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1. WO2020117886 - METHODS OF INHIBITING OSTEOCLASTOGENESIS AND OSTEOCLAST ACTIVITY

Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

[ EN ]

CLAIMS

1 claim:

1. A method of inhibiting osteoclastogenesis or inhibiting osteoclast activity comprising: administering to a s ubject a compound of Formula (I) or a pharmaceutically

acceptable salt thereof,

wherein

a compound of Formula (1) has the structure shown below


wherein

X1 is =N- or Cl !-:

X2 is C! R1 )- and X3 is Ci -l.-G)-: or X2 is =C(-L-G)- and X3 is C( R!

G is hydrogen, -Ci-8 alkyl, -C3-10 cycloalkyl, -Ci-e alkylene-Cmo cycloaklyl,

heterocyclyl, -Ci-6 alkylene-C3-io heterocyclyl, phenyl, heteroaryl, or NRh Rk, where the alkyl, alkylene, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from Rc; or G is -CH2Y3, -CH2CH2Y3, - CH2CH2CH2Y3, -Cl !{('! 1 ;}C! 1 ' 2 -CH2CH(Y3)CH3, - * v3

CH(Y3)CH3, -CH2C(Y3)(CH3)2S -C(Y3)(CH3)2, or A where Y3 is cyclopropyl, -CF3, -OCF3, -OCH3, -OCH2CH3, -F, -Cl, -OH, -<>{('[ I O -Ol 1. - 0(CH2)2-F, -SCI 1 -Si ()}'-( ! I i -SCH2CH3, -S(0)2CH2CH3, -NH-CH3, -NH- CH2CH3, -N(CH3)2, tetrahydropyran-4-yl, tetrahydrofuran-2-yl, morpholin-2- yl, morphoim-4-yi, piperidin-l-yl, 4-hydroxy-piperidin-l-yl, 3-hydroxy- piperidin-1 -yl, -NH-C(0)-CH3, -NH-C(0)-CH2CH3, tetrahydrofuran-2-yl- methyloxy, or -C(0)-Y4, where Y4 is -OH, -OCH3, -OCH2CLL·, -OC(CH3)3, -

M i ·. -NH-CHs, -NH-CH2CH3, -N(CH3)2, -N(CH2CH3)2, morpholin-4-yl, 4- methy]-piperazin-l-yl, pyrrolidin-l-yl, or piperazin-l -yl;

L is -CH2-C(0)N(R6)-, -C(0)N(R6)-, -( {OH)-. -SO2-, -( {())-. heteroaiylene

optionally substituted one or more times with substituents independently selected from Rx, or heterocyclylene optionally substituted one or more limes with substituents independently selected from Rx; or the group -L-G is -cyano; R1 is hydrogen, Ra, phenyl, or heteroaryl, where the phenyl and heteroaryl groups are optionally substituted one or more times with substituents independently selected from Rx;

R2 is Rb:

R3 is hydrogen, -Ci-6 alkyl, or -Ci~6 alkylene-C3-io cycloaklyl, where the alkyl,

alkylene, and cycloalkyl groups are optionally substituted one or more times with substituents independently selected from Rz;

R4 is -Ci -6 alkyl or -C1-0 alkylene-CVio cycloaklyl, where the alkyl, alkylene, and cycloalkyl groups are optionally substituted one or more times with substituents independently selected from Ry;

R6 is hydrogen, -C1-6 alkyl, -Ci-6 alkylene-C3-io cycloaklyl, where the alkyl, alkylene, and cycloalkyl groups are optionally substituted one or more times with substituents independently selected from Rx;

Ra is

a) -halogen,

b) -Ci -6 alkyl,

c) -C3-io cycloalkyl,

d) -heterocyclyl,

e) -cyano,

0 -CFJ,

g) -OCF3,

h) -0-Rd,

1) -S(0)w-Rd,

j) -S(0)20-Rd,

k) -NRdRe,

l) -C(0)-Rd,

m) -C(0)-0-Rd,

n) -OC(0)-Rd,

o) -C(0)NRd Re,

p) -C(0)-heierocyclyl,

q) -NRd C(0)Re,


where the alkyl, cycloalkyl, and heterocyclyl groups are optionally substituted one or more times with substituents independently selected from Ry;

a) -halogen,

b) -Ci-6 alkyl,

c) -C3-10 cycloalkyl,

d) -heterocyclyl,

e) -phenyl,

i) -heteroaryl,

g) -cyano,

h) -CFs,

i) -OCF3,

j) -0-Rf,

k) -S(0)w-Rf,

l) -S(0)20~llf,

m) -NRfR8,

n) -C(0)-Rf,

0) -C(0)-0-Rf,

p) -OC(0)-Rf,

q) -C(0)NRfRg,

r) -C(0)-heterocyciyl,

s) -NRf C(0)Rg,

t) -OC(0)NRf Rg,

u) -NRf C(0)ORf, or

v) -NRf C(0)NRf Rg,

where the alkyl, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from Rz;

a) -halogen,

b) -Ci-6 alkyl,

c) -Cs-io cycloalkyl,

d) -heterocyclyl,

e) -cyano,

f) -CFs,

g) -OCF3,

h) -0~Rh,

i) -S(0)w-R\

j) -S(0)2()-Rh,

k) -NRhRk,

l) ~C(0)~Rh,

m) -C(G)-Q-Rh,

n) -OC(0)-Rh,

o) -C(0)NRh Rk,

p) -C(0)-he†erocydyl,

q) -NRh C(0)Rk,

r) -OC(0)NRh Rk,

s) -NRh C(G)ORk,

t) -NRh C(0)NRh Rk,

u) -NRh S(0)wRk,

v) -phenyl,

w) -heteroaryl, or

x) -0-(Ci4 alkylene)-0-(Ci-4 alkylene)-N(Rh)C(0)-ORk,

where the alkyl ene, alkyl, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from Rx;

