744</td><td>H.</td><td>Cl</td><td>H.</td><td>Cl</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F745</td><td>H.</td><td>Cl</td><td>H.</td><td>Cl</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F746</td><td>H.</td><td>Cl</td><td>H.</td><td>Cl</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F747</td><td>H.</td><td>Cl</td><td>H.</td><td>Cl</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F748</td><td>H.</td><td>Cl</td><td>H.</td><td>Cl</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F749</td><td>H.</td><td>Cl</td><td>H.</td><td>Cl</td><td>CFs</td><td>CFs</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F750</td><td>H.</td><td>Cl</td><td>H.</td><td>Cl</td><td>CFs</td><td>CFs</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F751</td><td>H.</td><td>Cl</td><td>H.</td><td>Cl</td><td>CFs</td><td>CFs</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F752</td><td>H.</td><td>Cl</td><td>H.</td><td>Cl</td><td>CFs</td><td>CFs</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F753</td><td>H.</td><td>Cl</td><td>H.</td><td>Cl</td><td>CF2CF3</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F754</td><td>H.</td><td>Cl</td><td>H.</td><td>Cl</td><td>CF2CF3</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F755</td><td>H.</td><td>Cl</td><td>H.</td><td>Cl</td><td>CF2CF3</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F756</td><td>H.</td><td>Cl</td><td>H.</td><td>Cl</td><td>CF2CF3</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F757</td><td>H.</td><td>Cl</td><td>H.</td><td>Cl</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F758</td><td>H.</td><td>Cl</td><td>H.</td><td>Cl</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F759</td><td>H.</td><td>Cl</td><td>H.</td><td>Cl</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F760</td><td>H.</td><td>Cl</td><td>H.</td><td>Cl</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F761</td><td>H.</td><td>Cl</td><td>H.</td><td>Cl</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F762</td><td>H.</td><td>Cl</td><td>H.</td><td>Cl</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F763</td><td>H.</td><td>Cl</td><td>H.</td><td>Cl</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F764</td><td>H.</td><td>Cl</td><td>H.</td><td>Cl</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F765</td><td>H.</td><td>H.</td><td>Cl</td><td>Cl</td><td>CFs</td><td>H.</td><td>Br</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F766</td><td>H.</td><td>H.</td><td>Cl</td><td>Cl</td><td>CFs</td><td>H.</td><td>Cl</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F767</td><td>H.</td><td>H.</td><td>Cl</td><td>Cl</td><td>CFs</td><td>H.</td><td>CFs</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F768</td><td>H.</td><td>H.</td><td>Cl</td><td>Cl</td><td>CFs</td><td>H.</td><td>CHs</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F769</td><td>H.</td><td>H.</td><td>Cl</td><td>Cl</td><td>CFs</td><td>H.</td><td>Br</td><td>CHs</td><td>s</td><td>CH2CH3</td>

<td>F770</td><td>H.</td><td>H.</td><td>Cl</td><td>Cl</td><td>CFs</td><td>H.</td><td>Cl</td><td>CHs</td><td>s</td><td>CH2CH3</td>

<td>F771</td><td>H.</td><td>H.</td><td>Cl</td><td>Cl</td><td>CFs</td><td>H.</td><td>CFs</td><td>CHs</td><td>s</td><td>CH2CH3</td>

<td>F772</td><td>H.</td><td>H.</td><td>Cl</td><td>Cl</td><td>CFs</td><td>H.</td><td>CHs</td><td>CHs</td><td>s</td><td>CH2CH3</td>

<td>F773</td><td>H.</td><td>H.</td><td>Cl</td><td>Cl</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CH3</td>

153

EP-2934142B1PL

<td>Relationship number</td><td>R1</td><td>R2</td><td>R3</td><td>R4</td><td>R6</td><td>R8</td><td>R10</td><td>R11a</td><td>X5</td><td>R11b</td>

<td>F774</td><td>H.</td><td>H.</td><td>Cl</td><td>Cl</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F775</td><td>H.</td><td>H.</td><td>Cl</td><td>Cl</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F776</td><td>H.</td><td>H.</td><td>Cl</td><td>Cl</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F777</td><td>H.</td><td>H.</td><td>Cl</td><td>Cl</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F778</td><td>H.</td><td>H.</td><td>Cl</td><td>Cl</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F779</td><td>H.</td><td>H.</td><td>Cl</td><td>Cl</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F780</td><td>H.</td><td>H.</td><td>Cl</td><td>Cl</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F781</td><td>H.</td><td>H.</td><td>Cl</td><td>Cl</td><td>CFs</td><td>CFs</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F782</td><td>H.</td><td>H.</td><td>Cl</td><td>Cl</td><td>CFs</td><td>CFs</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F783</td><td>H.</td><td>H.</td><td>Cl</td><td>Cl</td><td>CFs</td><td>CFs</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F784</td><td>H.</td><td>H.</td><td>Cl</td><td>Cl</td><td>CFs</td><td>CFs</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F785</td><td>H.</td><td>H.</td><td>Cl</td><td>Cl</td><td>CF2CF3</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F786</td><td>H.</td><td>H.</td><td>Cl</td><td>Cl</td><td>CF2CF3</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F787</td><td>H.</td><td>H.</td><td>Cl</td><td>Cl</td><td>CF2CF3</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F788</td><td>H.</td><td>H.</td><td>Cl</td><td>Cl</td><td>CF2CF3</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F789</td><td>H.</td><td>H.</td><td>Cl</td><td>Cl</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F790</td><td>H.</td><td>H.</td><td>Cl</td><td>Cl</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F791</td><td>H.</td><td>H.</td><td>Cl</td><td>Cl</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F792</td><td>H.</td><td>H.</td><td>Cl</td><td>Cl</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F793</td><td>H.</td><td>H.</td><td>Cl</td><td>Cl</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F794</td><td>H.</td><td>H.</td><td>Cl</td><td>Cl</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F795</td><td>H.</td><td>H.</td><td>Cl</td><td>Cl</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F796</td><td>H.</td><td>H.</td><td>Cl</td><td>Cl</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F797</td><td>H.</td><td>Cl</td><td>F.</td><td>Cl</td><td>CFs</td><td>H.</td><td>Br</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F798</td><td>H.</td><td>Cl</td><td>F.</td><td>Cl</td><td>CFs</td><td>H.</td><td>Cl</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F799</td><td>H.</td><td>Cl</td><td>F.</td><td>Cl</td><td>CFs</td><td>H.</td><td>CFs</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F800</td><td>H.</td><td>Cl</td><td>F.</td><td>Cl</td><td>CFs</td><td>H.</td><td>CHs</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F801</td><td>H.</td><td>Cl</td><td>F.</td><td>Cl</td><td>CFs</td><td>H.</td><td>Br</td><td>CHs</td><td>s</td><td>CH2CH3</td>

<td>F802</td><td>H.</td><td>Cl</td><td>F.</td><td>Cl</td><td>CFs</td><td>H.</td><td>Cl</td><td>CHs</td><td>s</td><td>CH2CH3</td>

<td>F803</td><td>H.</td><td>Cl</td><td>F.</td><td>Cl</td><td>CFs</td><td>H.</td><td>CFs</td><td>CHs</td><td>s</td><td>CH2CH3</td>

154

EP-2934142B1PL

<td>Relationship number</td><td>R1</td><td>R2</td><td>R3</td><td>R4</td><td>R6</td><td>R8</td><td>R10</td><td>R11a</td><td>X5</td><td>R11b</td>

<td>F804</td><td>H.</td><td>Cl</td><td>F.</td><td>Cl</td><td>CFs</td><td>H.</td><td>CHs</td><td>CHs</td><td>S.</td><td>CH2CH3</td>

<td>F805</td><td>H.</td><td>Cl</td><td>F.</td><td>Cl</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F806</td><td>H.</td><td>Cl</td><td>F.</td><td>Cl</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F807</td><td>H.</td><td>Cl</td><td>F.</td><td>Cl</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F808</td><td>H.</td><td>Cl</td><td>F.</td><td>Cl</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F809</td><td>H.</td><td>Cl</td><td>F.</td><td>Cl</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F810</td><td>H.</td><td>Cl</td><td>F.</td><td>Cl</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F811</td><td>H.</td><td>Cl</td><td>F.</td><td>Cl</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F812</td><td>H.</td><td>Cl</td><td>F.</td><td>Cl</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F813</td><td>H.</td><td>Cl</td><td>F.</td><td>Cl</td><td>CFs</td><td>CFs</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F814</td><td>H.</td><td>Cl</td><td>F.</td><td>Cl</td><td>CFs</td><td>CFs</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F815</td><td>H.</td><td>Cl</td><td>F.</td><td>Cl</td><td>CFs</td><td>CFs</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F816</td><td>H.</td><td>Cl</td><td>F.</td><td>Cl</td><td>CF2CF3</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F817</td><td>H.</td><td>Cl</td><td>F.</td><td>Cl</td><td>CF2CF3</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F818</td><td>H.</td><td>Cl</td><td>F.</td><td>Cl</td><td>CF2CF3</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F819</td><td>H.</td><td>Cl</td><td>F.</td><td>Cl</td><td>CF2CF3</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F820</td><td>H.</td><td>Cl</td><td>F.</td><td>Cl</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F821</td><td>H.</td><td>Cl</td><td>F.</td><td>Cl</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F822</td><td>H.</td><td>Cl</td><td>F.</td><td>Cl</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F823</td><td>H.</td><td>Cl</td><td>F.</td><td>Cl</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F824</td><td>H.</td><td>Cl</td><td>F.</td><td>Cl</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F825</td><td>H.</td><td>Cl</td><td>F.</td><td>Cl</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F826</td><td>H.</td><td>Br</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>Cl</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F827</td><td>H.</td><td>Br</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>CFs</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F828</td><td>H.</td><td>Br</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>CHs</td><td>CHs</td><td> 0</td><td>CH2CH3</td>