Rd and Re are independently hydrogen, Ci-6 alkyl, or C3-10 cycloalkyl, where the alkyl and cycloalkyl groups are optionally substituted one or more times with substituents independently selected from Ry; or, if Rd and Re are both attached to the same nitrogen atom, together with that nitrogen atom may optionally form a heterocyclic ring selected from the group consisting of azetidino, pyrrolidine, pyrazolidino, imidazolidino, oxazolidmo, isoxazolidino,

thiazolidino, isothiazolidino, piperidino, piperazino, morpholino,

thiomorpholino, and azepano, where each ring is optionally substituted one or more times with substituents independently selected from Ry;

R1 and Rg are independently hydrogen, Ci-6 alkyl, C3-10 cy cloalkyl, phenyl, or

heteroaryl, where the alkyl, cycloalkyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from Rz; or, if R1 and Rs are both attached to the same nitrogen atom, together with that nitrogen atom may optionally form a heterocyclic ring selected from the group consisting of azetidino, pyrrols dino, pyrazolidino, imidazolidino, oxazolidino, isoxazoiidino, thiazolidino, isothiazolidino, piperidino, piperazino, morpholino, thiomorpholino, and azepano, where each ring is optionally substituted one or more times with substituents

independently selected from Rz;

Rh and Rk are independently hydrogen, Ci-6 alkyl, C3-10 cycloalkyl, heterocyelyi, phenyl, or heteroaryl, where the alkyl, cycloalkyl, heterocyelyi, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from Rx; or, if Rn and Rk are both attached to the same nitrogen atom, together with that nitrogen atom may optionally form a heterocyclic ring selected from the group consisting of azetidino, pyrroiidino, pyrazolidino, imidazolidino, oxazolidino, isoxazoiidino, thiazolidino, isothiazolidino, piperidino, piperazino, morpholino,

thiomorpholino, and azepano, where each ring is optionally substituted one or more times with substituents independently selected from Rx;

Ry is

a) -halogen,

hi -NI-Ϊ2,

c) -cyano,

d) -carboxy,

e) -hydroxy,

1) -thiol,

g) -CF3,

h) -OCF3,

i) -C(0)-NH2,

j) -SCO) -Nf I .

k) oxo,

l) ~C 1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, -OH, -O-Ci-6 alkyl, -Nth, -NH-Ci-6 alkyl, and -N(C i-e alkyl)?.,

rn) -heierocycly] optionally substituted one or more times with substituents selected independently from the group consisting of halogen, -OH, -O-Ci-6 alkyl, -NH?, -NH-CI-G alkyl, and -N(CI-6 alkyl)?,

n) -C3-10 cycloalkyl optionally substituted one or more times with substituents selected independently from the group consisting of halogen, -OH, -O-Ci-6 alkyl, -NH?, -NH-CI-6 alkyl, and -N(C I-6 alkyl)?,

0) -O-Ci-6 alkyl optionally substituted one or more times with substituents selected independently from the group consisting of halogen, -OH, -O-Ci-e alkyl, -N1 1 ·. -NH-CI-6 alkyl, and -N(CI-6 alkyl)?,

p) -O-C3-10 cycloalkyl optionally substituted one or more times with

substituents selected independently from the group consisting of halogen, - OH, -O-Ci-e alkyl, -NH?, -NH-Ci-e alkyl, and -N(Ci-e alkyl)?,

q) -NH-CI-6 alkyl optionally substituted one or more times with substituents selected independently from the group consisting of halogen, -OH, -O-Ci-e alkyl, -NH?, -NH-Ci-e alkyl, and -N(Ci-e alkyl)?,

r) -N(CI 6 alkyl)? optionally substituted one or more times with substituents selected independently from the group consisting of halogen, -OH, -O-Ci-6 alkyl, -NH?, -NH-C1-0 alkyl, and -N(CI-6 alkyl)?,

s) -C(0)-Ci-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, -OH, -Q-Ci-e alkyl, -NH?, -NH-CI-6 alkyl, and -N(C I-6 alkyl)?,

t) -C(0)-0-Ci-6 alkyl, optionally substituted one or more times with

substituents selected independently from the group consisting of halogen, - OH, -O-Ci-6 alkyl, -NH?, -NH-Ci-6 alkyl, and -N(Ci-6 alkyl)?,

u) -S-Ci-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, -OH, -O-Ci-e alkyl, -NH?, -NH-Ci-6 alkyl, and -N(Ci-6 alkyl)?,

v) -S(0)?-Ci-6 alkyl, optionally substituted one or more times with

substituents selected independently from the group consisting of halogen, - OH, -Q-C i -6 alkyl, -NH?, -NH-C 1-6 alkyl, and -N(C 1-6 alkyl)?,

w) -C(0)-NH-CI-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, - OH, -O-Ci-6 alkyl, -NH2, -NH-C 1-6 alkyl, and -N(CI-6 alkyl K

x) -C(0)-N(CI-6 alky l)?., optionally substituted one or more times with

substituents selected independently from the group consisting of halogen, - OH, -Q~C ϊ -6 alkyl, -NH2, -NH-C 1-6 alkyl, and ~N(C i-6 alkyl)?, y) -S(0)? NH-Ci-6 alkyl, optionally substituted one or more times with

substituents selected independently from the group consisting of halogen, - OH, -O-Ci-6 alkyl, -NH2, -NH-C 1-6 alkyl, and -N(Ci-e alkyl)?, z) -S(0)2-N(CI-6 alkyl)?, optionally substituted one or more times with

s ubstituents selected independently from the group consisting of halogen, - OH, -O-Ci-6 alkyl, -NH?, -NH-C 1-6 alkyl, and -N(CI-6 alkyl)?, aa) -NH-C (O)-C 1-6 alkyl, optionally substituted one or more times with

substituents selected independently from the group consisting of halogen, - OH, -O-Ci-6 alkyl, -NH?, -NH-C 1-6 alkyl, and -N(Ci-6 alkyl)?, or bb) -NH-S(Q)2-CI-6 alkyl, optionally substituted one or more times with

substituents selected independently from the group consisting of halogen, - OH, -O-Ci-6 alkyl, -NH?, -NH-C 1-6 alkyl, and -N(Ci-6 alkyl)?;

R · is

a) ~Ry

b) -phenyl, optionally substituted one or more times with substituents

selected independently from the group consisting of halogen, -OH, -O-C1-0 alkyl, -NH?, -NH-CI-6 alkyl, and -N(CI-6 alkyl)?,

c) -heteroaryl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, -OH, -O-Ci-e alkyl, -NH2, -NH-Ci-e alkyl, and -NiCi-e alkyl)2,

d) -O-phenyl,

e) -O-heteroaryl,

f) -C(0)-phenyl,

g) -C(0)-heteroaryl,

h) -C(0)-0-phenyl, or

i) -C(0)-0-heteroaryl;

Rz is

a) -Ry

b) -phenyl,

c) -heteroaryl;

d) -O-phenyl,

e) -O-heteroaryl,

0 -C(0)-phenyl,

g) -C(0)-heteroaryl,

h) -C(0)-0-phenyl, or

i) -C(0)-0-heteroaryl;

v is an integer from 0 to 4, and

w is an integer from 0 to 2.

2 The method of claim 1 , wherein the method further comprises the step of

determining whether a subject is at risk for or has a bone related disease by

obtaining or having obtained a biological sample from the subject and performing or having performed a bodily fluid test on the biological sample to determine if the subject has biomarkers for a hone related disease.

3. The method of any one of claims 1 to 2, wherein the method further comprises the step of

determining whether a subject is at risk for or has a bone related disease by

performing or having performed a first skeletal survey on an area of the

subject’s skeleton to determine if the subject has a bone density level associated with a bone related disease.

4. The method of any one of claims 1 to 3, wherein the method further comprises the step of

obtaining or having obtained biological samples over a period from the subject, performing or having performed a bodily fluid test on the biological samples to

determine whether the level of one or more biochemical resorptive markers are increasing or decreasing over the period, and

if the level of one or more biochemical resorptive markers are increasing or are not decreasing then administering a greater dose of a compound of Formula (1) or a pharmaceutically acceptable salt thereof.

5 The method of claim 3, wherein the method further comprises the step of performing or having performed a second skeletal survey to determine whether the subject’s bone density has changed from the first skeletal survey, and if the subject’s bone density has decreased from the first to the second skeletal survey then administering a greater dose and/or a more frequent dose of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

6 The method of claim l, wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of:

l-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-lH-benzoimidazole-5- carboxylic acid ((S)-2-hydroxy-propyl)-amide;

3-Methyl-2-(6-trif]uoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5- b]pyridine-6~carboxyliC acid (2-methoxy-ethyl)-amide;

l-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-li/-benzimidazole-5- carboxylic acid dimethylcarbamoylmethyl-amide; and

l-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-lH-benzoimidazole-5- carboxylic acid [2-(2-hydroxy-ethoxy)-ethyl]-amide;

or a pharmaceutically acceptable salt thereof.

7 A method of treating periodontitis or gingivitis comprising

administering to a subject a compound of Formula (I) or a pharmaceutically acceptable salt thereof,

wherein

a compound of Formula (I) has the structure shown below


wherein

X1 is =N- or Cl !-:

X2 is =C(R1)- and X3 is =C(-L-G)-; or X2 is =C(-L-G)- and X3 is ^(R1)-;

G is hydrogen, -Ci-s alkyl, -C3-10 cycloalkyl, -Ci-e alkylene-Ch-io cycloaklyl, heterocyclyl, -Ci-e alkyl ene-C3-io heterocyclyl, phenyl, heteroaryl, or NRh Rk, where the alkyl, alkylene, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from Rc; or G is -CH2Y3, -CH2CH2Y\ - CH2CH2CH2Y3, -CH(CH3)CH2Y3, -CH2CH(Y3)CH3, - * y3

CH(Y3)CH3, -CH2C(Y3)(CH3)2, -C(Y3)(CH3)2, or D where Y3 is cyclopropyl, -CFs, -OCF3, -OCH3, -OCH2CH3, -F, -Cl, -OH, -0(CH2)2-0H, - 0(CH2)2-F, -SCI-I3, -S(0)2-CH3, -SCH2CH3, -S(0)2CH2CH3, -NH-CH3, -M i · CH2CH3, -N(CH3)2, tetrahydropyran-4-yl, tetrahydrofuran-2-yl, morpholin-2- yl, morpholin-4-yl, piperidin-l-yl, 4-hydroxy-piperidin-l-yl, 3-hydroxy ~ pipendin-l-yl, -NH-C(0)-CH3, -NH-C(0)-CH2CH3, tetrahydrofuran-2-yl- methyloxy, or -C(0)-Y4, where Y4 is -OH, -OCH3, -OCH2CH3, -OC(CH3)3, - M-Ϊ2, -NH-CHs, -NH-CH2CH3, -N(CH3)2, -N(CH2CH3)2, morpholin-4-yl, 4- methyl-piperazin-i-yl, pyrrolidin-l-yl, or piperazin-l-yl;