<td>F829</td><td>H.</td><td>Br</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>Br</td><td>CHs</td><td>s</td><td>CH2CH3</td>

<td>F830</td><td>H.</td><td>Br</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>Cl</td><td>CHs</td><td>s</td><td>CH2CH3</td>

<td>F831</td><td>H.</td><td>Br</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>CFs</td><td>CHs</td><td>s</td><td>CH2CH3</td>

<td>F832</td><td>H.</td><td>Br</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>CHs</td><td>CHs</td><td>s</td><td>CH2CH3</td>

<td>F833</td><td>H.</td><td>Br</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CH3</td>

155

EP-2934142B1PL

<td>Relationship number</td><td>R1</td><td>R2</td><td>R3</td><td>R4</td><td>R6</td><td>R8</td><td>R10</td><td>R11a</td><td>X5</td><td>R11b</td>

<td>F834</td><td>H.</td><td>Br</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F835</td><td>H.</td><td>Br</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F836</td><td>H.</td><td>Br</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CH3</td>

<td>F837</td><td>H.</td><td>Br</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>Br</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F838</td><td>H.</td><td>Br</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F839</td><td>H.</td><td>Br</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F840</td><td>H.</td><td>Br</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td>S.</td><td>CH2CH3</td>

<td>F841</td><td>H.</td><td>Br</td><td>H.</td><td>Br</td><td>CFs</td><td>CFs</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F842</td><td>H.</td><td>Br</td><td>H.</td><td>Br</td><td>CFs</td><td>CFs</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F843</td><td>H.</td><td>Br</td><td>H.</td><td>Br</td><td>CFs</td><td>CFs</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F844</td><td>H.</td><td>Br</td><td>H.</td><td>Br</td><td>CFs</td><td>CFs</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F845</td><td>H.</td><td>Br</td><td>H.</td><td>Br</td><td>CF2CF3</td><td>H.</td><td>Br</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F846</td><td>H.</td><td>Br</td><td>H.</td><td>Br</td><td>CF2CF3</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F847</td><td>H.</td><td>Br</td><td>H.</td><td>Br</td><td>CF2CF3</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F848</td><td>H.</td><td>Br</td><td>H.</td><td>Br</td><td>CF2CF3</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F849</td><td>H.</td><td>Br</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F850</td><td>H.</td><td>Br</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F851</td><td>H.</td><td>Br</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td> 0</td><td>CH2CF3</td>

<td>F852</td><td>H.</td><td>Br</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>Cl</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F853</td><td>H.</td><td>Br</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>CFs</td><td>H.</td><td>S.</td><td>CH2CF3</td>

<td>F854</td><td>H.</td><td>Br</td><td>H.</td><td>Br</td><td>CFs</td><td>H.</td><td>CHs</td><td>H.</td><td>S.</td><td>CH2CF3</td>

Example A: BIOLOGICAL TESTS ON BEET ARMWORM (BAW) AND AMERICAN SUNFLOWER (CEW) AND NI SHINY (CL)

[0746] BAW has a few parasites, diseases, or predators that lower its population. BAW infects many weeds, trees, grasses, legumes, and sweat crops. In various places, it is of economic importance to asparagus, cotton, corn, soybeans, tobacco, alfalfa, sugar beet, pepper, tomatoes, potatoes, onions, peas, sunflowers, and citrus, among other plants. It is known that 10 CEW attacks maize and tomatoes, but it also attacks artichokes, asparagus, cabbage, cantaloupe, garden cabbage, snakeskin, cucumbers, eggplant, lettuce, crescent beans, melon, butternut squash, peas, pepper, potatoes, squash. , green beans, spinach, pumpkin, sweet potatoes, and watermelons, in between

156

Other plants. CEW is also known to be resistant to certain pesticides. CL feeds on a variety of farm plants and weeds. It feeds easily on cruciferous crustaceans, and has been reported to damage broccoli, vegetable cabbage, cauliflower, Chinese cabbage, garden cabbage, kale, mustard, radish, kohlrabi, and watercress. Other damaged plant crops include beetroot, cantaloupe, celery, cucumbers, crescent beans, lettuce, parsnips, peas, peppercorns, potatoes, green beans, spinach, pumpkin, sweet potatoes, tomatoes, and watermelons. CL is also known to be resistant to certain pesticides. Consequently, in view of the above factors, the control of these pests is important. In addition, molecules that control these pests are useful in controlling other pests.

[0747] Certain molecules disclosed in this document were tested against BAW and CEW and CL using the procedures described in the following examples. When quoting the results, the BAW and CEW and CL Rating Table (See Chapter Tables) was used.

BIOLOGICAL TESTS FOR BAW (Spodoptera exigua)

[0748] BAW bioassays were performed using the 128-well diet tray test. one to five second-stage BAW nymphs between moults were placed in each well (3 ml) of a diet tray that had previously been filled with 1 ml of artificial diet and applied with 50 pg / cm² test compound (dissolved in 50 µL of 90:10 acetone-water mixture) (into each of the eight wells) and then allowed to dry. The trays were covered with a transparent pressure sensitive lid, and kept at 25 ° C with a 14:10 light: dark cycle for five to seven days. Percent mortality was recorded for nymphs in each well; the activity over the eight wells was then averaged. The results are shown in the table entitled Table 3: Test Results (See Chapter Tables).

CEW BIOLOGICAL TESTS (Helicoverpa zea)

[0749] CEW bioassays were performed using the 128-well diet tray test. one to five second-stage CEW nymphs between moult were placed in each well (3 ml) of a diet tray that had previously been filled with 1 ml of artificial diet and applied with 50 pg / cm² test compound (dissolved in 50 µL of 90:10 acetone-water mixture) (into each of the eight wells) and then allowed to dry. The trays were covered with a transparent pressure sensitive lid, and kept at 25 ° C with a 14:10 light: dark cycle for five to seven days. Percent mortality was recorded for nymphs in each well; the activity over the eight wells was then averaged. The results are shown in the table entitled Table 3: Test Results (See Chapter Tables).

Biological tests for CL (Trichoplusia ni)

[0750] Bioassays for CL were performed using the 128-well diet tray test. One to five second stage CL nymphs between moults were placed in each well (3 ml) of a diet tray that had previously been filled with 1 ml of artificial diet and applied with 50 pg / cm.² test compound (dissolved in 50 µL of 90:10 acetone-water mixture) (into each of the eight wells) and then allowed to dry. The trays were covered with a transparent pressure sensitive lid, and kept at 25 ° C with a 14:10 light: dark cycle for five to seven days. Percent mortality was recorded for nymphs in each well; the activity over the eight wells was then averaged. The results are shown in the table entitled Table 3A: Test Results (See Chapter Tables).

Example B: BIOLOGICAL TESTS ON A GREEN PEACH APHID (GPA) MACHINE (Myzus persicae).

[0751] GPA is the most important pest of peach trees among aphids, causing reduced growth, leaf wrinkling, and death of a variety of tissues. It is also dangerous because

157

It acts as a vector for the transmission of plant viruses such as Potato Y virus and Potato leaf roll virus to members of the Solanaceae / Solanaceae family and various mosaic viruses to many other food crops. GPA attacks crops such as broccoli, burdock, cabbage, carrots, cauliflower, turnips, eggplant, bean pods, lettuce, macadamia, papaya, pepper, sweet potatoes, tomatoes, watercress, and zucchini, among other plants. GPA also attacks many ornamental crops such as carnation, chrysanthemum, white ornamental cabbage, poinsettia, and roses. GPA has acquired resistance to many pesticides.

[0752] Certain molecules disclosed in this document were tested against GPA using the procedures described in the following example. When quoting the results, the GPA Grading Table (See Chapter Tables) was used.