L is -CH2-C(0)N(R6)-, -C(0)N(R6)-, -C(0)-0-, -SO2-, -C(0)-, heteroarylene

optionally substituted one or more times with substituents independently selected from Rx, or heterocyclylene optionally substituted one or more times with substituents independently selected from Rx; or the group -L-G is -cyano;

R1 is hydrogen, Ra, phenyl, or heteroaryd, where the phenyl and heteroaryl groups are optionally substituted one or more times with substituents independently selected from Rx;

R2 is Rb;

R3 is hydrogen, -Ci-6 alkyl, or -Ci-6 alkyl ene-C3-io cycloaklyl, where the alkyl,

alkylene, and cycloalkyl groups are optionally substituted one or more times with substituents independently selected from Rz;

R4 is -Ci-e alkyl or -Ci-e aikylene-Cs-io cycloaklyl, where the alkyl, alkylene, and cycloalkyl groups are optionally substituted one or more times with substituents independently selected from Ry;

R6 is hydrogen, -Ci-6 alkyl, -Ci-6 alkylene-ih-io cycloaklyl, where the alkyl, alkylene, and cycloalkyl groups are optionally substituted one or more times with substituents independently selected from Rx;

Ra is

a) -halogen,

b) -Ci-6 alkyl,

c) -Cs-io eycloalkyl,

d) -heterocydyl,

e) -cyano,

1) -CFs,

g) -OCFs,

h) -0-Rd,

i) -S(0)w-Rd,

j) -S(0)20-Rd,

k) -NRdRe,

l) -C(0)-Rd,

m) -C(0)-0-Rd,

n) -OC(0)-Rd,

o) -C(())NRdRe,

p) -C(0)-heterocyclyl,

q) -NRd C(0)Re,


where the alkyl, cycloalkyl, and heterocydyl groups are optionally substituted one or more times with substituents independently selected from Ry;

a) -halogen,

b) -Ci-6 alkyl,

c) -C3-10 cycloalkyl,

d) -heterocydyl,

e) -phenyl,

1) -heteroaryl,

g) -cyano,

h) Cl d

i) -OCF3,

j) -0-Rf,

k) -S(0)w-Rf,


n) -C(0)-Rf,

o) -C(G)-G-Rf,

p) -0C(0)-Rf,

q) -C(0)NRfRg,

r) -C(0)-heterocyclyl,

s) -NRf C(0)Rg,

t) -0C(0)NRf Rg,

u) -NRf C(0)0Rf, or

v) -NRf C(0)NRf R8,

where the alkyl, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from Rz;

Rc is

a) -halogen,

b) -Ci -6 alkyl,

c) -C3-10 cycloalkyl,

d) -heterocyclyl,

e) -cyano,

f) -CF3,

g) -OCF3,

h) -0~Rh,

i) -S(0)w-Rh,


l) -C(0)-Rh,

m) -C(0)-0-Rh,

n) -OC(0)-Rh,

0) -C(0)NRh Rk,

p) -C(0)-heterocyciyl,

q) -NRh C(0)Rk,

r) -OC(0)NRh Rk,

s) -NRh C(0)ORk,

ί) -NRh C(0)NRh Rk,

u) -NRh S(0)wRk,

v) -phenyl,

w) -heteroaryl, or

x) -0-(CM alk lene)-0-(Ci alky]ene)-N(Rh)C(0)-ORk,

where the alkylene, alkyl, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from Rx;

R° and Re are independently hydrogen, Ci-6 alkyl, or Cs-io cycloalkyl, where the alkyl and cycloalkyl groups are optionally substituted one or more times with substituents independently selected from Ry; or, if Rd and Rc are both attached to the same nitrogen atom, together with that nitrogen atom may optionally form a heterocyclic ring selected from the group consisting of azetidino, pyrrolidmo, pyrazoiidino, imidazolidino, oxazolidmo, isoxazohdino, thiazolidino, isothiazohdino, pipendino, piperazino, morpholino,

thiomorpholino, and azepano, where each ring is optionally substituted one or more times with substituents independently selected from Ry;

R1 and Rg are independently hydrogen, Ci-6 alkyl, C3-10 cycloalkyl, phenyl, or

heteroaryl, where the alkyl, cycloalkyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from Rz; or, if R1 and Rs are both attached to the same nitrogen atom, together with that nitrogen atom may optionally form a heterocyclic ring selected from the group consisting of azetidino, pyrrolidine, pyrazoiidino, imidazolidino, oxazolidino, isoxazohdino, thiazolidino, isothiazohdino, piperidine, piperazino, morpholino, thiomorpholino, and azepano, where each ring is optionally substituted one or more times with substituents

independently selected from Rz;

Rh and Rk are independently hydrogen, Ci-6 alkyl, C3-10 cycloalkyl, heterocyclyl, phenyl, or heteroaryl, where the alkyl, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from Rx; or, if Rn and Rk are both attached to the same nitrogen atom, together with that nitrogen atom may optionally form a heterocyclic ring selected from the group consisting of azetidino, pyrroiidino, pyrazoiidino, imidazolidino, oxazolidino, isoxazohdino,

thiazolidino, isothiazolidino, piperidino, piperazino, morpholino,

thiomorpholino, and azepano, where each ring is optionally substituted one or more times with substituents independently selected from Rx;

Ry is

a) -halogen,

b) -NH¾

c) -cyano,

d) -carboxy,

e) -hydroxy,

f) -thiol,

8) -CFB,

h) -OCF3,

i) -C(0)-NH2,

j) -S(0)?-Nl 1

k) oxo,

l) -C 1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, -OH, -O-Ci-6 alkyl, -NH2, -NH-Ci-6 alkyl, and -N(C I-6 alkyl)?.,

rn) -heterocyclyl optionally substituted one or more times with substituents selected independently fro the group consisting of halogen, -OH, -O-Ci-6 alkyl, -NH2, -NH-Ci-6 alkyl, and -N(CI-6 alkyl)?,

n) -C3-10 cycloalkyl optionally substituted one or more times with substituents selected independently from the group consisting of halogen, -OH, -O-Ci-6 alkyl, -NH?, -NH-CI-6 alkyl, and -N(C I-6 alkyl)?,

0) -O-Ci-6 alkyl optionally substituted one or more times with substituents selected independently from the group consisting of halogen, -OH, -O-Ci-e alkyl, -NH?, -NH-CI-6 alkyl, and -N(CI-6 alkyl)?,

p) -O-C3-10 cycloalkyl optionally substituted one or more times with

substituents selected independently from the group consisting of halogen, - OH, -O-Ci-e alkyl, -NH?, -NH-Ci-e alkyl, and -N(Ci-e alkyl)?, q) -NH-Ci-6 alkyl optionally substituted one or more times with substituents selected independently from the group consisting of halogen, -OH, -O-Ci-e alkyl, -NH?, -NH-Ci-e alkyl, and -N(Ci-e alkyl)?,

r) -N(CI-6 alkyl)? optionally substituted one or more times with substituents selected independently from the group consisting of halogen, -OH, -O-Ci-6 alkyl, -M 1 ·. -NH-Ci-6 alkyl, and -N(C -6 alky i ).·.

s) -C(0)-Ci-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, -OH, -O-Ci-6 alkyl, -N1 1 ·. -NH-CI-6 alkyl, and -N(CI-6 alkyl)?,

t) -C(0)-0-Ci-6 alkyl, optionally substituted one or more times with

substituents selected independently from the group consisting of halogen, - OH, -O-Ci-e alkyl, -NH?, -NH-CI-6 alkyl, and -N(CI-6 alkyl)?,

u) -S-Ci-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, -OH, -O-Ci-e alkyl, -NH?, -NH-Ci-e alkyl, and -NiCi-e alkyl)?,

v) -S(0)?-Ci-6 alkyl, optionally substituted one or more times with

substituents selected independently from the group consisting of halogen, - OH, -O-Ci-e alkyl, -NH?, -NH-CI-6 alkyl, and -N(CI-6 alkyl)?,

w) -C(0)-NH-CI-6 alkyl, optionally substituted one or more times with

substituents selected independently from the group consisting of halogen, - OH, -O-Ci-6 alkyl, -NH?, -NH-Ci-6 alkyl, and -N(Ci-6 alkyl)?,

x) -C(0)-N(CI-6 alkyl)?, optionally substituted one or more times with

substituents selected independently from the group consisting of halogen, - OH, -0-C]-6 alkyl, -NH?, -NH-Ci-6 alkyl, and -N(Ci-6 alkyl)?,

y) -S(Q)?-NH-Ci alkyl, optionally substituted one or more times with

substituents selected independently from the group consisting of halogen, - OH, -O-Ci-e alkyl, -NH?, -NH-Ci-e alkyl, and -N(Ci-e alkyl)?,

z) -S(0)?-N(CI~6 alkyl)?, optionally substituted one or more times with

substituents selected independently from the group consisting of halogen, - OH, -O-C i -6 alkyl, -NH?, -NH-C i-6 alkyl, and ~N(C i-6 alkyl)?,

aa) -NH-C (O)-C 1 -6 alkyl, optionally substituted one or more times with

substituents selected independently from the group consisting of halogen, - OH, -O-Ci-e alkyl, -NH?, -NH-Ci-e alkyl, and -N(Ci-e alky])?, or bb) -NH-S(0)?-C 1-6 alkyl, optionally substituted one or more times with

s ubstituents selected independently from the group consisting of halogen, - OH, -O-Ci-6 alkyl, -NH?, -NH-Ci-e alkyl, and -N(Ci-6 alkyl)?;

Rx is

a) -Ry

b) -phenyl, optionally substituted one or more times with substituents

selected independently from the group consisting of halogen, -OH, -O-Ci-6 alkyl, -NH2, -NH-Ci-e alkyl, and -NiCi-e alkyl)2,

c) -heteroaryl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, -OH, -O-Ci-6 alkyl, -NH?„ -NH-C1-0 alkyl, and -N(CI-6 aikyi)2,

d) -O-phenyl,

e) -O-heteroaiyl,

f) -C(0)-phenyl,

g) -C(0)-heteroaryl,

h) -C(0)-0-phenyl, or

1) -C(0)-0-heteroaryl;

Rz is

a) -Ry

b) -phenyl,

c) -heteroaryl;

d) -O-phenyl,

e) -O-heteroaiyl,

f) -C(0)-phenyl,

g) -C(0)-heteroaryl,

h) -C(0)-0-phenyl, or

i) -C(0)-0-heteroaryl;

v is an integer from 0 to 4, and

w is an integer from 0 to 2.

8. The method of claim 7, wherein a compound of Formula (1) or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to inhibit

osteoclastogenesis or osteoclast activity' in the subject.

9. The method of any one of claims 7 and 8, wherein the method further comprises the step of

determining whether a subject is at risk for or has a bone related disease by obtaining or having obtained a biological sample from the subject and performing or having performed a bodily fluid lest on the biological sample to determine if the subject has biomarkers for a bone related disease.