[0753] Cabbage seedlings grown in three-inch pots with 2-3 small (3-5 cm) true leaves were used as the test medium. The seedlings were contaminated with 20-50 GPA (wingless adult and nymph stages) one day prior to application of chemicals. Four pots with separate seedlings were used for each treatment. Test compounds (2 mg) were dissolved in 2 mL of acetone / methanol (1: 1) solvent to prepare stock solutions containing 1000 ppm of test compound. The stock solutions were diluted 5X with 0.025% Tween 20 in H 2 O to give a solution containing 200 ppm of test compound. A pump-type hand sprayer was used to spray the solution on both sides of the cabbage leaves until exhausted. Reference plants (solvent treated controls) were sprayed only with the diluent containing 20% ​​v / v acetone / methanol (1: 1) solvent. The treated plants were kept in storage for three days at approximately 25 ° C and ambient relative humidity (RH) prior to evaluation. The evaluation was carried out by counting the number of live aphids per plant under a microscope. The control percentage was measured by using the Abbott correction formula (WS Abbott, A Method of Computing the Effectiveness of an Insecticide, J. Econ. Entomol. 18 (1925), pp. 265-267) as follows.

Corrected% of Control = 100 * (X - Y) / X where

X = Number of live aphids on the solvent-treated plants, i

Y = Number of live aphids on the treated plants

[0754] The results are shown in the table entitled Table 3: Test Results (See Section Tables). PESTICIDALLY ACCEPTABLE ADDITIONAL SALTS WITH ACIDS, SALT DERIVATIVES, SALVATES, ESTER DERIVATIVES, POLYMORPHAS, ISOTOPES AND RADIONUCLIDES

[0755] Molecules of Formula One can be formulated into pesticidally acceptable acid addition salts. For example, but without limitation, the amine function can form salts with hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, benzoic, lemon, malonic, salicylic, malic, fumaric, oxalic, amber, tartaric, lactic, gluconic, ascorbic, maleic acids. aspartic, benzenesulfonic, methanesulfonic, ethanesulfonic, hydroxymethanesulfonic, and hydroxyethanesulfonic. Additionally, by way of example but not limitation, the acid function can form salts including those derived from alkali or alkaline earth metals and those derived from ammonia and amines. Examples of the preferred cations include sodium, potassium, and magnesium.

[0756] Molecules of Formula One can be formulated as salt derivatives. By way of example and not limitation, a salt derivative can be prepared by contacting the free base with a sufficient amount

158

Desired acid to form a salt. The free base can be regenerated by treating the salt with a dilute aqueous solution of a suitable base such as dilute aqueous sodium hydroxide (NaOH), potassium carbonate, ammonia, and sodium bicarbonate. As an example, in many cases, a pesticide such as 2,4-D is made more water-soluble by converting it to its dimethylamine salt.

[0757] Molecules of Formula One can be stable complexed with a solvent such that the complex remains intact after uncomplexed solvent is removed. These complexes are often referred to as solvates. However, it is especially desirable to make stable hydrates with water as the solvent.

[0758] Molecules of Formula One can be converted to ester derivatives. These ester derivatives can then be used in the same manner as the invention disclosed herein is used.

[0759] Molecules of Formula One can be prepared as a variety of crystal polymorphs. Polymorphism is important in the design of agrochemicals as different crystal polymorphs or structures of the same molecule can have enormously different physical properties and biological efficiencies.

[0760] Molecules of Formula One can be prepared with a variety of isotopes. Of particular importance are molecules having 2H (also known as deuterium) instead¹H.

[0761] Molecules of Formula One can be prepared with a variety of radionuclides. Molecules having a particular importance are¹⁴C.

STEREOISOMERS

[0762] Molecules of Formula One can exist as one or more stereoisomers. Thus, certain molecules can be produced as racemic mixtures. It should be understood by those skilled in the art that one stereoisomer may be more active than the other stereoisomers. Individual stereoisomers may be obtained by known selective synthetic procedures, by conventional synthetic procedures using separated starting materials, or by conventional separation procedures. Certain molecules disclosed herein may exist as two or more isomers. The various isomers include geometric isomers, diastereomers, and enantiomers. Thus, the molecules disclosed herein include geometric isomers, racemic mixtures, individual stereoisomers, and optically active mixtures. Those skilled in the art should understand that one isomer may be more active than the others. The structures disclosed in this disclosure are drawn in only one geometric form for clarity, but are intended to represent all geometric forms of the molecule.

COMBINATIONS

[0763] The molecules of Formula One may also be used in combination (such as in a mixture of compositions, or simultaneous or sequential use) with one or more compounds having acaricidal, algicidal, avicide, bactericidal, fungicidal, herbicidal, insecticidal, molluscicidal properties. , nematicidal, rodenticidal, or virucidal. Additionally, the molecules of Formula One may also be used in combination (such as in a mixture of compositions, or concurrent or sequential use) with compounds that are antifidants, bird repellants, chemosteroids, herbicide safeners, insect attractants, insect repellants, mammalian repellants, etc. swarm disruptors, plant activators, plant growth regulators, or synergists. Examples of such compounds in the above groups can be used with the molecules of Formula

159

EP-2934142B1PL

One is - mercury (3-ethoxypropyl) bromide, 1,2-dichloropropane, 1,3-dichloropropene, 1-methylcyclopropene, 1-naphthol, 2- (octylthio) ethanol, 2,3,5-tri-iodobenzoic acid, 2,3 , 6-TBA, 2,3,6-TBAdimethylamine, 2,3,6-TBA-lithium, 2,3,6-TBA-potassium, 2,3,6-TBA sodium, 2,4,5-T, 2 , 4,5-T 2-butoxypropyl, 2,4,5-T 2-ethylhexyl, 2,4,5-T 3-butoxypropyl, 2,4,5-TB, 2,4,5-T butomethyl, 2,4 , 5-T butotyl, 2,4,5-T butyl, 2,4,5-T isobutyl, 2,4,5-T isoctyl, 2,4,5-T isopropyl, 2,4,5-T methyl , 2,4,5-T pentyl, 2,4,5-T sodium, 2,4,5-T-triethylamine, 2,4,5-Ttrolamine, 2,4-D, 2,4-D 2-butoxypropyl , 2,4-D 2-ethylhexyl, 2,4-D 3-butoxypropyl, 2,4-D amine, 2,4-DB, 2,4-DB butyl, 2,4-DB-dimethylamine, 2,4 -DB isoctyl, 2,4-DB potassium, 2,4-DB sodium, 2,4-D butotyl, 2,4-D butyl, 2,4-D-diethylamine, 2,4-D-dimethylamine, 2, 4-D-diolamine, 2,4-D-dodecylamine, 2,4-DEB, 2,4-DEP, 2,4-D ethyl, 2,4-D-heptylamine, 2,4-D isobutyl, 2, 4-D isoctyl, 2,4-D isopropyl, 2,4-D-isopropylamine, 2,4-D-lithium, 2,4-D meptyl, 2,4-D methyl, 2,4-D octyl, 2,4-D pentyl, 2,4-D potassium , 2,4-D-propyl, 2,4-D sodium, 2,4-D tefuryl, 2,4-Dtetradecylamine, 2,4-D-triethylamine, 2,4-D-tris (2-hydroxypropyl) ammonium, 2,4-D-trolamine, 2iP, 2-methoxyethylmercury chloride, 2-phenylphenol, 3,4-DA, 3,4-DB, 3,4-DP, 4-aminopyridine, 4-CPA, 4-CPA potassium, 4-CPA sodium, 4-CPB, 4-CPP, 4-hydroxyphenethyl alcohol, 8-hydroxyquinoline sulfate, 8-phenyl mercurioxyquinoline, abamectin, abscisic acid, ACC, acephate, acequinocyl, acetamiprid, acetion, acetochlor, acetophos, acetoprole, acybenzolar, acybenzolar-S-methyl, acifluorfen, acifluorfen methyl, sodium acifluorphen, acloniphene, acrepacrylinocyl, acipetin, acryinetin, acrylonisryl acypetacs-zinc, alachlor, alanycarb, albendazole, aldicarb, aldimorph, aldoxycarb, aldrin, allethrin, allicin, alidochlor, allosamidin, alloxydim, sodium alloxydim, allyl alcohol, allixycarb, alorac, alpha-cypermethrin, alpha-endosulfan, ametoctradine, ametridione, amethrin, amibuzine, amicarbazone, amicartiazole, amidithio, amidoflumet, amidosulfuron, aminocarb, aminocyclopirachlor, aminocyclopirachlor methyl, aminocyclopyryirachiralidaside, aminopiropyrrolidine, aminophydroxyiropropylate, aminophydroxyiropropylate, aminophydroxyiropropylate, aminophydroxyiriphalidas, aminopyropyrrolidine , amiprofos, amisulbrom, amiton, amitonium oxalate, amitraz, amitrole, ammonium sulfamate, ammonium α-naphthaleneacetate, amobam, ampropylphos, anabazine, ancimidol, anilazine, anilophos, anisuron, anthraquinone, ANTU, afolate, aramite, arsenous oxide, asomat, aspirin, asulam, potassium asulam, sodium asulam, atidation, atraton, atrazine, aureofungin, aviglycin, avigenachinonhydrochloride, azafironachithin, azafironachithin, azadafenachlycin, azadafenachithin azimsulfuron, azinophos-ethyl, azinophos-methyl, aziprotrin, azitram, azobenzene, azocyclocin, nitrate, azoxystrobin, bachmedesh, barban, barium hexafluorosilicate, barium polysulfide, bartrin, BCPC, beflubutamide, benalaxyl, benalaxyl-M, benazoline, benazoline-dimethylamine, benazoline ethyl, benazoline potassium, bencarbazone, benklothiaz, bendiocarb, benfluralin, benfuracarb, benfuresat, benodanil, benomyl, benoxacor, benoxafos, methylsulfuron, bensuron, bensuron, bensapuron, bensapuronox , bentazone, sodium bentazone, benthiavalicarb, isopropyl benthiavalicarb, bentiazole, bentranil, benzadox, amine benzadox, benzalkonium chloride, benzamacryl, isobutyl benzamacryl, benzamorph, benzfendizone, benzipram, benzobicyclone, benzofenap, benzofluor, benzohydroxamic acid, benzoximate, benzoylprop, benzoylprop-ethyl, benzthiazuron, benzyl benzoate, benzyladenine, berberine, berberine chloride, beta-cyfluthrin, bibycin, biphirinifrin, bibazinzinifrinifrin , bilanafos, bilanaphos sodium, binapacryl, bingqingxiao, bioalethrin, bioethanometrin, biopermethrin, bioresmetrin, biphenyl, bisazir, bismertiazole, bispyribac, sodium bispyribac, bistrifluron, biterthanol, bithionol, bixafen, blasticidin-S, borax, Bordeaux mixture, boric acid, boscalid, brassynolide, ethyl brassinolide,

160

EP-2934142B1PL brevicomine, brodifacoum, brofenvalerate, brofluthrinate, bromacil, lithium bromacil, sodium bromacil, bromadiolone, brometalin, bromethine, bromfenvinphos, bromoacetamide, bromobonil, bromobomophenosyl, bromoacetamide, bromobonil, bromobomophenosyl, bromopheniol, bromobomophenosyl, bromophenosyl bromoxynil, bromoxynil butyrate, bromoxynil heptanoate, bromoxynil octoate, potassium bromoxynil, brompirazone, bromuconazole, bronopol, bucarpolate, bufencarb, buminafos, bupirimate, buprofezin, Burgundian liquid, busulfan, butacarb, butachlor, butafenacil, butamiphos, butathiophos, butenachlor, butethrin, butidazole, butiobate, butiuron, butocarboxime, butonate, butopyronoxyl, butoxycarboxim, butralin, butroxydim, butafuron, butylstylamine, butylsthenylamine calcium arsenate, calcium chlorate, calcium cyanamide, calcium polysulfide, calvinphos, cambendichlor, camphechlor, camphor, captafol, captan, carbamorph, carbanolate, carbaryl, carbasulam, carbendazim, carbendazim benzenesulfonate, carbendazim sulfite, carbetamide, carbofuran, carbon disulfide, carbon tetrachloride, carbophenothio, carbosulfan, carboxazole, carboxide, carboxin, carfentrazone, ethyl carfentrazone, carpropamide, kartap, cartap hydrochloride, carvacrol, carvone, CDEA, cellocyclic Cheshunt mixture, chinomethionate, chitosan, chlobenthiazone, chlomethoxifene, chloralose, chloramben, amine chloramben, chloramben-diolamine, methyl chloramben, Methylammonium chloramben, sodium chloramben, chloramate phosphorus, chloramphenicol, chloraniformethane, chloranil, chloranocryl, chlorantraniliprole, chlorazifop, chlorazifop propargyl, chlorazine, chlorobenzide, chlorbenzuron, chlorbicyclen, chlorbrorethomuron, chlordimuron, chlordimuron, chlordimuron, chlordimuron, chlordimuron, chlordimuron, chlordimuron, chlordimuron, chlordimuron, chlordimuron, chlordimuron, chlordimuronform , chlorofenac, chlorofenac amine, chlorofenac sodium, chlorfenapyr, chlorphenazole, chlorphenetol, chlorofenprop, chlorofensone, chlorfensulfide, chlorfenvinfos, chlorfluazuron, chlorflurazole, chlorfluren, methyl chlorfluren, chlorflurenol, methyl chlorflurenol, chloridazone, chlorimuron, chlorimuron ethyl, chloromefos, chloromequat, chloromuronhthone, chloromaphthone, chloroformenitrofenal, chloroformenitrofenal, chlorophacinone, sodium chlorophacinone, chloropicrin, chloropone, chloropropylate, chlorothalonil, chlorotoluron, chloroxuron, chloroxynil, chlorfonium, chlorfonium chloride, chlorphoxime, chlorprazophos, chlorprocarb, chlorpropham, chloropyrifos, chloropyrifos-methyl, chlorquinox, chlorsulfuron, chlortal, dimethyl chlortal, monomethyl chlorthal, chlorthiamid, chlorthiophosin, choline cerinate, chrominate , ethyl cinidon, cinnmethylin, cinosulfuron, ciobutide, cisanilide, cismethrin, clethodim, climbazole, cliodinate, clodinafop, clodinafop propargyl, cloetocarb, clofencet, clofencet potassium, clofentezine, clofibric acid, clofop, isobutyl clofop, clomazone, clomeprop, cloprop, cloproxydim, clopyralid, clopyralid-methyl, clopyralid olamine, clopyralid potassium, clopralid tris, clintocetylvocylvocetam (2-hydroxyvocetam) methyl chloransulam, chlosantel, clothianidin, clotrimazole, HMCPA, sodium HMCPA, CMA, kodlelur, colophonate, copper acetate, copper acetoarsenite, copper arsenate, copper carbonate, basic, copper hydroxide, copper naphthenate, copper oleate, copper oxychloride, copper silicate, copper sulphate, copper and zinc chromate, coumachlor, coumafuril, coumafos, coumatetralil, coumitrile, coumoxystrobin, CPMC, CPMF, CPPC, credazine, cresol, crimithosin, crotoxamiphos , krufomat, cryolite, cue-lure, cufraneb, cumyluron, cuprobam, cuprous oxide, curcumenol, cyanamide, cyanathrin, cyanine, cyanophenphos, cyanophos, cyantoate, cyantraniliprole, cyazofamide, cyfuramid, cyclanilide, cycletrin, cyclo, cycloheximide, cycloprat, cycloprotrin, cyclosulfamuron, cycloxapride, cycloxydim, cycluron, cyenopyrafen, cyflufenamid, cyflumetofen, cyfluthrin, cyhalophop,

161

EP-2934142B1PL cyhalophop butyl, cyhalothrin, cyhexatin, cymiazole, cymiazole hydrochloride, cymoxanil, cyometrinil, cypendazole, cypermethrin, cyperquat, cyperquat chloride, digitenothrin, cyprazine, cypimonprazole, cypromurinazole, cyprofoconprazole, cyprofoconprazole, cypromodilazole, dalapone, calcium dalapone, magnesium dalapone, sodium dalapone, daminoside, dayoutong, dazomet, sodium dazomet, DBCP, d-camphor, DCIP, DCPTA, DDT, debacarb, decafentin, decarbofuran, dehydroacetic acid, delachlor, deltamethrin, demephion, demephion-O, demephion-S, demeton, methyl demeton, demeton-O, demeton-O-methyl, demeton-S, demeton-S-methyl, demeton-S-methylsulfone, desmedipham, desmetrin, d-fanshiluquebingjuzhi, diafentiuron, dialifos, dialate, diamidaphos, diatomaceous earth, diazinon, dibutyl phthalate, dibutyl succinate, dicamba, dicamba-diglycolamine, dicambadimethylamine, dicamba-diolamine, dicamba-diolamine, dicamba-diolamine, dicamba-methyl-olamine, dicamba-methyl-olamine potassium dicamba, sodium dicamba, dicambetrolamine, dicapton, dichlobenil, dichlofenthion, dichlofluanid, dichlone, dichloralurea, dichlorbenzuron, dichlorflurenol, methyl dichlorflurenol, dichlormate, dichlormide, dichlorpropyl 2-dichloropropyl, dichloro-propyl 2-dichloropropyl ethylammonium, isoctyl dichlorprop, methyl dichlorprop, dichlorprop-P, dichlorprop-P 2-ethylhexyl, dichlorprop-P-dimethylamine, potassium dichlorprop, sodium dichlorprop, dichlorvos, dichlozoline, dichlobutrazole, dichlocymet, dichlofop, dichlofop-methyl, dichlomesine, sodium dichlomesine, dichlorane, dichlosulam, dicofol, dicoumarol, dicresil, dicrotophos, diclocyclanilate, diclocyclanilate, dicloclanilate, diclocloclanilate , diethofencarb, diethylate, diethyl pyrocarbonate, diethyltoluamide, difenacoum, difenoconazole, diphenopentene, ethyl diphenopentene, diphenoxuron, difenzoquat, difenzoquat methyl sulfate, difethialone, diflowidazine, diflubenzuron, diflufenican, diflufenzopyr, diflufenzopyr sodium, diflumetorim, dicegulac, sodium dicegulac, dilor, dimatif, dimefluthrin, dimefox, dimefuron, dimepiperate, dimethachlon, dimethacarbethamide, dimethacarbethamide, dimethacarbethane, dimethacarbethane dimethirimol, dimethoate, dimethomorph, dimethrin, dimethyl carbate, dimethyl phthalate, dimethylinfos, dimethylate, dimexane, dimidazone, dimoxystrobin, dinex, dinex-diclexin, dingjunezuo, diniconazole, diniconazole-M, dinitramine, dinobuton, dinocap, dinocap-4, dinocap-6, dinoctone, dinophenate, dinopenton, dinoprop, dinosame, dinoseb, dinoseb acetate, amine dinoseb, dinoseb-diolamine, sodium dinoseb, dinoseb-trolamine, dinotefurulfone , dinoterb, dinoterb acetate, dinoterbone, diophenolate, dioxabenzophos, dioxacarb, dioxathion, diphacinone, sodium diphacinone, diphenamid, diphenylsulfone, diphenylamine, dipropalin, dipropethrin, dipyrtion, diquat, diquat dibromide, disulfiram disulfur, disparlur, disulfoton, sodium disul, ditalimphos, dithianon, dithicrofos, dithioether, dithiopyr, diuron, d-limonene, DMPA, DNOC, amine DNOC, potassium DNOC, sodium DNOC, dodemorph, dodemorph acetate, dodemorph benzoate, dodicin, dodicin dodicin hydrochloride, dodine, dofenapine, dominicalur, doramectin, drazoxolone, DSMA, dufulin, EBEP, EBP, ecdysterone, edifenphos, eglinin, ethyl eglinin, emamectin, emamectin benzoate, EMPC, empentrin, endosulfan, endotal, endotal diammonium endotal dipotassium, endotal disodium, endotion, endrin, enestroburin, EPN, epocholeone, epophenonate, epoxiconazole, eprinomectin, epronase, EPTC, erbon, ergocalciferol, erlujixiancaoan, esdepallethrine, esfenvalerate, etafenvalerate, etafenvalerate, etafenvalerate, etafenvalerate, etafenvalerate, etafenvalerate, etafenvalerate, etafenvalerate, etafenvalerate, etafenvalerate, etafenvalerate, etafenvalerate, etafenvalerate, etafenvalerate. etalfluralin, etametsulfuron, etametsulfuron-methyl, steprochlor, etephon, ethidimuron, etiophencarb, ethiolate, ethion, etiosin, etiprole, ethirimol, methyl etoate, etofumesate, etohexadiol, etoprofos, ethoxyphene, ethyl ethoxyphen, ethoxyquine, ethoxysulfuron, ethylchlosate, ethyl formate, ethyl α-naphthaleneacetate, ethyl DDD, ethylene, ethylene dibromide, ethylene dichloride, ethylene oxide, ethylicin, ethylmercury 2,3-dihydroxypropyl mercapeptide, ethylmercury acetate