10 The method of any one of claims 7 to 9, wherein the method further comprises the step of

determining whether a subject is at risk for or has a bone related disease by

performing or hav ing performed a first skeletal survey on an area of the

subject’s skeleton to determine if the subject has a bone density level associated with a bone related disease.

11. The method of any one of claims 7 to 10, wherein the method further comprises the step of

obtaining or having obtained biological samples over a period from the subject, performing or having performed a bodily fluid test on the biological samples to

determine whether the level of one or more biochemical resorptive markers are increasing or decreasing over the period, and

if the level of one or more biochemical resorptive markers are increasing or are not decreasing then administering a greater dose of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

12. The method of claim 11, wherein the method further comprises the step of

performing or having performed a second skeletal survey to determine whether the subject’s bone density has changed from the first skeletal survey, and if the subject’s bone density' has decreased from the first to the second skeletal survey then administering a greater dose and/or a more frequent dose of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

13. The method of claim 7, wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of;

l-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-lH-benzoimidazole-5- carboxylic acid ((S)~2-hydroxy-propyi)-amide;

3-Methyl-2-(6-trifluoromeihoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5~

b]pyridme-6~carboxyliC acid (2-methoxy~ethyl)-amide;

no

l-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-li7-benzimidazole-5- carboxylic acid dimethylcarbamoyimethyl-amide; and

l-Methyl-2-(6-trifluoromethyl~benzothiazoi~2-ylamino)-lH-benzoimidazole-5- carboxyiic acid [2-(2-hydroxy -ethoxy )-ethyl ]-amide;

or a pharmaceutically acceptable salt thereof.

14. A method of inhibiting bone destruction, inhibiting bone loss, of inhibiting the rate of reduction of bone density, of maintaining bone density, or of increasing bone density comprising

administering to a subject a compound of Formula (I) or a pharmaceutically

acceptable salt thereof,

wherein

a compound of Formula (I) has the structure shown below


wherein

X! is =N- or =CH~;

X2 is =C(R!)- and X3 is =C(-L-G)-; or X2 is =C(-L-G)- and X3 is =C(R])-;

G is hydrogen, -Ci-s alkyl, -C3-10 cycloalkyl, -Ci-e alkylene-Ch-io cycloaklyi,

heterocydyl, -Ci-e alkylene-C3-ioheterocyclyl, phenyl, heteroaryl, or NRh Rk, where the alkyl, alky!ene, cycloalkyl, heterocydyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from Rc; or G is -CH2Y3, ~CH2CH2YJ, - CH2CH2CH2Y3, ~CH(CH3)CH2Y3, -CH2CH(Y3)CH3, - * y3

CH(Y3)CH3, -CH2C(Y3)(CH3)2, -C(Y3)(CH3)2, or D , where Y3 is cyclopropyl, -CF3, -OCF3, -OCH3, -OCHbCHy -F, -Cl, -OH, -0(CH2)2-QH, - Old !2)2·I·. - sell·.. -S(0)2-CH3, -SCH2CH3, -S(0)2CH2CH3, -NH-CHS, - XI I - CH2.CH3, -N(CH3)2, tetrahydropyran-4-yl, tetrahydrofuran-2-yl, morpholin-2- yl, morpholin-4-yl, piperidin-l-yl, 4-hydroxy-piperidin-l-yl, 3-hydroxy-

piperidin-1 -y!, -NH-C(0)-CH3, -NH-C(0)-CH2G¾, tetrahydrofuran-2-yJ- methyloxy, or -C(0)-Y4, where Y4 is -OH, -OCH3, -OCH2CH3, -OC(CH3)3, - M l ·. -NH-CH3, -NH-CH2CH3, -N(CH3)2, -NiCi bCi h) ·. morpholin-4-yl, 4- methyl-piperazin-l-yl, pyrrolidin-l-yl, or piperazin-l-yl;

L is -CH2-C(0)N(R6)-, -C(0)N(R6)-, -C(0)-0-, -SO2-, -C(O)-, heteroarylene

optionally substituted one or more times with substituents independently selected from Rx, or heterocyclylene optionally substituted one or more times with substituents independently selected from Rx; or the group -L-G is -cyano; R5 is hydrogen, R3, phenyl, or heteroaryl, where the phenyl and heteroaryl groups are optionally substituted one or more times with substituents independently selected from Rx;

R2 is Rb;

R3 is hydrogen, -Ci-6 alkyl, or -Ci-6 alkyl ene-Ci- 10 cycloaklyl, where the alkyl,

alkylene, and cycloalkyl groups are optionally substituted one or more times with substituents independently selected from Rz;

R4 is -Ci-6 alkyl or -Ci-6 a!ky!ene-Cmo cycloaklyl, where the alkyl, alkylene, and cycloalkyl groups are optionally substituted one or more times with substituents independently selected from Ry;

R6 is hydrogen, -Ci-6 alkyl, -Ci-e alkylene-C3-io cycloaklyl, where the alkyl, alkylene, and cycloalkyl groups are optionally substituted one or more times with substituents independently selected from Rx;