162

EP-2934142B1PL ethyl mercury bromide, ethyl mercury chloride, ethyl mercuric phosphate, ethinophen, etnipromide, etobenzanide, etofenprox, ethoxazole, etridiazole, etrimfos, eugenol, EXD, famoxadone, famfur, fenamidone, phenaminosulfine, fenamidapan, fenaminosulfine fenbuconazole, fenbutatin oxide, fenchlorazole, fenchlorazole ethyl, fenchlorfos, fenchlorim, fenetacarb, fenfluthrin, fenfuram, fenhexamid, fenitropan, fenitrothione, fenjuntong, fenobucarb, fenoprop, 3-butoxypropyl phenoprop, butomethyl phenoprop, butotyl phenoprop, butyl phenprop, isoctyl phenprop, methyl phenprop, potassium phenprop, phenothiocarb, phenoxacrim, fenoxanil, fenoxaprop, ethyl fenoxaprop, phenoxapropox-P, phenoxapropox-P, phenonpyripropyl , fenpropathrin, fenpropidin, fenpropimorph, fenpyrazamine, fenpyroximate, fenridazone, fenridazone potassium, fenridazone propyl, fenson, fensulfothio, fenteracol, fentiaprop, fentiaprop ethyl, fenthion, fentyl ethyl, fentin, fentin acetate, fentin chloride, fentin hydroxide, fentrazamide, fentrifanil, fenuron, fenuron TCA, fenvalerate, ferbam, ferimzone, ferrous sulphate, fipronil, flamprop, flampropam-methyl flampropam , flamprop-M isopropyl, flamprop-M methyl, flazasulfuron, flocoumafen, flometochine, flonicamid, florasulam, fluacrypyrim, fluazifop, fluazifop-butyl, fluazifop-methyl, fluazifop-P, fluazifop-P-butyl, fluazinam, fluazolate, fluazuron, flubendiamide, flubenzimine, flucarbazone, flucarbazone sodium, flucetosulfuron, fluchloralin, flucofuron, flucycloxuron, flucytrinate, fludioxonil, fluenetyl, fluensulfone, flufenacet, flufenprofuron, flufenumetrin, flufenacetyl, flufenumetrin, flufenacetyl flumetralin, flumetsulam, flumezine, flumiclorac, pentyl flumiclorac, flumioxazine, flumipropin, flumorph, fluometuron, fluopicolide, fluopyram, fluorobenzide, fluoridamide, fluoroacetamide, fluorodifene, fluoroglycophen, fluoroglycophene ethyl, fluoroimide, fluoromidine, fluoronitrofen, fluotiuron, fluotrimazole, fluoxastrobin, flupoxam, flupropacil, flupropadine, flupropanate, flupropanate sodium, flupurulfurulfurolup, flupurulfurulfurolup sodium, flupurulfurulfurolup butyl flurenol, methyl flurenol, fluridone, flurochloridone, fluroxypyr, fluroxypyr butomethyl, fluroxypyr meptyl, fluroprimidol, flursulamide, flurtamone, flusilazole, flusulfamide, flutiacet, flutiacet-methyl, flutianil, flutolanil, flutriafol, fluvalinate, fluxapyroxad, fluxphenim, folpet, fomesafen, fomesafen sodium, phonophos, forphorphionhydrate, formetanhydrate, formetanhydrate, formetanide, formetanide formparanatu, fosamine, amino fosamine, fosetyl, aluminum fosetyl, phosmetylan, fospirate, fosthiazate, fostietan, frontalin, fuberidazole, fucaojing, fucaomi, funaihecaoling, fufentiourea, furalan, furalaxyl, furamethrin, furametpyr, furathiocarb, furkarbanil, furconazole, furconazole-cis, furetrin, furfural, furylazole, furmecyclox, furofanate, furyloxyphene, gamma-cyhalothrin, gamma-gliftoriberelinic acid, glaftoriberelinic acid, glaftoriberelinic acid , glufosinate-amine, glufosinate-P, glufosinate-P-amine, glufosinate-P sodium, gliodin, glyoxime, glyphosate, diammonium glyphosate, glyphosate-dimethylamine, glyphosate-isopropylamine, monoammonium glyphosate, glyphosate Sesquisodium glyphosate, glyphosate-trimesium, glyphosin, gossyplur, grandlur, griseofulvin, guazatine, guazatine acetates, halacrinate, halfenpro, halophenozide, halosaphene, halosulfuron, halosulfuron-methyl, halyphoxy-ethoxy, halyphoxy-ethoxy-methyl ethyl, haloxyfop-P-methyl, sodium haloxyfop, HCH, hemel, hempa, HEOD, heptachlor, heptenophos, heptopargyl, heterophos, hexachloroacetone, hexachlorobenzene, hexachlorobutadiene, hexachlorophene, hexaconazole, hexaflumuron, hexaflurate, hexalur, hexamid, hexazinone, hexylthiophos, hexythiazox, HHDN, holosulf, huancaiwo, huangcaoling, huanjunzuo, hydramethylonone, hydrargaphene, ibranilane, hydrocarbinolAsanilane, hexaline hydrogen, hydrogenated hydrogen imazalil, imazalil sulfate, imazametabenz,

163

EP-2934142B1EN imazametabenz-methyl, imazamox, imazamox amine, imazapic, imazapic amine, imazapyr, imazapyr-isopropylamine, imazaquin, imazaquin amine, imazaquin methyl, imazaquin sodium, imazethapyr, imazethapyridosulfonazin, imazetapyridachinazinazin, imazethapyridosulfonazin iminoctadine triacetate, iminoctadine trialbesate, imiprotrin, inabenfide, indanophan, indaziflam, indoxacarb, inesine, iodobonil, iodocarb, iodomethane, iodosulfuron, iodosulfuron-methyl, iodosulfuron-methylsodium, iofensulfuron, iofensulfuron sodium, ioxynil, ioxynil octanoate, lithium ioxynil, sodium ioxynil, ipazine, ipconazole, ipfencarbazone, iprobenfos, iprodione, iprimidicarbazone, ipsenofenz, ipsenofenz, ipsenofenz, ipsenofenz isocarbophos, isocyl, isodrin, isofenphos, isofenphos-methyl, isolate, isomethiosin, isonoruron, isopolinate, isoprocarb, isopropalin, isoprothiolane, isoproturon, isopyrazam, isopyrimol, isothioate, isothianil, isouron, isovaledione, isoxaben, isoxachlorthol, isoxadifene, isoxadifene-ethyl, isoxaflutole, isoxapyrifop, isoxathion, ivermectin, isopamphos, japonilur, japotrins, jasmongol Ihu, jasmolin II, jangoliniaxianca, jangoliniaxianca, jangoliniaxianca, jangolinic acid juvenile hormone I, juvenile hormone II, juvenile hormone III, cadethrin, carbutylate, karetazan, potassium karetazan, kasugamycin, kasugamycin hydrochloride, kejunlin, kelevan, ketospiradox, potassium ketospiradox, kinetin, kinopren, krezoxime-methyl, kuicaoxi, lactophene, lambda-cyhalothrin, latilur, lead arsenate, lenacil, lepimectin, leptophos, lindane, lineatin, linuron, lirymenjunhosin, lirfathionlurin, litlurfenjunzolin , MAA, malathion, maleic hydrazide, malonobene, maltodextrin, MAMA, mankoper, mancozeb, mandipropamide, maneb, matrin, mazidox, MCPA, 2-ethylhexyl MCPA, butotyl MCPA, butyl MCPA, MCPA-dimethylamine, MCPA-diolamine, MCPA ethyl, MCPA isobutyl, MCPA isoctyl, MCPA isopropyl, MCPA methyl, MCPA-olamine, MCPA potassium, MCPA sodium, MCPA-thioethyl, MCPA-trolamine, MCPB, MCPB methyl, MCPB methyl, MCPB methyl, MCPB mecarbam, mecarbamide, mecarfone, mecoprop, 2-ethylhexyl mecoprop, mecopropdimethylamine, mecopropdiolamine, ethadyl mecroprop, isoctyl mecroprop, methyl mecoprop, mecoprop-P, mecoprop-P, 2-mecopropyl-p-2-mecopropyl-p-dimethyl mecoprop potassium, mecoprop-P potassium, mecoprop sodium, mecoprop-trolamine, medimeform, medinoterb, medinoterb acetate, medlur, mefenacet, mefenpyr, mefenpyr diethyl, mefluidide, mefluidyddioloamine, mefipyrimolepanic acid, mefipyridephalate, mefipyridepanic acid, mefipyridephasic acid , mepiquat, mepiquat chloride, mepiquat pentaborate, mepronil, meptyldinocap, mercuric chloride, mercuric oxide, mercurous chloride, merfos, mesoprazine, mesosulfuron, mesosulfuron-methyl, mesotrione, mosulfen, mosulfenfos, metaflumizone, metalaxyl, metalaxyl-M, metaldehyde, metam, amine metam, metamfop, metamitron, potassium metam, sodium metam, metazachlor, metazosulfuron, metazoxolone, metconazole, metepa, metflurazfosur, metabenzaltriazon, metabenzaltryazfid , metazol, metfuroxam, metydation, metiobencarb, metiocarb, metiopyrsulfuron, metiotepa, metiozoline, metiuron, metrocrotophos, methomethone, methomyl, methoprene, metoprotrin, butyl methoquinone, methotrin, methoxychlor, methoxyphenozide, methoxyphenone, methyl afolate, methyl bromide, methyl eugenol, methyl iodide, methyl isothiocyanate, methylacetophos, methylchloroform, methyldimrone, methylene chloride, methylmercury benzoate, methylmercury dicyandiamide, methirophenoxanide, methironelorophenamide, pentachlorodloroquamide, pentachlorophenoxide metolcarb, metominostrobin, metosulam, methoxadiazone, methoxuron, metrafenone, metribuzin, metsulfovax, metsulfuron, metsulfuron-methyl, mewinfos, mexacarbate, miehuan, milbemectin, milbemycin oxime, milneb, mipafox, mirex, MNAF, moguchun, molinate,

164

EP-2934142B1PL molosultap, monalide, monizouron, monochloroacetic acid, monocrotophos, monolinuron, monosulfuron, monosulfuron-ester, monuron, monuron TCA, morphamquat, morphamquat dichloride, moroxidine, moroxidin, morphamquat hydrochloride, mycoxidine, morphamquatine, myclothionine hydrochloride, muscyclin, MS , N- (ethyl mercury) - p -toluenesulfonanilide, nabam, naphthalophos, naledium, naphthalene, naphthaleneacetamide, naphthalic anhydride, naphthoxyacetic acids, naproanilide, napropamide, naptalam, sodium naptalam, natamycin, neburon, niclosamide, niclosamide-olamine, nicosulfuron, nicotine, nifluridide, nipiraclofen, nitenpyram, nithiazine, nitraline, nitrapirin, nitrilacarb, nitrofen, nitrofluorfen, nitrostyrene, nitrotal isopropidon, norflotylurna, noremolurna , OCH, octachlorodipropyl ether, octylinone, ofuras, omethoate, orbencarb, orfralur, orthodichlorobenzene, orthosulfamuron, oryktalur, oryzastrobin, oryzalin, ostol, ostryon, oxabetrinil, oxadiargil, oxadiazon, oxadixyl, oxamate, oxamyl, oxapirazone, oxapirazone-dimolamine, sodium oxapirazone, oxasulfuron, oxacyclomephone, oxin-copper, oxolinic acid, oxo-tononazole, oxin-copper, oxamate, oxyconazole, oxydemetryphoxin, oxyboxydemetryphoxin, oxyboxydemetryphoxin, oxyansyclosulfonazole, oxyboxydraphyxin oxytetracycline hydrochloride, paclobutrazole, paichongding, para-dichlorobenzene, parafluron, paraquat, paraquat dichloride, paraquat dimethyl sulfate, parathion, methyl parathion, parinol, pebulate, pefurazoate, pelargonic acid, penconazole, pencycuron, pendimethalin, penflufen, penfluron, penoxulam, pentachlorophenol, pentanochlor, penthiopyrad, pentmetrin, pentoxazone, perifacrylonidone, phenomethrin, phenmedaphenaidone, phenomethrin, phenyrinhamine , phenmedipham ethyl, phenobenzuron, phenothrin, fenproxide, phenylmercuronate, phenylmercuriurea, phenylmercuric acetate, phenylmercuric chloride, phenylmercury derivative of pyrocatechin, phenylmercuric nitrate, phenylmercury salicylate, forat, phosacetim, phosalone, phosdiphene, phospholate, methyl phospholate, phosphine, phosmet, phosphorus, phosphamidone, phosphine, phosphocarb, phosphorus, fostin, phoxim, methyl phoxim, phthalide, piclortylam, picloramoctyl, picloramoc 2-ethylhexamoc methyl, picloram-olamine, potassium picloram, picloram-triethylamine, picloram tris (2-hydroxypropyl) ammonium, picolinafen, picoxystrobin, pindone, sodium pindone, pinoxaden, piperalin, piperonyl butoxide, piperonyl cyclonene, piperophos, piproctanyl, piproctanyl bromide, piprotal, pyrimetaphos, pyrimicarb, pyrymioxifos, pyrimiphos-ethyl, pyrimiphos-methyl, piphenate, polycarbamate, polyoxins, polyoxorim, zinc polyoxorim, potassium gersenate, potassium azibereidate, potassium azibereidate, aribereidate potassium, potassium polysulfide, potassium thiocyanate, potassium α-naphthaleneacetate, pp-DDT, pralethrin, precocene I, precocene II, precocene III, pretilachlor, primidophos, primisulfuron, primisulfuron methyl, probenazole, prochloraz, manganese prochlorase, proclonol, procyansin, procymidone, prodiamine, profenophos, profluazole, profluralin, profluthrin, propoxydim, proglinazine, ethyl proglinazine, prohexadionium, promethexadionium, promhexadionium calcium, promhexadionium calcium propachlor, propamidine, propamidine dihydrochloride, propamocarb, propamocarb hydrochloride, propanil, propaphos, propaquisafop, propargite, proparthrin, propazine, propetamphos, profam, propiconazole, propineb, propisochlor, propoxur, propoxycarbazone, sodium propoxycarbazone, propilisone, propirysulfuron, propyzamide, prquinazide, prosuler, prosulfalin, prosulfocarb, prosulfuron, protydation, prothiocarb, prothiocarbazol hydrochloride, prothiocarifanbrotoxide, prothiocarbazole, prothiocarbazone hydrochloride , prynachlor, pydanon, pymetrozine, pyracarbolide, pyraclofos, pyraclonil, pyraclostrobin, pyraflufen, pyraflufen-ethyl, pyrafluprole, pyramate, pyramethostrobin, pyraoxystrobin, pyraoxystrobin, pyrazolinate, pyrazophos, pyrazosulfuron, pyrazosulfuron-ethyl, pyrazothione, pyrazoxifene, pyresmetrin, pyrethrin I, pyrethrin II, pyrethrins, isopropyl pyribenzene, propyl pyribenzene, pyribenzcarbimbenz,