R3 is

a) -halogen,

b) -Cue alkyl,

c) -C3-10 cycloalkyl,

d) -heterocyclyl,

e) -cyano,

f) -CF3,

g) -OCF3,

h) -0~Rd,

i) -S(0)w-Rd,

j) -S(0)2()-Rd,

k) -NRdRe,

l) -C(0)-Rd,

m) -C(())-()-Rd,

n) -0C(0)~Rd,

o) -C(0)NRd Re,

p) -C(0)-heterocyclyl,

q) -NRd C(0)Re,

r) ~0C(0)NRd Re,

s) -NRd C(G)ORd, or

t) -NRd C(0)NRd Re,

where the alky], cycloalkyl, and heterocyclyl groups are optionally substituted one or more times with substituents independently selected from Ry;

a) -halogen,

b) -Ci-6 alkyl,

c) -C3-10 cycloalkyl,

d) -heterocyclyl,

e) -phenyl,

f) -heteroaryi,

g) -cyano,

h) -CFJ,

i) -OCF3,

j) -OR1:

k) -S(0)w-Rf,

l) -SiObO-Rk

m) -NRfRg,

n) -C(0)-Rf,

0) -C(0)-0-Rf,

p) -OC(0)-Rf,

q) -C(0)NRfR®,

r) -C(())-heterocyclyl,

s) -NRf C(0)Rs,

t) -OC(0)NRf Rg,

u) -NRf C(0)ORf, or

v) -NRf C(0)NRf Rg,

where the alkyl, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from Rz;

Rc is

a) -halogen,

b) -Ci-6 alkyl,

c) -C3-10 cycloalkyl,

d) -heterocyclyl,

e) -cyano,

0 -CFs,

8) -OCF3,

h) -0-Rh,

i) -S(0)w-Rh,

j) -S(0)20-Rh,

k) -NRhRk,


p) -C(0)-heterocyclyl,

q) -NRh C(0)Rk,

r) -OC(0)NRh Rk,

s) -NRh C(0)ORk,

t) -NRh C(0)NRh Rk,

u) -NRh S(0)vvRk,

v) -phenyl,

w) -heteroaryl, or

x) -Q-iCi-4 alkylene)-0-(Ci-4 alkylene)-N(Rh)C(0)-ORk,

where the alkyl ene, alkyl, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are optionally substituted one or more limes with substituents independently selected from R ':

Ra and Re are independently hydrogen, Ci~6 alkyl, or C3-10 cycloalkyl, where the alkyl and cycloalkyl groups are optionally substituted one or more times with substituents independently selected from Ry; or, if Rd and Re are both attached to the same nitrogen atom, together with that nitrogen atom may optionally form a heterocyclic ring selected from the group consisting of azetidino, pyrrolidino, pyrazolidino, imidazolidino, oxazolidino, isoxazolidino, thiazolidino, isothiazolidmo, piperidmo, piperazino, morpholine,

thiomorpholino, and azepano, where each ring is optionally substituted one or more times with substituents independently selected from Ry;

Rf and R8 are independently hydrogen, Ci-e alkyl, CVio cycloalkyl, phenyl, or

heteroaryl, where the alkyl, cycloalkyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from R'; or, if Rf and R8 are both attached to the same nitrogen atom, together with that nitrogen atom may optionally form a heterocyclic ring selected from the group consisting of azetidino, pyrrolidino, pyrazolidino, imidazolidino, oxazolidino, isoxazolidino, thiazolidino, isothiazolidino, pipendino, piperazino, morpholmo, thiomorpholino, and azepano, where each ring is optionally substituted one or more times with substituents

independently selected from Rz;

Rh and Rk are independently hydrogen, Ci-6 alkyl, C3-10 cycloalkyl, heterocyclyl, phenyl, or heteroaryl, where the alkyl, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from Rx; or, if Rh and Rk are both attached to the same nitrogen atom, together with that nitrogen atom may optionally form a heterocyclic ring selected from the group consisting of azetidino, pyrrolidino, pyrazolidino, imidazolidino, oxazolidino, isoxazolidino, thiazolidino, isothiazolidino, piperidine, piperazino, morph o!ino,

thiomorpholino, and azepano, where each ring is optionally substituted one or more times with substituents independently selected from Rx;

Ry is

a) -halogen,

b) -NH2,

c) -cyano,

d) -carboxy,

e) -hydroxy,

0 -thiol,

g) -CFj,

h) -OCFs,

i) -C(0)-NH2,

j) -S(0).?-Xl I .

k) oxo,

l) -Ci-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, -OH, -O-Ci-6 alkyl, -NH2, -NH-Ci-6 alkyl, and -N(Ci-& alkyl):?,

m) -heterocyclyl optionally substituted one or more times with substituents selected independently from the group consisting of halogen, -OH, -O-Ci-6 alkyl, -NH2, -NH-CI-6 alkyl, and -N(C I-6 alkyl)2,

n) -C3-10 cycloalkyl optionally substituted one or more times with substituents selected independently from the group consisting of halogen, -OH, -O-Ci-6 alkyl, -N1 1 ·. -NH-Ci-6 alkyl, and -N(CI-6 alkyl)?,

0) -O-Ci-6 alkyl optionally substituted one or more times with substituents selected independently from the group consisting of halogen, -OH, -O-C1-0 alkyl, -M l ·. -NH-CI-6 alkyl, and -N(C I-6 alkyl)2,

p) -O-C3-10 cycloalkyl optionally substituted one or more times with

s ubstituents selected independently from the group consisting of halogen, - OH, -O-Ci-6 alkyl, -NH2, -NH-CI-6 alkyl, and -N(CI-6 alkyl)2,

q) -NH-C I-6 alkyl optionally substituted one or more times with substituents selected independently from the group consisting of halogen, -OH, -O-Ci-6 alkyl, -NH , -NH-CI-6 alkyl, and -N(Ci-6 alkyl) ,

r) -N(CI-6 alkyl)2 optionally substituted one or more times with substituents selected independently from the group consisting of halogen, -OH, -O-Ci-6 alkyl, -NH2, -NH-CI-6 alkyl, and -N(C I-6 alkyi)2,

s) -C(0)-Ci-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, -OH, -O-Ci-6 alkyl, -NH2, -NH-Ci-6 alkyl, and -N(Ci-& alkyl):?,

t) -C(0)-0-Ci-6 alkyl, optionally substituted one or more times with

substituents selec ted independently from the group consisting of halogen, - OH, -O-Ci-e alkyl, -NH2, -NH-Ci-e alkyl, and -N(Ci-e alkyl )'.