165

EP-2934142B1PL pyributicarb, pyrimethanil, pyridaben, pyridafol, pyridalil, pyridafention, pyridate, pyridinitrile, pyrifenox, pyrifluquinazone, pyriphthalide, pyrimethanil, pyrimidiphene, pyriminobac, pyriminobac, pyrimethanil, pyrimoniphylphenol, pyriminiprimisulfanol, pyriminiphylphenol, pyriminiphylphenol, pyrimeniphenylethanol sodium pyrithiobacterium, pyrolan, pyroquilone, pyroxasulfone, piroxulam, pyroxychlor, pyroxyfur, acidia, quinacetol, quinacetol sulfate, quinalphos, methyl quinalphos, quinazamide, quinclorac, quinkonazole, quinmerac, quinoclamine, quinonamide, quinothion, quinoxifene, chintiophos, chintozen, quisalophop, quizalophop ethyl, quizalofop-P, quizalophop-ethyl, quizalofop-P-tefuryl, quinonamide, rhodoxidenzidazolyingna, rhodoxidenzidazolyingna, rhodoxidenzidazolyingna -III, ribavirin, rimsulfuron, rotenone, ryania, saflufenacil, saijunmao, saisentong, salicylanilide, sanguinarine, santonin, schradan, scyliroside, sebutylazine, secbumeton, sedaxane, selamectin, semiamitraz, semiamitraz chloride, sesamex, sesamoline, sethoxydim, shuangjiaancaolin, siduron, siglur, silafluofen, silatran, silica gel, silthiofam, simazine, simeconazole, simeton, simethrin, sintophene, SMA, S-metolachlor, sodium arsenite, sodium azide, sodium azide sodium, sodium fluoroacetate, sodium hexafluorosilicate, sodium naphthenate, sodium orthophenylphenoxide, sodium pentachlorophenoxide, sodium polysulfide, sodium thiocyanate, sodium αnaphthaleneacetate, sofamid, spinetoram, spinosad, spirodiclofen, spiromesifen, spirotetramat, spiroxamine, streptomycin, streptomycin sesquisulfate, strychnine, sulcatol, sulcofuron, sulcofuron sodium, sulcotrione, sulfallate, sulfentrazone, sulfiram, sulfluramide, sulfometuron, sulfomethuronium, sulfuram, sulfuramide, sulfometuron, sulfoxyl chloride, sulfosulfloride, sulfosulfloride sulfuryl fluoride, sulglicapine, sulprophos, sultropen, swep, tau-fluvalinate, tavron, thazimcarb, TCA, amine TCA, calcium TCA, etadyl TCA, magnesium TCA, sodium TCA, TDE, tebuconazole, tebufenozide, tebufenpyrad, tebufloquine, tebupirimfos, tebutam, tebutiuron, tecloftalam, tecnazene, tecoram, teflubenzuron, tefluthrin, tefuryltrion, temeflorbotrion, terbucet, tefuryltrion, temeflorbotrion, terbucetone, tefuryltrion, temeflorbotrion, tefluthrin, tefuryltrion, temeflorbotrion, terbutrion, terbutylazine, terbuthrin, tetcyklacis, tetrachloroethane, tetrachlorvinphos, tetraconazole, tetradifon, tetrafluron, tetramethrin, tetramethylfluthrin, tetramine, tetranactin, tetrasul, thallium sulfate, tenylchlorine, theta-cypermethrin, thiabendazole, thiacloprid, thiadifluor, thiamethoxam, thiapronil, thiazafluron, thiazopyr, thicrophos, thicophen, thidiazimine, thidiazuron, thiencarbazone, methyl thiencarbazone, thiapriflaminocyclic, thifensiflaminocyclic, thifensulflamencarbimylcyclic thiocyclam, copper thiodiazole, thiodicarb, thiophanox, thiofluoximate, thiohempa, thiomersal, thiometone, thionazine, thiophanate, thiophanate-methyl, thioquinox, thiosemicarbazide, thiosultap, thiosultap diammonium, thiosultap disodium, thiosultap monosodium, thiotepa, tiram, thuringiensin, tiadinil, thiaojiean, thiocarbazil, thioclorim, thioximide, tirpat, tolklphos-methyl, toxenpyrlutrynometh, toxenpyrincirhylacetate, toxenpyrincilutryna alkyl , transpermethrin, tretamine, triacontanol, triadimephon, triadimenol, triafammon, tri-allate, triamphos, triapenthenol, triarathene, triarimol, triasulfuron, triazamate, triazbutyl, triaziflam, triazophos, triazoxide, tribenuron, tribenuron methyl, tribufos, tributyltin oxide, tricamba, trichlamide, trichlorphon, trichlormetaphos-3, trichloronate, trichlopyr, trichlopyrbutotyl, trichlopyrifan, trichlopyrphan, trichlopyrphan, trichlopyrphan, trichlopyrphan, trichlopyrifan, trichlopyrhyltin, tricamba, trichlamide, trichlorphon, trichlormetaphos-3 trifenophos, trifloxystrobin, trifloxysulfuron, sodium trifloxysulfuron, triflumizole, triflumuron, trifluralin, triflusulfuron, triflusulfuron-methyl, trifop, trifop-methyl, trifopsim, triforin, trihydroxytriazine, trimedlur, trimethacarb, trimethuron, trinexapac, trinexapak-ethyl, tripren, tripropindan, tryptolide, tritac, triticonazole, tritosulfuron, truncall, uniconazole, uniconazole-P, urbidenamidin, valepaamidin, uredepaamidin, uredepaamidicin , wangard, vaniliprole, vernolat, vinclozoline, warfarin, potassium warfarin, sodium warfarin, xiaochongliulin,

166

EP-2934142B1PL xinjunan, xiwojunan, XMC, xylachlor, xylenols, xylylcarb, yishijing, zarylamide, zeatin, zengxiaoan, zeta-cypermethrin, zinc naphthenate, zinc phosphide, thiazolongzinc, zineb, zirohydram, zolamidaprin, zolamidaprin, zolamidaprim, zolamidaprin, zolamidaprin -ecdysone, α-multistriatin, and α-naphthalene acetic acid. For more information, see COMPENDIUM OF PESTICIDE COMMON NAMES 'at http://www.alanwood.net/pesticides/index.html. See also THE PESTICIDE MANUAL Issue 14, Editor of CDS Tomlin, Copyright 2006 British Crop Production Council, or previous or newer editions thereof.

BIOPESTICIDES

[0764] The molecules of Formula One can also be used in combination (such as in a mixture composition, or used simultaneously or sequentially) with one or more biopesticides. The term biopesticide is used to refer to microbial biological pest control agents that are used in a similar manner to chemical pesticides. They are commonly bacterial, but there are also examples of fungal control agents including Trichoderma spp. and Ampelomyces quisqualis (grapevine powdery mildew control agent). Bacillus subtilis is used to combat plant pathogens. Weeds and rodents were also combated with microbial agents. One known example of an insecticide is Bacillus thuringiensis, Lepidoptera, Coleoptera, and Diptera bacterial disease. As it has little effect on other organisms, it is considered to be more environmentally friendly than synthetic pesticides. Biological insecticides include products based on:

1. entomopathogenic fungi (e.g. Metarhizium anisopliae);

2. entomopathogenic nematodes (e.g. Steinernema feltiae); and

3. entomopathogenic viruses (e.g. apple grit virus, Cydia pomonella).

[0765] Other examples of entomopathogenic organisms include, but are not limited to, baculoviruses, bacteria, and other prokaryotic organisms, fungi, protozoa, and Microsproridia. Bio-derived insecticides include, but are not limited to, rotenone, veratridine, as well as microbial toxins; insect tolerant or resistant plant cultivars; and organisms modified by recombinant DNA technology to either produce insecticides or to confer insect resistance properties to the genetically modified organism. In one embodiment, the molecules of Formula One can be used with one or more biopesticides in the field of plant treatment and soil improvement. The Manual of Biocontrol Agents gives an overview of the available biological insecticide products (and other control agents on a biological basis). Copping LG (ed.) (2004). The Manual of Biocontrol Agents (formerly The Biopesticide Manual) 3rd edition. British Crop Production Council (BCPC), Farnham, Surrey United Kingdom.