u) -S-Ci-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, -OH, -O-Ci-e alkyl, -N1 1 ·. -NH-Ci-6 alkyl, and -N(CI-6 alkyl)?,

v) -S(0)2-Ci-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, - OH, -O-Ci-6 alkyl, -NH2, -NH-C 1-6 alkyl, and -N(CI-6 alkyl K

w) -C(0)-NH-CI-6 alkyl, optionally substituted one or more times with

substituents selected independently from the group consisting of halogen, - OH, -Q~C ϊ -6 alkyl, -NH2, -NH-C 1-6 alkyl, and ~N(C i-6 alkyl)2,

x) -C(0)-N(C I-6 alkyl)2, optionally substituted one or more times with

substituents selected independently from the group consisting of halogen, - OH, -O-Ci-6 alkyl, -NH2, -NH-C 1-6 alkyl, and -N(Ci-e alkyl >2,

y) -S(0)2-NH-C I-6 alkyl, optionally substituted one or more times with

s ubstituents selected independently from the group consisting of halogen, - OH, -O-Ci-6 alkyl, -NH2, -NH-C 1-6 alkyl, and -N(Ci-6 alkyl)2,

z) -S(0)2-N(Ci-6 alky 1)2, optionally substituted one or more times with

substituents selected independently from the group consisting of halogen, - OH, -O-Ci-6 alkyl, -NH2, -NH-C 1-6 alkyl, and -N(Ci-6 alkylfe,

aa) -NH-C(0)-Ci-6 alkyl, optionally substituted one or more times with

substituents selected independently from the group consisting of halogen, - OH, -O-Ci-6 alkyl, -NIL·, -NH-C 1-6 alkyl, and -N(Ci-6 alkyl)2, or bb) -NH-S(0)2-CI-6 alkyl, optionally substituted one or more times with

substituents selected independently from the group consisting of halogen, - OH, -O-Ci-6 alkyl, -NH2, -NH-C i -6 alkyl, and -N(CI-6 alkyl)2;

a) -Ry

b) -phenyl, optionally substituted one or more times with substituents

selected independently from the group consisting of halogen, -OH, -O-Ci-e alkyl, -NH2, -NH-Ci-e alkyl, and -NiCi-e alkyl)2,

c) -heteroaryl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, -OH, -O-Ci-6 alkyl, -NH2, -NH-Ci-6 alkyl, and -N(Ci-6 aikyi)2,

d) -O-phenyl,

e) -O-heteroaryl,

f) -C(0)-phenyl,

g) -C(0)-heteroaryl,

h) -C(0)-0-phenyl, or

i) -C(0)-0-heteroaryl;

z is

a) -R- b) -phenyl,

c) -heteroaryl;

d) -O-phenyl,

e) -O-heteroaryl,

1) -C(0)-phenyl,

g) -C(0)-heteroaryl,

h) -C(0)-0-phenyl, or

i) -C(0)-0-heteroaryl;

v is an integer from 0 to 4, and

w is an integer from 0 to 2.

15. The method of claim 14, wherein the amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof administered is sufficient to inhibit osteoclastogenesis or osteoclast activity in the subject.

16 The method of any one of claims 14 and 15, wherein that subject has been diagnosed with periodontitis, gingivitis, osteoporosis, osteoarthritis, or rheumatoid arthritis.

17. The method of any one of claims 14 and 16, wherein the method further comprises the step of

determining whether a subject is at risk for or has a bone related disease by

obtaining or having obtained a biological sample from the subject and performing or having performed a bodily fluid test on the biological sample to determine if the subject has biomarkers for a bone related disease.

18. The method of any one of claims 14 to 17, wherein the method further comprises the step of

determining whether a subject is at risk for or has a bone related disease by

performing or having performed a first skeletal survey on an area of the

subject’s skeleton to determine if the subject has a bone density level associated with a bone related disease.

19. The method of any one of claims 14 to 1 8, wherein the method further comprises the step of

obtaining or having obtained biological samples over a period from the subject, performing or having performed a bodily fluid test on the biological samples to determine whether the level of one or more biochemical resorptive markers are increasing or decreasing over the period, and

if the level of one or more biochemical resorptive markers are increasing or are not decreasing then administering a greater dose of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

20 The method of claim 19, wherein the method further comprises the step of

performing or having performed a second skeletal survey to determine whether the subjects bone density has changed from the first skeletal survey, and if the subject’s bone density has decreased from the first to the second skeletal survey then administering a greater dose a d/or a more frequent dose of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

21. The method of claim 14, wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of:

l-Methyl-2-(6-tiifluoromethoxy-benzothiazol-2-ylamino)-lH-benzoimidazole-5- carboxylic acid ((S)-2-hydroxy-propyl)-amide;

3-Methy]-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3FI-imidazo[4,5- b]pyridine-6-carboxy!ic acid (2-methoxy-ethyl)-amide;

1 -Metbyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)- li -benzimidazole-5- carboxylic acid dimethylcarbamoylmethyl-amide; and

l-Methyl-2-(6-tiifluoromethyl-benzothiazol-2-ylamino)-lH-benzoimidazole-5- carboxylic acid [2-(2-hydroxy-ethoxy)-ethyl]-amide;

or a pharmaceutically acceptable salt thereof.