OTHER ACTIVE COMPOUNDS

The molecules of Formula One may also be used in combination (such as in a mixture composition, or used simultaneously or sequentially) with one or more of the following: 1.3- (4-chloro-2,6-dimethylphenyl) -4 -hydroxy-8-oxa-1-azaspiro [4.5] dec-3-en-2-one;

2. 3- (4'-chloro-2,4-dimethyl [1,1'-biphenyl] -3-yl) -4-hydroxy-8-oxa-1-azaspiro [4.5] dec-3-en-2-one ;

3. 4 - [[(6-chloro-3-pyridinyl) methyl] methylamino] -2 (5H) -furanone;

4. 4 - [[(6-chloro-3-pyridinyl) methyl] cyclopropylamino] -2 (5H) -furanone;

5. 3-chloro-N²- [(1S) -1-methyl-2- (methylsulfonyl) ethyl] -N¹ - [2-methyl-4- [1,2,2,2-tetrafluoro-1-

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6. 2-cyano-N-ethyl-4-fluoro-3-methoxy-benzenesulfonamide;

7. 2-cyano-N-ethyl-3-methoxy-benzenesulfonamide;

8. 2-cyano-3-difluoromethoxy-N-ethyl-4-fluoro-benzenesulfonamide;

9. 2-cyano-3-fluoromethoxy-N-ethyl benzenesulfonamide;

10. 2-cyano-6-fluoro-3-methoxy-N, N-dimethylbenzenesulfonamide;

11.2-cyano-N-ethyl-6-fluoro-3-methoxy-N-methyl-benzenesulfonamide;

12. 2-cyano-3-difluoromethoxy-N, N-dimethylbenzenesulfonamide;

13. 3- (difluoromethyl) -N- [2- (3,3-dimethylbutyl) phenyl] -1-methyl-1H-pyrazole-4-carboxamide;

14. N-ethyl-2,2-dimethylpropionamide 2- (2,6-dichloro-α, α-trifluoro-p -tolyl) hydrazone;

15. N-ethyl-2,2-dichloro-1-methylcyclopropane carboxamide nicotine 2- (2,6-dichloro-α, α-trifluoro-p -tolyl) hydrazone;

16. O - {(E -) - [2- (4-chloro-phenyl) -2-cyano-1- (2-trifluoromethylphenyl) vinyl]} S-methyl thiocarbonate;

17. (E) - N¹ - [(2-chloro-1,3-thiazol-5-ylmethyl)] - N²-cyano-N¹ -methylacetamidine;

18. 1- (6-chloropyridin-3-ylmethyl) -7-methyl-8-nitro-1,2,3,5,6,7-hexahydroimidazo [1,2-a] pyridin-5-ol;

19. 4- [4-chlorophenyl- (2-butylidinhydrazono) methyl)] phenyl mesylate; and

twenty. N-ethyl-2,2-dichloro-1-methylcyclopropanecarboxamide 2- (2,6-dichloro-alpha, alpha, alpha-trifluoro-p -tolyl) hydrazone.

SYNERGIC MIXTURES

[0767] The molecules of Formula One can be used with some active compounds to form synergistic mixtures where the mode of action of the compounds is the same, similar, or different as compared to that of the molecules of Formula One. Examples of modes of action include, but are not limited to: an acetylcholinesterase inhibitor; sodium channel modulator; chitin biosynthesis inhibitor; GABA-gated chloride channel antagonist and glutamate; GABA-gated chloride channel agonist and glutamate; an acetylcholine receptor agonist; acetylcholine receptor antagonist; a MET I inhibitor; magnesium stimulated ATPase inhibitor; nicotinic acetylcholine receptor; midgut membrane disrupter; an oxidative phosphorylation interruptor, and ryanodine receptor (RyRs). Generally, the weight ratio of the molecules of Formula One in a synergistic mixture with another compound is from about 10: 1 to about 1:10, in another embodiment from about 5: 1 to about 1: 5, and in another embodiment from about 3: 1 , and in another embodiment about 1: 1.

FORMULATIONS

[0768] A pesticide is rarely suitable for use in its pure form. It is usually necessary to add other substances so that the pesticide can be used in the required concentration and in the correct form, allowing for ease of application, handling, transport, storage, and maximum pesticide activity. Thus, pesticides are formulated as, for example, baits, concentrated emulsions, dusts, emulsion concentrates, fumigants, gels, granules, microcapsules, seed dressings, suspension concentrates, suspoemulsions, tablets, water-soluble liquids, water-dispersible or dry granules. bulk formulations, wettable powders, and ultra-low volume solutions. For further information on formulation types, see Catalog of Pesticide Formulation Types and International Coding System, Technical Monograph No. 2, Issue 5, CropLife International (2002).

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[0769] Pesticides are most commonly used as aqueous suspensions or emulsions made from concentrated formulations of such pesticides. Such water-soluble, water-dispersible, or emulsifiable formulations are either solids, usually known as wettable powders, or water-dispersible granules, or liquids, usually known as emulsion concentrates, or aqueous suspensions. Wettable powders that can be compressed into water-dispersible granules contain a homogeneous mixture of pesticide, carrier, and surfactants. The concentration of the pesticide is usually from about 10% to about 90% by weight. The support is typically selected from attapulgite clays, montmorillonite clays, diatomaceous earths, or purified silicates. Effective surfactants, ranging from about 0.5% to about 10% of the wettable powder, are found among sulfonated lignins, condensed naphthalenesulfonates, naphthalenesulfonates, alkylbenzenesulfonates, alkyl sulfates, and nonionic surfactants such as alkylphenol ethylene oxide adducts.

[0770] Pesticide emulsion concentrates contain a convenient pesticide concentration, such as from about 50 to about 500 grams per liter of liquid dissolved in a carrier which is either a water-miscible solvent or a mixture of a water-immiscible organic solvent and emulsifiers. Useful organic solvents include aromatics, especially xylenes, and petroleum fractions, especially high-boiling naphthalene and olefinic petroleum portions such as naphtha. Other organic solvents such as terpene solvents, including rosin derivatives, aliphatic ketones such as cyclohexanone, and complex alcohols such as 2-ethoxyethanol, can also be used. Emulsifiers suitable for emulsion concentrates are selected from conventional anionic and nonionic surfactants.

[0771] Aqueous suspensions include suspensions of water-insoluble pesticides dispersed in an aqueous carrier at a concentration ranging from about 5% to about 50% by weight. Slurries are made by finely grinding the pesticide and vigorously mixing it with a vehicle composed of water and surfactants. Ingredients such as inorganic salts and synthetic or natural gums may also be added to increase the density and viscosity of the aqueous carrier. It is often most effective to simultaneously mill and mix the pesticide by making an aqueous mixture and homogenizing it in an apparatus such as a sand mill, ball mill, or piston type homogenizer.

[0772] Pesticides can also be applied as granular compositions which are particularly suitable for soil application. Granular compositions typically contain from about 0.5% to about 10% by weight of the pesticide dispersed in a carrier that contains clay or the like. Such compositions are typically prepared by dissolving the pesticide in a suitable solvent and applying it to a granular carrier that has been previously shaped to the appropriate particle size ranging from about 0.5 to about 3 mm. Such compositions may also be formulated by preparing a dough or paste from the carrier and compound, and grinding and drying to provide the desired particle size of the grains.

[0773] Pesticide-containing dusts are prepared by intimately mixing the pesticide in powder form with a suitable powdery agricultural carrier such as kaolin clay, ground volcanic rock, and the like. Dusts may conveniently contain from about 1% to about 10% of the pesticide. They can be used as seed dressing or applied to the leaves using a duster.

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[0774] It is equally practical to apply the pesticide as a solution in a suitable organic solvent, usually a petroleum oil such as spray oils which are widely used in agricultural chemistry.

[0775] Pesticides can also be applied in the form of an aerosol composition. In such compositions, the pesticide is dissolved or dispersed in a carrier that is in a mixture with a pressure-generating propellant. The aerosol composition is packaged in a container from which the mixture is dispensed through a spray valve.

[0776] Pesticide baits are created when a pesticide is mixed with food or an attractant or both. When pests eat the bait, they also eat the pesticide. The baits can take the form of granules, gels, free flowing powders, liquids, or solids. They can be used in places of shelter for pests.

[0777] Fumigants are pesticides that have a relatively high vapor pressure and hence can exist as a gas in concentrations sufficient to kill pests in soil or confined spaces. The fumigant toxicity is proportional to its concentration and exposure time. They have a good diffusion capacity and act by penetrating the pest's respiratory system or absorbed into the pest's cuticle. Fumigants are used to control pests of products stored under gas-tight sheets, in gas-tight rooms or buildings, or in special chambers.

[0778] Pesticides can be microencapsulated by suspending pesticide particles or droplets in various types of plastic polymers. By varying the chemistry of the polymer or by varying processing factors, microcapsules of various sizes, solubilities, wall thicknesses, and degrees of permeability can be produced. These factors govern the rate at which the active ingredient is released from the agent, which in turn affects the residual efficacy, speed of action, and odor of the product.

[0779] Oil solution concentrates are prepared by dissolving the pesticide in a solvent that will keep the pesticide in solution. Pesticide oily solutions typically infect and kill pests faster than other formulations due to the fact that the solvents themselves are pesticidal and dissolve the waxy coating of the body coat, increasing the pesticide uptake rate. Other advantages of oil solutions include better shelf life, better penetration of crevices and better adhesion to oily surfaces.

[0780] Another embodiment is an oil-in-water emulsion, wherein the emulsion comprises oily spheres each having a liquid crystal lamellar coating, and dispersed in an aqueous phase, each oily ball containing at least one agriculturally active compound and is Separately coated with a monolamellar or oligolamellar layer, containing: (1) at least one non-ionic lipophilic surfactant, (2) at least one non-ionic hydrophilic surfactant, and (3) at least one ionic surfactant, wherein the beads have a mean particle diameter of less than 800 nanometers. Further information on an embodiment is disclosed in US Patent Application Publication No. 20070027034 published February 1, 2007, having patent application order number 11 / 495,228. For ease of use, this embodiment will be referred to as OIWE.